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Herpesviridae
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Herpesviridae is a large family of DNA viruses that cause infections and certain
diseases in animals, including humans.[1][2][3] The members of this family are also
known as herpesviruses. The family name is derived from the Greek word ἕρπειν
(herpein 'to creep'), referring to spreading cutaneous lesions, usually involving
blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster
(shingles).[4] In 1971, the International Committee on the Taxonomy of Viruses
(ICTV) established Herpesvirus as a genus with 23 viruses among four groups.[5] As
of 2020, 115 species are recognized, all but one of which are in one of the three
subfamilies.[6] Herpesviruses can cause both latent and lytic infections. The
occurrence of latent infections caused by these viruses could be linked to the
genome's abundance in inversions which facilitate viral genome integration.[7]
Herpesviridae
Herpesviridae EM PHIL 2171 lores.jpg
Virus classification e
(unranked):
Virus
Realm:
Duplodnaviria
Kingdom:
Heunggongvirae
Phylum:
Peploviricota
Class:
Herviviricetes
Order:
Herpesvirales
Family:
Herpesviridae
Subfamilies and genera
See text
Nine herpesvirus types are known to primarily infect humans,[8] at least five of
which – herpes simplex viruses 1 and 2 (HSV-1 and HSV-2, also known as HHV-1 and
HHV-2; both of which can cause orolabial herpes and genital herpes), varicella
zoster virus (or HHV-3; the cause of chickenpox and shingles), Epstein–Barr virus
(EBV or HHV-4; implicated in several diseases, including mononucleosis and some
cancers), and human cytomegalovirus (HCMV or HHV-5) – are extremely common among
humans. More than 90% of adults have been infected with at least one of these, and
a latent form of the virus remains in almost all humans who have been infected.[9]
[10][11] Other human herpesviruses are human herpesvirus 6A and 6B (HHV-6A and HHV-
6B), human herpesvirus 7 (HHV-7), and Kaposi's sarcoma-associated herpesvirus
(KSHV, also known as HHV-8).[8]
In total, more than 130 herpesviruses are known,[12] some of them from mammals,
birds, fish, reptiles, amphibians, and molluscs.[8] Among the animal herpesviruses
are pseudorabies virus, the causative agent of Aujeszky's disease in pigs, and
bovine herpesvirus 1, the causative agent of bovine infectious rhinotracheitis and
pustular vulvovaginitis.
TaxonomyEdit
Subfamily Alphaherpesvirinae
Iltovirus
Mardivirus
Scutavirus
Simplexvirus
Varicellovirus
Subfamily Betaherpesvirinae
Cytomegalovirus
Muromegalovirus
Proboscivirus
Quwivirus
Roseolovirus
Subfamily Gammaherpesvirinae
Bossavirus
Lymphocryptovirus
Macavirus
Manticavirus
Patagivirus
Percavirus
Rhadinovirus
Additionally, the species Iguanid herpesvirus 2 is currently unassigned to a genus

and subfamily.[6]
See Herpesvirales#Taxonomy for information on taxonomic history, phylogenetic

research, and the nomenclatural system.
StructureEdit
Schematic drawing of a Herpesviridae virion
All members of the Herpesviridae share a common structure; a relatively large,

monopartite, double-stranded, linear DNA genome encoding 100-200 genes encased
within an icosahedral protein cage (with T=16 symmetry) called the capsid, which is
itself wrapped in a protein layer called the tegument containing both viral
proteins and viral mRNAs and a lipid bilayer membrane called the envelope. This
whole particle is known as a virion. The structural components of a typical HSV
virion are the Lipid bilayer envelope, Tegument, DNA, Glycoprotein spikes and
Nucleocapsid. The four-component Herpes simplex virion encompasses the double-
stranded DNA genome into an icosahedral nucleocapsid. There is tegument around.
Tegument contains filaments, each 7 nm wide. It is an amorphous layer with some
structured regions. Finally, it is covered with a lipoprotein envelope. There are
spikes made of glycoprotein protruding from each virion. These can expand the
diameter of the virus to 225 nm. The diameters of virions without spikes are around
186 nm. There are at least two unglycosylated membrane proteins in the outer
envelope of the virion. There are also 11 glycoproteins. These are gB, gC, gD, gE,
gG, gH, gI, gJ, gK, gL and gM. Tegument contains 26 proteins. They have duties such
as capsid transport to the nucleus and other organelles, activation of early gene
transcription, and mRNA degradation. The icosahedral nucleocapsid is similar to
that of tailed bacteriophage in the order Caudovirales. This capsid has 161
capsomers consisting of 150 hexons and 11 pentons, as well as a portal complex that
allows entry and exit of DNA into the capsid.[13][14]
Life cycleEdit
All herpesviruses are nuclear-replicating—the viral DNA is transcribed to mRNA

within the infected cell's nucleus.[citation needed]
Infection is initiated when a viral particle contacts a cell with specific types of
receptor molecules on the cell surface. Following binding of viral envelope
glycoproteins to cell membrane receptors, the virion is internalized and
dismantled, allowing viral DNA to migrate to the cell nucleus. Within the nucleus,
replication of viral DNA and transcription of viral genes occurs.[citation needed]
During symptomatic infection, infected cells transcribe lytic viral genes. In some
host cells, a small number of viral genes termed latency-associated transcript
(LAT) accumulate, instead. In this fashion, the virus can persist in the cell (and
thus the host) indefinitely. While primary infection is often accompanied by a
self-limited period of clinical illness, long-term latency is symptom-free.
[citation needed]
Chromatin dynamics regulate the transcription competency of entire herpes virus

genomes. When the virus enters a cell, the cellular immune response is to protect
the cell. The cell does so by wrapping the viral DNA around histones and condensing
it into chromatin, causing the virus to become dormant, or latent. If cells are
unsuccessful and the chromatin is loosely bundled, the viral DNA is still
accessible. The viral particles can turn on their genes and replicate using
cellular machinery to reactivate, starting a lytic infection.[15]
Reactivation of latent viruses has been implicated in a number of diseases (e.g.

shingles, pityriasis rosea). Following activation, transcription of viral genes
transitions from LAT to multiple lytic genes; these lead to enhanced replication
and virus production. Often, lytic activation leads to cell death. Clinically,
lytic activation is often accompanied by emergence of nonspecific symptoms, such as
low-grade fever, headache, sore throat, malaise, and rash, as well as clinical
signs such as swollen or tender lymph nodes and immunological findings such as
reduced levels of natural killer cells.[citation needed]
In animal models, local trauma and system stress have been found to induce
reactivation of latent herpesvirus infection. Cellular stressors like transient
interruption of protein synthesis and hypoxia are also sufficient to induce viral
reactivation.[16]
Genus Subfamily Host details Tissue tropism Entry details
Release details Replication site Assembly site Transmission
Iltovirus α Birds: galliform: psittacine None Cell receptor endocytosis
Budding Nucleus Nucleus Oral-fecal, aerosol
Proboscivirus β Elephants None Glycoproteins Budding Nucleus
Nucleus Contact
Cytomegalovirus β Humans; monkeys Epithelial mucosa Glycoproteins
Budding Nucleus Nucleus Urine, saliva
Mardivirus α Chickens; turkeys; quail None Cell receptor endocytosis
Budding Nucleus Nucleus Aerosol
Rhadinovirus γ Humans; mammals B-lymphocytes Glycoproteins
Budding Nucleus Nucleus Sex, saliva
Macavirus γ Mammals B-lymphocytes Glycoproteins Budding
Nucleus Nucleus Sex, saliva
Roseolovirus β Humans T-cells; B-cells; NK-cell; monocytes;
macrophages; epithelial Glycoproteins Budding Nucleus Nucleus
Respiratory contact
Simplexvirus α Humans; mammals Epithelial mucosa Cell receptor
endocytosis Budding Nucleus Nucleus Sex, saliva
Scutavirus α Sea turtles None Cell receptor endocytosis Budding
Nucleus Nucleus Aerosol
Varicellovirus α Mammals Epithelial mucosa Glycoproteins
Budding Nucleus Nucleus Aerosol
Percavirus γ Mammals B-lymphocytes Glycoproteins Budding
Nucleus Nucleus Sex, saliva
Lymphocryptovirus γ Humans; mammals B-lymphocytes Glycoproteins
Budding Nucleus Nucleus Saliva
Muromegalovirus β Rodents Salivary glands Glycoproteins Budding
Nucleus Nucleus Contact
EvolutionEdit
The three mammalian subfamilies – Alpha-, Beta- and Gamma-herpesviridae – arose

approximately 180 to 220 mya.[17] The major sublineages within these subfamilies
were probably generated before the mammalian radiation of 80 to 60 mya. Speciations
within sublineages took place in the last 80 million years probably with a major
component of cospeciation with host lineages.[citation needed]
All the currently known bird and reptile species are alphaherpesviruses. Although
the branching order of the herpes viruses has not yet been resolved, because herpes
viruses and their hosts tend to coevolve this is suggestive that the
alphaherpesviruses may have been the earliest branch.[citation needed]
The time of origin of the genus Iltovirus has been estimated to be 200 mya while
those of the mardivirus and simplex genera have been estimated to be between 150
and 100 mya.[18]
Immune system evasionsEdit
Learn more
This section is missing information about latency mechanisms beyond CMV, e.g. HSV
LAT and ICP-47; whether there is a common mechanism in the family. (November 2021)
Herpesviruses are known for their ability to establish lifelong infections. One way
this is possible is through immune evasion. Herpesviruses have many different ways
of evading the immune system. One such way is by encoding a protein mimicking human
interleukin 10 (hIL-10) and another is by downregulation of the major
histocompatibility complex II (MHC II) in infected cells.
cmvIL-10Edit
Research conducted on cytomegalovirus (CMV) indicates that the viral human IL-10
homolog, cmvIL-10, is important in inhibiting pro-inflammatory cytokine synthesis.
The cmvIL-10 protein has 27% identity with hIL-10 and only one conserved residue
out of the nine amino acids that make up the functional site for cytokine synthesis
inhibition on hIL-10. There is, however, much similarity in the functions of hIL-10
and cmvIL-10. Both have been shown to down regulate IFN-γ, IL-1α, GM-CSF, IL-6 and
TNF-α, which are all pro-inflammatory cytokines. They have also been shown to play
a role in downregulating MHC I and MHC II and up regulating HLA-G (non-classical
MHC I). These two events allow for immune evasion by suppressing the cell-mediated
immune response and natural killer cell response, respectively. The similarities
between hIL-10 and cmvIL-10 may be explained by the fact that hIL-10 and cmvIL-10
both use the same cell surface receptor, the hIL-10 receptor. One difference in the
function of hIL-10 and cmvIL-10 is that hIL-10 causes human peripheral blood
mononuclear cells (PBMC) to both increase and decrease in proliferation whereas
cmvIL-10 only causes a decrease in proliferation of PBMCs. This indicates that
cmvIL-10 may lack the stimulatory effects that hIL-10 has on these cells.[19]
It was found that cmvIL-10 functions through phosphorylation of the Stat3 protein.
It was originally thought that this phosphorylation was a result of the JAK-STAT
pathway. However, despite evidence that JAK does indeed phosphorylate Stat3, its
inhibition has no significant influence on cytokine synthesis inhibition. Another
protein, PI3K, was also found to phosphorylate Stat3. PI3K inhibition, unlike JAK
inhibition, did have a significant impact on cytokine synthesis. The difference
between PI3K and JAK in Stat3 phosphorylation is that PI3K phosphorylates Stat3 on
the S727 residue whereas JAK phosphorylates Stat3 on the Y705 residue. This
difference in phosphorylation positions seems to be the key factor in Stat3
activation leading to inhibition of pro-inflammatory cytokine synthesis. In fact,
when a PI3K inhibitor is added to cells, the cytokine synthesis levels are
significantly restored. The fact that cytokine levels are not completely restored
indicates there is another pathway activated by cmvIL-10 that is inhibiting
cytokine system synthesis. The proposed mechanism is that cmvIL-10 activates PI3K
which in turn activates PKB (Akt). PKB may then activate mTOR, which may target
Stat3 for phosphorylation on the S727 residue.[20]
MHC downregulationEdit
Another one of the many ways in which herpes viruses evade the immune system is by
down regulation of MHC I and MHC II. This is observed in almost every human
herpesvirus. Down regulation of MHC I and MHC II can come about by many different
mechanisms, most causing the MHC to be absent from the cell surface. As discussed
above, one way is by a viral chemokine homolog such as IL-10. Another mechanism to
down regulate MHCs is to encode viral proteins that detain the newly formed MHC in
the endoplasmic reticulum (ER). The MHC cannot reach the cell surface and therefore
cannot activate the T cell response. The MHCs can also be targeted for destruction
in the proteasome or lysosome. The ER protein TAP also plays a role in MHC down
regulation. Viral proteins inhibit TAP preventing the MHC from picking up a viral
antigen peptide. This prevents proper folding of the MHC and therefore the MHC does
not reach the cell surface.[21]
Human herpesvirus typesEdit
Below are the nine (9) distinct viruses in this family known to cause disease in
humans.[22][23][24]
Human herpesvirus (HHV) classification[1][23]
Name Synonym Subfamily Primary Target Cell Syndrome Site of Latency
Means of Spread
HHV-1 Herpes simplex virus-1 (HSV-1) α (Alpha) Mucoepithelial Oral
and/or genital herpes, herpetic gingivostomatitis, pharyngitis, eczema herpeticum,
herpetic whitlow, herpes simplex keratitis, erythema multiforme, encephalitis, as
well as other herpes simplex infections Neuron (sensory ganglia) Close
contact (oral or sexually transmitted infection)
HHV-2 Herpes simplex virus-2 (HSV-2) α Mucoepithelial Oral and/or
genital herpes, herpetic gingivostomatitis, pharyngitis, eczema herpeticum,
herpetic whitlow, herpes simplex keratitis, erythema multiforme, Mollaret's
meningitis, as well as other herpes simplex infections Neuron (sensory ganglia)
Close contact (oral or sexually transmitted infection)
HHV-3 Varicella zoster virus (VZV) α Mucoepithelial Chickenpox and
shingles Neuron (sensory ganglia) Respiratory and close contact (including
sexually transmitted infection)
HHV-4 Epstein–Barr virus (EBV) Lymphocryptovirus γ (Gamma) B cells and
epithelial cells Epstein-Barr virus-associated lymphoproliferative diseases, a
large group of benign, pre-malignant, and malignant diseases including Epstein-Barr
virus-positive reactive lymphoid hyperplasia, severe mosquito bite allergy,
Epstein-Barr virus-positive reactive lymphoid hyperplasia, Infectious
mononucleosis, Burkitt's lymphoma, Epstein–Barr virus-positive Hodgkin lymphoma,
extranodal NK/T cell lymphoma, nasal type, Epstein–Barr virus-associated aggressive
NK cell leukemia, CNS lymphoma in AIDS patients, post-transplant
lymphoproliferative syndrome (PTLD), nasopharyngeal carcinoma, HIV-associated hairy
leukoplakia, multiple sclerosis B cell Close contact, transfusions, tissue
transplant, and congenital
HHV-5 Cytomegalovirus (CMV) β (Beta) Monocytes and epithelial cells
Infectious mononucleosis-like syndrome,[25] retinitis Monocyte, and ?
Saliva, urine, blood, breast milk
HHV-6A and 6B Roseolovirus β T cells and ? Sixth disease (roseola
infantum or exanthem subitum) T cells and ? Respiratory and close
contact?
HHV-7 β T cells and ? drug-induced hypersensitivity syndrome,
encephalopathy, hemiconvulsion-hemiplegia-epilepsy syndrome, hepatitis infection,
postinfectious myeloradiculoneuropathy, pityriasis rosea, and the reactivation of
HHV-4 (EBV), leading to "mononucleosis-like illness" T cells and ? ?
HHV-8 Kaposi's sarcoma-associated herpesvirus
(KSHV), a type of Rhadinovirus γ Lymphocyte and other cells Kaposi's
sarcoma, primary effusion lymphoma, some types of multicentric Castleman's disease
B cell Close contact (sexual), saliva?
Zoonotic herpesvirusesEdit
In addition to the herpesviruses considered endemic in humans, some viruses

associated primarily with animals may infect humans. These are zoonotic infections:
Zoonotic herpesviruses
Species Type Synonym Subfamily Human Pathophysiology
Macaque monkey CeHV-1 Cercopithecine herpesvirus 1, (monkey B virus) α
Very unusual, with only approximately 25 human cases reported.[26] Untreated
infection is often deadly; sixteen of the 25 cases resulted in fatal
encephalomyelitis. At least four cases resulted in survival with severe neurologic
impairment.[26][27] Symptom awareness and early treatment are important for
laboratory workers facing exposure.[28]
Mouse MuHV-4 Murid herpesvirus 68 (MHV-68) γ Zoonotic infection
more common in laboratory workers handling infected mice.[29][30] ELISA tests show
factor-of-four (x4) false positive results, due to antibody cross-reaction with
other herpesviruses.[29]
Animal herpesvirusesEdit
In animal virology, the best known herpesviruses belong to the subfamily

Alphaherpesvirinae. Research on pseudorabies virus (PrV), the causative agent of
Aujeszky's disease in pigs, has pioneered animal disease control with genetically
modified vaccines. PrV is now extensively studied as a model for basic processes
during lytic herpesvirus infection, and for unraveling molecular mechanisms of
herpesvirus neurotropism, whereas bovine herpesvirus 1, the causative agent of
bovine infectious rhinotracheitis and pustular vulvovaginitis, is analyzed to
elucidate molecular mechanisms of latency. The avian infectious laryngotracheitis
virus is phylogenetically distant from these two viruses and serves to underline
similarity and diversity within the Alphaherpesvirinae.[2][3]
Research
See also
References
External links
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Papillomaviridae
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Papillomaviridae is a family of non-enveloped DNA viruses whose members are known
as papillomaviruses.[1] Several hundred species of papillomaviruses, traditionally
referred to as "types",[2] have been identified infecting all carefully inspected
mammals,[2] but also other vertebrates such as birds, snakes, turtles and fish.[3]
[4][5] Infection by most papillomavirus types, depending on the type, is either
asymptomatic (e.g. most Beta-PVs) or causes small benign tumors, known as
papillomas or warts (e.g. human papillomavirus 1, HPV6 or HPV11). Papillomas caused
by some types, however, such as human papillomaviruses 16 and 18, carry a risk of
becoming cancerous.[6]
Papillomaviridae
Papillomavirus.jpg
Electron micrograph of papillomavirus, scale bar 70 nm
(unranked):
Virus
Realm:
Monodnaviria
Kingdom:
Shotokuvirae
Phylum:
Cossaviricota
Class:
Papovaviricetes
Order:
Zurhausenvirales
Family:
Papillomaviridae
Subfamilies and genera
Firstpapillomavirinae
Alphapapillomavirus
Betapapillomavirus
Chipapillomavirus
Deltapapillomavirus
Dyochipapillomavirus
Dyodeltapapillomavirus
Dyoepsilonpapillomavirus
Dyoetapapillomavirus
Dyoiotapapillomavirus
Dyokappapapillomavirus
Dyolambdapapillomavirus
Dyomupapillomavirus
Dyonupapillomavirus
Dyoomegapapillomavirus
Dyoomikronpapillomavirus
Dyophipapillomavirus
Dyopipapillomavirus
Dyopsipapillomavirus
Dyorhopapillomavirus
Dyosigmapapillomavirus
Dyotaupapillomavirus
Dyothetapapillomavirus
Dyoupsilonpapillomavirus
Dyoxipapillomavirus
Dyozetapapillomavirus
Epsilonpapillomavirus
Etapapillomavirus
Gammapapillomavirus
Iotapapillomavirus
Kappapapillomavirus
Lambdapapillomavirus
Mupapillomavirus
Nupapillomavirus
Omegapapillomavirus
Omikronpapillomavirus
Phipapillomavirus
Pipapillomavirus
Psipapillomavirus
Rhopapillomavirus
Sigmapapillomavirus
Taupapillomavirus
Thetapapillomavirus
Treisdeltapapillomavirus
Treisepsilonpapillomavirus
Treisetapapillomavirus
Treisiotapapillomavirus
Treiskappapapillomavirus
Treisthetapapillomavirus
Treiszetapapillomavirus
Upsilonpapillomavirus
Xipapillomavirus
Zetapapillomavirus
Secondpapillomavirinae
Alefpapillomavirus
Papillomaviruses are usually considered as highly host- and tissue-tropic, and are
thought to rarely be transmitted between species.[7] Papillomaviruses replicate
exclusively in the basal layer of the body surface tissues. All known
papillomavirus types infect a particular body surface,[2] typically the skin or
mucosal epithelium of the genitals, anus, mouth, or airways.[8] For example, human
papillomavirus (HPV) type 1 tends to infect the soles of the feet, and HPV type 2
the palms of the hands, where they may cause warts. Additionally, there are
descriptions of the presence of papillomavirus DNA in the blood and in the
peripheral blood mononuclear cells.
Papillomaviruses were first identified in the early 20th century, when it was shown
that skin warts, or papillomas, could be transmitted between individuals by a
filterable infectious agent. In 1935 Francis Peyton Rous, who had previously
demonstrated the existence of a cancer-causing sarcoma virus in chickens, went on
to show that a papillomavirus could cause skin cancer in infected rabbits. This was
the first demonstration that a virus could cause cancer in mammals.
Taxonomy of papillomavirusesEdit
Selected papillomavirus types
There are over 100 species of papillomavirus recognised,[9] though the ICTV
officially recognizes a smaller number, categorized into 53 genera, as of 2019.[10]
[11][12] All papillomaviruses (PVs) have similar genomic organizations, and any
pair of PVs contains at least five homologous genes, although the nucleotide
sequence may diverge by more than 50%. Phylogenetic algorithms that permit the
comparison of homologies led to phylogenetic trees that have a similar topology,
independent of the gene analyzed.[13]
Phylogenetic studies strongly suggest that PVs normally evolve together with their
mammalian and bird host species, but adaptive radiations, occasional zoonotic
events and recombinations may also impact their diversification.[13] Their basic
genomic organization appears maintained for a period exceeding 100 million years,
and these sequence comparisons have laid the foundation for a PV taxonomy, which is
now officially recognized by the International Committee on Taxonomy of Viruses.
All PVs form the family Papillomaviridae, which is distinct from the Polyomaviridae
thus eliminating the term Papovaviridae. Major branches of the phylogenetic tree of
PVs are considered genera, which are identified by Greek letters. Minor branches
are considered species and unite PV types that are genomically distinct without
exhibiting known biological differences. This new taxonomic system does not affect
the traditional identification and characterization of PV "types" and their
independent isolates with minor genomic differences, referred to as "subtypes" and
"variants", all of which are taxa below the level of "species".[14] Additionally,
phylogenetic groupings at higher taxonomic level have been proposed.[15]
This classification may need revision in the light of the existence of papilloma–
polyoma virus recombinants.[16] Additional species have also been described. Sparus
aurata papillomavirus 1 has been isolated from fish.[17]
Human papillomavirusesEdit
Main article: Human papillomavirus infection
Over 170 human papillomavirus types have been completely sequenced.[18] They have
been divided into 5 genera: Alphapapillomavirus, Betapapillomavirus,
Gammapapillomavirus, Mupapillomavirus and Nupapillomavirus. At least 200 additional
viruses have been identified that await sequencing and classification.[citation
needed]
Animal papillomavirusesEdit
Viral papilloma in a dog
Individual papillomavirus types tend to be highly adapted to replication in a

single animal species. In one study, researchers swabbed the forehead skin of a
variety of zoo animals and used PCR to amplify any papillomavirus DNA that might be
present.[19] Although a wide variety of papillomavirus sequences were identified in
the study, the authors found little evidence for inter-species transmission. One
zookeeper was found to be transiently positive for a chimpanzee-specific
papillomavirus sequence. However, the authors note that the chimpanzee-specific
papillomavirus sequence could have been the result of surface contamination of the
zookeeper's skin, as opposed to productive infection.[citation needed]
Cottontail rabbit papillomavirus (CRPV) can cause protuberant warts in its native
host, the North American rabbit genus Sylvilagus. These horn-like warts may be the
original basis for the urban legends of the American antlered rabbit the Jackalope
and European Wolpertinger.[20] European domestic rabbits (genus Oryctolagus) can be
transiently infected with CRPV in a laboratory setting. However, since European
domestic rabbits do not produce infectious progeny virus, they are considered an
incidental or "dead-end" host for CRPV.[21]
Inter-species transmission has also been documented for bovine papillomavirus (BPV)
type 1.[22] In its natural host (cattle), BPV-1 induces large fibrous skin warts.
BPV-1 infection of horses, which are an incidental host for the virus, can lead to
the development of benign tumors known as sarcoids. The agricultural significance
of BPV-1 spurred a successful effort to develop a vaccine against the virus.
[citation needed]
A few reports have identified papillomaviruses in smaller rodents, such as Syrian

hamsters, the African multimammate rat and the Eurasian harvest mouse.[23] However,
there are no papillomaviruses known to be capable of infecting laboratory mice. The
lack of a tractable mouse model for papillomavirus infection has been a major
limitation for laboratory investigation of papillomaviruses.[citation needed]
Four papillomaviruses are known to infect birds: Fringilla coelebs papillomavirus

1, Francolinus leucoscepus papillomavirus 1, Psittacus erithacus papillomavirus 1
and Pygoscelis adeliae papillomavirus 1.[24] All these species have a gene (E9) of
unknown function, suggesting a common origin.
EvolutionEdit
The evolution of papillomaviruses is thought to be slow compared to many other

virus types, but there are no experimental measurements currently available. This
is probably because the papillomavirus genome is composed of genetically stable
double-stranded DNA that is replicated with high fidelity by the host cell's DNA
replication machinery.[citation needed]
It is believed that papillomaviruses generally co-evolve with a particular species

of host animal over many years, although there are strong evidences against the
hypothesis of coevolution.[13][25] In a particularly speedy example, HPV-16 has
evolved slightly as human populations have expanded across the globe and now varies
in different geographic regions in a way that probably reflects the history of
human migration.[26][27] Cutaneotropic HPV types are occasionally exchanged between
family members during the entire lifetime, but other donors should also be
considered in viral transmission.[28]
Other HPV types, such as HPV-13, vary relatively little in different human
populations. In fact, the sequence of HPV-13 closely resembles a papillomavirus of
bonobos (also known as pygmy chimpanzees).[29] It is not clear whether this
similarity is due to recent transmission between species or because HPV-13 has
simply changed very little in the six or so million years since humans and bonobos
diverged.[27]
The most recent common ancestor of this group of viruses has been estimated to have
existed 424 million years ago.[30]
There are five main genera infecting humans (Alpha, Beta, Gamma, Mu and Nu). The
most recent common ancestor of these genera evolved 49.7 million years ago-58.5
million years ago.[31] The most recent ancestor of the gamma genus was estimated to
have evolved between 45.3 million years ago and 67.5 million years ago.[citation
needed]
StructureEdit
Papillomavirus capsid from bovine papillomavirus
Papillomaviruses are non-enveloped, meaning that the outer shell or capsid of the
virus is not covered by a lipid membrane. A single viral protein, known as L1, is
necessary and sufficient for formation of a 55–60 nanometer capsid composed of 72
star-shaped capsomers (see figure). Like most non-enveloped viruses, the capsid is
geometrically regular and presents icosahedral symmetry. Self-assembled virus-like
particles composed of L1 are the basis of a successful group of prophylactic HPV
vaccines designed to elicit virus-neutralizing antibodies that protect against
initial HPV infection. As such, papillomaviridæ are stable in the environment.
[citation needed]
The papillomavirus genome is a double-stranded circular DNA molecule ~8,000 base

pairs in length. It is packaged within the L1 shell along with cellular histone
proteins, which serve to wrap and condense DNA.[citation needed]
The papillomavirus capsid also contains a viral protein known as L2, which is less
abundant. Although not clear how L2 is arranged within the virion, it is known to
perform several important functions, including facilitating the packaging of the
viral genome into nascent virions as well as the infectious entry of the virus into
new host cells. L2 is of interest as a possible target for more broadly protective
HPV vaccines.
The viral capsid consists of 72 capsomeres of which 12 are five-coordinated and 60

are six-coordinated capsomeres, arranged on a T = 7d icosahedral surface lattice.
[32]
Tissue specificityEdit
Papillomaviruses replicate exclusively in keratinocytes. Keratinocytes form the

outermost layers of the skin, as well as some mucosal surfaces, such as the inside
of the cheek or the walls of the vagina. These surface tissues, which are known as
stratified squamous epithelia, are composed of stacked layers of flattened cells.
The cell layers are formed through a process known as cellular differentiation, in
which keratinocytes gradually become specialized, eventually forming a hard,
crosslinked surface that prevents moisture loss and acts as a barrier against
pathogens. Less-differentiated keratinocyte stem cells, replenished on the surface
layer, are thought to be the initial target of productive papillomavirus
infections. Subsequent steps in the viral life cycle are strictly dependent on the
process of keratinocyte differentiation. As a result, papillomaviruses can only
replicate in body surface tissues.[citation needed]
Life cycleEdit
Infectious entryEdit
Papillomaviruses gain access to keratinocyte stem cells through small wounds, known
as microtraumas, in the skin or mucosal surface. Interactions between L1 and
sulfated sugars on the cell surface promote initial attachment of the virus.[33]
[34] The virus is then able to get inside from the cell surface via interaction
with a specific receptor, likely via the alpha-6 beta-4 integrin,[35][36] and
transported to membrane-enclosed vesicles called endosomes.[37][38] The capsid
protein L2 disrupts the membrane of the endosome through a cationic cell-
penetrating peptide, allowing the viral genome to escape and traffic, along with
L2, to the cell nucleus.[39][40][41]
Viral persistenceEdit
After successful infection of a keratinocyte, the virus expresses E1 and E2

proteins, which are for replicating and maintaining the viral DNA as a circular
episome. The viral oncogenes E6 and E7 promote cell growth by inactivating the
tumor suppressor proteins p53 and pRb. Keratinocyte stem cells in the epithelial
basement layer can maintain papillomavirus genomes for decades.[8]
Production of progeny virusEdit
The expression of the viral late genes, L1 and L2, is exclusively restricted to
differentiating keratinocytes in the outermost layers of the skin or mucosal
surface. The increased expression of L1 and L2 is typically correlated with a
dramatic increase in the number of copies of the viral genome. Since the outer
layers of stratified squamous epithelia are subject to relatively limited
surveillance by cells of the immune system, it is thought that this restriction of
viral late gene expression represents a form of immune evasion.[citation needed]
New infectious progeny viruses are assembled in the cell nucleus. Papillomaviruses
have evolved a mechanism for releasing virions into the environment. Other kinds of
non-enveloped animal viruses utilize an active lytic process to kill the host cell,
allowing release of progeny virus particles. Often this lytic process is associated
with inflammation, which might trigger immune attack against the virus.
Papillomaviruses exploit desquamation as a stealthy, non-inflammatory release
mechanism.[citation needed]
Genus Host details Tissue tropism Entry details Release details
Replication site Assembly site Transmission
Dyoxipapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Omikronpapillomavirus Porpoises Epithelial: mucous; epithelial: skin Cell
receptor endocytosis Lysis Nucleus Nucleus Contact
Dyodeltapapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Omegapapillomavirus Vertebrates Epithelial: mucous; epithelial: skin
Cell receptor endocytosis Lysis Nucleus Nucleus Contact
Nupapillomavirus Humans Epithelial: mucous; epithelial: skin Cell
Dyomupapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Dyozetapapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Kappapapillomavirus Rabbits Epithelial: mucous; epithelial: skin Cell
Upsilonpapillomavirus Vertebrates Epithelial: mucous; epithelial: skin
Dyoetapapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Sigmapapillomavirus Vertebrates Epithelial: mucous; epithelial: skin
Lambdapapillomavirus Cats; dogs Epithelial: mucous; epithelial: skin Cell
Taupapillomavirus Vertebrates Epithelial: mucous; epithelial: skin
Betapapillomavirus Humans Epithelial: mucous; epithelial: skin Cell
Xipapillomavirus Bovines Epithelial: mucous; epithelial: skin Cell
Dyoepsilonpapillomavirus Vertebrates None Cell receptor endocytosis
Lysis Nucleus Nucleus Contact
Thetapapillomavirus Birds Epithelial: mucous; epithelial: skin Cell
Etapapillomavirus Birds Epithelial: skin Cell receptor endocytosis
Rhopapillomavirus Vertebrates Epithelial: mucous; epithelial: skin
Dyothetapapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Dyoomikronpapillomavirus Vertebrates None Cell receptor endocytosis
Gammapapillomavirus Humans Epithelial: mucous; epithelial: skin Cell
Alphapapillomavirus Humans; monkeys Epithelial: mucous; epithelial: skin
Cell receptor endocytosis Lysis Nucleus Nucleus Sex; contact
Zetapapillomavirus Horses Epithelial: mucous; epithelial: skin Cell
Deltapapillomavirus Ruminants Epithelial: mucous; epithelial: skin Cell
Dyolambdapapillomavirus Vertebrates None Cell receptor endocytosis
Dyosigmapapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Dyorhopapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Psipapillomavirus Vertebrates Epithelial: mucous; epithelial: skin
Dyokappapapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Pipapillomavirus Hamsters Epithelial: mucous; epithelial: skin Cell
Iotapapillomavirus Rodents Epithelial: mucous; epithelial: skin Cell
Epsilonpapillomavirus Bovines Epithelial: skin Cell receptor endocytosis
Phipapillomavirus Vertebrates Epithelial: mucous; epithelial: skin
Dyonupapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Dyopipapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Dyoiotapapillomavirus Vertebrates None Cell receptor endocytosis Lysis
Mupapillomavirus Humans Epithelial: mucous; epithelial: skin Cell
Association with cancerEdit
Although some papillomavirus types can cause cancer in the epithelial tissues they
inhabit, cancer is not a typical outcome of infection. The development of
papillomavirus-induced cancers typically occurs over the course of many years.
Papillomaviruses have been associated with the development of cervical cancer,
penile cancer[42] and oral cancers.[43] An association with vulval cancer and
urothelial carcinoma with squamous differentiation in patients with neurogenic
bladder has also been noted.[44][45] There are cancer causing papillomavirus genome
that encodes two small proteins called E6 and E7 that mimic cancer causing
oncogenes. The way they work is that they stimulate unnatural growth of cells and
block their natural defenses. Also they act on many signaling proteins that control
proliferation and apoptosis.[46]
Laboratory studyEdit
The fact that the papillomavirus life cycle strictly requires keratinocyte
differentiation has posed a substantial barrier to the study of papillomaviruses in
the laboratory, since it has precluded the use of conventional cell lines to grow
the viruses. Because infectious BPV-1 virions can be extracted from the large warts
the virus induces on cattle, it has been a workhorse model papillomavirus type for
many years. CRPV, rabbit oral papillomavirus (ROPV) and canine oral papillomavirus
(COPV) have also been used extensively for laboratory studies. As soon as
researchers discovered that these viruses cause cancer, they worked together to
find a vaccine to it. Currently, the most effective way to go about it is to mimic
a virus that is composed of L1 protein but lack the DNA. Basically, our immune
system builds defenses against infections, but if these infections do not cause
disease they can be used as a vaccine. PDB entry 6bt3 shows how antibodies surfaces
attack the surface of the virus to disable it.[47]
Some sexually transmitted HPV types have been propagated using a mouse "xenograft"
system, in which HPV-infected human cells are implanted into immunodeficient mice.
More recently, some groups have succeeded in isolating infectious HPV-16 from human
cervical lesions. However, isolation of infectious virions using this technique is
arduous and the yield of infectious virus is very low.[citation needed]
The differentiation of keratinocytes can be mimicked in vitro by exposing cultured

keratinocytes to an air/liquid interface. The adaptation of such "raft culture"
systems to the study of papillomaviruses was a significant breakthrough for in
vitro study of the viral life cycle.[48] However, raft culture systems are
relatively cumbersome and the yield of infectious HPVs can be low.[49]
The development of a yeast-based system that allows stable episomal HPV replication
provides a convenient, rapid and inexpensive means to study several aspects of the
HPV lifecycle (Angeletti 2002). For example, E2-dependent transcription, genome
amplification and efficient encapsidation of full-length HPV DNAs can be easily
recreated in yeast (Angeletti 2005).
Recently, transient high-yield methods for producing HPV pseudoviruses carrying

reporter genes has been developed. Although pseudoviruses are not suitable for
studying certain aspects of the viral life cycle, initial studies suggest that
their structure and initial infectious entry into cells is probably similar in many
ways to authentic papillomaviruses.
Human papillomavirus binds to heparin molecules on the surface of the cells that it
infects. Studies have shown that the crystal of isolated L1 capsomeres has the
heparin chains recognized by lysines lines grooves on the surface of the virus.
Also those with the antibodies show that they can block this recognition.[50]
Genetic organization and gene expressionEdit
Genome organization of Human papillomavirus type 16
[51]
The papillomavirus genome is divided into an early region (E), encoding six open
reading frames (ORF) (E1, E2, E4, E5, E6, and E7) that are expressed immediately
after initial infection of a host cell, and a late region (L) encoding a major
capsid protein L1 and a minor capsid protein L2. All viral ORFs are encoded on one
DNA strand (see figure). This represents a dramatic difference between
papillomaviruses and polyomaviruses, since the latter virus type expresses its
early and late genes by bi-directional transcription of both DNA strands. This
difference was a major factor in establishment of the consensus that
papillomaviruses and polyomaviruses probably never shared a common ancestor,
despite the striking similarities in the structures of their virions.[citation
needed]
After the host cell is infected, HPV16 early promoter is activated and a
polycistronic primary RNA containing all six early ORFs is transcribed. This
polycistronic RNA contains three exons and two introns and undergoes active RNA
splicing to generate multiple isoforms of mRNAs.[51] One of the spliced isoform
RNAs, E6*I, serves as an E7 mRNA to translate E7 oncoprotein.[52] In contrast, an
intron in the E6 ORF that remains intact without splicing is necessary for
translation of E6 oncoprotein.[52] However, viral early transcription subjects to
viral E2 regulation and high E2 levels repress the transcription. HPV genomes
integrate into host genome by disruption of E2 ORF, preventing E2 repression on E6
and E7. Thus, viral genome integration into host DNA genome increases E6 and E7
expression to promote cellular proliferation and the chance of malignancy.[citation
needed]
A major viral late promoter in viral early region becomes active only in
differentiated cells and its activity can be highly enhanced by viral DNA
replication. The late transcript is also a polycistronic RNA which contains two
introns and three exons. Alternative RNA Splicing of this late transcript is
essential for L1 and L2 expression and can be regulated by RNA cis-elements and
host splicing factors.[51][53][54]
Technical discussion of papillomavirus gene functionsEdit
Genes within the papillomavirus genome are usually identified after similarity with
other previously identified genes. However, some spurious open reading frames might
have been mistaken as genes simply after their position in the genome, and might
not be true genes. This applies specially to certain E3, E4, E5 and E8 open reading
frames.[citation needed]
E1Edit
Encodes a protein that binds to the viral origin of replication in the long control
region of the viral genome. E1 uses ATP to exert a helicase activity that forces
apart the DNA strands, thus preparing the viral genome for replication by cellular
DNA replication factors.
E2Edit
The E2 protein serves as a master transcriptional regulator for viral promoters
located primarily in the long control region. The protein has a transactivation
domain linked by a relatively unstructured hinge region to a well-characterized DNA
binding domain. E2 facilitates the binding of E1 to the viral origin of
replication. E2 also utilizes a cellular protein known as Bromodomain-4 (Brd4) to
tether the viral genome to cellular chromosomes.[55] This tethering to the cell's
nuclear matrix ensures faithful distribution of viral genomes to each daughter cell
after cell division. It is thought that E2 serves as a negative regulator of
expression for the oncogenes E6 and E7 in latently HPV-infected basal layer
keratinocytes. Genetic changes, such as integration of the viral DNA into a host
cell chromosome, that inactivate E2 expression tend to increase the expression of
the E6 and E7 oncogenes, resulting in cellular transformation and possibly further
genetic destabilization.
E3Edit
This small putative gene exists only in a few papillomavirus types. The gene is not
known to be expressed as a protein and does not appear to serve any function.
E4Edit
Although E4 proteins are expressed at low levels during the early phase of viral
infection, expression of E4 increases dramatically during the late phase of
infection. In other words, its "E" appellation may be something of a misnomer. In
the case of HPV-1, E4 can account for up to 30% of the total protein at the surface
of a wart.[56] The E4 protein of many papillomavirus types is thought to facilitate
virion release into the environment by disrupting intermediate filaments of the
keratinocyte cytoskeleton. Viral mutants incapable of expressing E4 do not support
high-level replication of the viral DNA, but it is not yet clear how E4 facilitates
DNA replication. E4 has also been shown to participate in arresting cells in the G2
phase of the cell cycle.
E5Edit
The E5 are small, very hydrophobic proteins that destabilise the function of many
membrane proteins in the infected cell.[57] The E5 protein of some animal
papillomavirus types (mainly bovine papillomavirus type 1) functions as an oncogene
primarily by activating the cell growth-promoting signaling of platelet-derived
growth factor receptors. The E5 proteins of human papillomaviruses associated to
cancer, however, seem to activate the signal cascade initiated by epidermal growth
factor upon ligand binding. HPV16 E5 and HPV2 E5 have also been shown to down-
regulate the surface expression of major histocompatibility complex class I
proteins, which may prevent the infected cell from being eliminated by killer T
cells.
E6Edit
Structure of Sap97 PDZ3 bound to the C-terminal peptide of HPV18 E6[58]
E6 is a 151 amino-acid peptide that incorporates a type 1 motif with a consensus

sequence –(T/S)-(X)-(V/I)-COOH.[59][60] It also has two zinc finger motifs.[59]
E6 is of particular interest because it appears to have multiple roles in the cell

and to interact with many other proteins. Its major role, however, is to mediate
the degradation of p53, a major tumor suppressor protein, reducing the cell's
ability to respond to DNA damage.[61][62]
E6 has also been shown to target other cellular proteins, thereby altering several
metabolic pathways. One such target is NFX1-91, which normally represses production
of telomerase, a protein that allows cells to divide an unlimited number of times.
When NFX1-91 is degraded by E6, telomerase levels increase, inactivating a major
mechanism keeping cell growth in check.[63] Additionally, E6 can act as a
transcriptional cofactor—specifically, a transcription activator—when interacting
with the cellular transcription factor, E2F1/DP1.[59]
E6 can also bind to PDZ-domains, short sequences which are often found in signaling
proteins. E6's structural motif allows for interaction with PDZ domains on DLG
(discs large) and hDLG (Drosophila large) tumor suppressor genes.[60][64] Binding
at these locations causes transformation of the DLG protein and disruption of its
suppressor function. E6 proteins also interact with the MAGUK (membrane-associated
guanylate kinase family) proteins. These proteins, including MAGI-1, MAGI-2, and
MAGI-3 are usually structural proteins, and can help with signaling.[60][64] More
significantly, they are believed to be involved with DLG's suppression activity.
When E6 complexes with the PDZ domains on the MAGI proteins, it distorts their
shape and thereby impedes their function. Overall, the E6 protein serves to impede
normal protein activity in such a way as to allow a cell to grow and multiply at
the increased rate characteristic of cancer.
Since the expression of E6 is strictly required for maintenance of a malignant

phenotype in HPV-induced cancers, it is an appealing target of therapeutic HPV
vaccines designed to eradicate established cervical cancer tumors.
E7Edit
In most papillomavirus types, the primary function of the E7 protein is to

inactivate members of the pRb family of tumor suppressor proteins. Together with
E6, E7 serves to prevent cell death (apoptosis) and promote cell cycle progression,
thus priming the cell for replication of the viral DNA. E7 also participates in
immortalization of infected cells by activating cellular telomerase. Like E6, E7 is
the subject of intense research interest and is believed to exert a wide variety of
other effects on infected cells. As with E6, the ongoing expression of E7 is
required for survival of cancer cell lines, such as HeLa, that are derived from
HPV-induced tumors.[65]
E8Edit
Only a few papillomavirus types encode a short protein from the E8 gene. In the
case of BPV-4 (papillomavirus genus Xi), the E8 open reading frame may substitute
for the E6 open reading frame, which is absent in this papillomavirus genus.[66]
These E8 genes are chemically and functionally similar to the E5 genes from some
human papillomaviruses, and are also called E5/E8.
L1Edit
L1 spontaneously self-assembles into pentameric capsomers. Purified capsomers can

go on to form capsids, which are stabilized by disulfide bonds between neighboring
L1 molecules. L1 capsids assembled in vitro are the basis of prophylactic vaccines
against several HPV types. Compared to other papillomavirus genes, the amino acid
sequences of most portions of L1 are well-conserved between types. However, the
surface loops of L1 can differ substantially, even for different members of a
particular papillomavirus species. This probably reflects a mechanism for evasion
of neutralizing antibody responses elicited by previous papillomavirus infections.
[67]
L2Edit
L2 exists in an oxidized state within the papillomavirus virion, with the two
conserved cysteine residues forming an intramolecular disulfide bond.[68] In
addition to cooperating with L1 to package the viral DNA into the virion, L2 has
been shown to interact with a number of cellular proteins during the infectious
entry process. After the initial binding of the virion to the cell, L2 must be
cleaved by the cellular protease furin.[69] The virion is internalized, probably
through a clathrin-mediated process, into an endosome, where acidic conditions are
thought to lead to exposure of membrane-destabilizing portions of L2.[39] The
cellular proteins beta-actin[70] and syntaxin-18[71] may also participate in L2-
mediated entry events. After endosome escape, L2 and the viral genome are imported
into the cell nucleus where they traffic to a sub-nuclear domain known as an ND-10
body that is rich in transcription factors.[40] Small portions of L2 are well-
conserved between different papillomavirus types, and experimental vaccines
targeting these conserved domains may offer protection against a broad range of HPV
types.[72]
See also
References
External links
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Polyomaviridae
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Edit
Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and
birds.[1][2] As of 2020, there are six recognized genera and 117 species, five of
which are unassigned to a genus.[3] 14 species are known to infect humans, while
others, such as Simian Virus 40, have been identified in humans to a lesser extent.
[4][5] Most of these viruses are very common and typically asymptomatic in most
human populations studied.[6][7] BK virus is associated with nephropathy in renal
transplant and non-renal solid organ transplant patients,[8][9] JC virus with
progressive multifocal leukoencephalopathy,[10] and Merkel cell virus with Merkel
cell cancer.[11]
Polyomaviridae
Polyomavirus.jpg
Micrograph showing a polyomavirus infected cell—large (blue) cell below-center-
left. Urine cytology specimen.
(unranked):
Virus
Realm:
Monodnaviria
Kingdom:
Shotokuvirae
Phylum:
Cossaviricota
Class:
Papovaviricetes
Order:
Sepolyvirales
Family:
Polyomaviridae
Genera
Alphapolyomavirus
Betapolyomavirus
Deltapolyomavirus
Epsilonpolyomavirus
Gammapolyomavirus
Zetapolyomavirus
Structure and genomeEdit

A rendering of an icosahedral viral capsid comprising 72 pentamers of murine
polyomavirus VP1, colored such that areas of the surface closer to the interior
center appear blue and areas further away appear red. Rendered from PDB: 1SIE.
Polyomaviruses are non-enveloped double-stranded DNA viruses with circular genomes

of around 5000 base pairs. The genome is packaged in a viral capsid of about 40-50
nanometers in diameter, which is icosahedral in shape (T=7 symmetry).[2][12] The
capsid is composed of 72 pentameric capsomeres of a protein called VP1, which is
capable of self-assembly into a closed icosahedron;[13] each pentamer of VP1 is
associated with one molecule of one of the other two capsid proteins, VP2 or VP3.
[5]
Genome structure of the WU virus, a human polyomavirus. The early region is shown
on the left and contains the TAg (tumor antigen) proteins; the late region is on
the right and contains the capsid proteins.[14]
The genome of a typical polyomavirus codes for between 5 and 9 proteins, divided
into two transcriptional regions called the early and late regions due to the time
during infection in which they are transcribed. Each region is transcribed by the
host cell's RNA polymerase II as a single pre-messenger RNA containing multiple
genes. The early region usually codes for two proteins, the small and large tumor
antigens, produced by alternative splicing. The late region contains the three
capsid structural proteins VP1, VP2, and VP3, produced by alternative translational
start sites. Additional genes and other variations on this theme are present in
some viruses: for example, rodent polyomaviruses have a third protein called middle
tumor antigen in the early region, which is extremely efficient at inducing
cellular transformation; SV40 has an additional capsid protein VP4; some examples
have an additional regulatory protein called agnoprotein expressed from the late
region. The genome also contains a non-coding control or regulatory region
containing the early and late regions' promoters, transcriptional start sites, and
the origin of replication.[2][12][5][15]
Replication and life cycleEdit
Murine polyomavirus VP1 in complex with the GT1a glycan. GT1a is shown in yellow
and the VP1 monomer with a white surface and a blue protein backbone. A complex
network of hydrogen bonds, many water-mediated, is shown at the binding surface by
orange lines, with participating protein residues shown as sticks. Mutations of the
two residues shown in cyan at the bottom of the figure can significantly affect
pathogenicity. From PDB: 5CPW.[16]
The polyomavirus life cycle begins with entry into a host cell. Cellular receptors
for polyomaviruses are sialic acid residues of glycans, commonly gangliosides. The
attachment of polyomaviruses to host cells is mediated by the binding of VP1 to
sialylated glycans on the cell surface.[2][12][15][16] In some particular viruses,
additional cell-surface interactions occur; for example, the JC virus is believed
to require interaction with the 5HT2A receptor and the Merkel cell virus with
heparan sulfate.[15][17] However, in general virus-cell interactions are mediated
by commonly occurring molecules on the cell surface, and therefore are likely not a
major contributor to individual viruses' observed cell-type tropism.[15] After
binding to molecules on the cell surface, the virion is endocytosed and enters the
endoplasmic reticulum - a behavior unique among known non-enveloped viruses[18] -
where the viral capsid structure is likely to be disrupted by action of host cell
disulfide isomerase enzymes.[2][12][19]
The details of transit to the nucleus are not clear and may vary among individual
polyomaviruses. It has been frequently reported that an intact, albeit distorted,
virion particle is released from the endoplasmic reticulum into the cell cytoplasm,
where the genome is released from the capsid, possibly due to the low calcium
concentration in the cytoplasm.[18] Both expression of viral genes and replication
of the viral genome occur in the nucleus using host cell machinery. The early genes
- comprising at minimum the small tumor antigen (ST) and large tumor antigen (LT) -
are expressed first, from a single alternatively spliced messenger RNA strand.
These proteins serve to manipulate the host's cell cycle - dysregulating the
transition from G1 phase to S phase, when the host cell's genome is replicated -
because host cell DNA replication machinery is needed for viral genome replication.
[2][12][15] The precise mechanism of this dysregulation depends on the virus; for
example, SV40 LT can directly bind host cell p53, but murine polyomavirus LT does
not.[20] LT induces DNA replication from the viral genome's non-coding control
region (NCCR), after which expression of the early mRNA is reduced and expression
of the late mRNA, which encodes the viral capsid proteins, begins.[19] As these
interactions begin, the LTs belonging to several polyomaviruses, including Merkel
cell polyomavirus, present oncogenic potential.[21] Several mechanisms have been
described for regulating the transition from early to late gene expression,
including the involvement of the LT protein in repressing the early promoter,[19]
the expression of un-terminated late mRNAs with extensions complementary to early
mRNA,[15] and the expression of regulatory microRNA.[15] Expression of the late
genes results in accumulation of the viral capsid proteins in the host cell
cytoplasm. Capsid components enter the nucleus in order to encapsidate new viral
genomic DNA. New virions may be assembled in viral factories.[2][12] The mechanism
of viral release from the host cell varies among polyomaviruses; some express
proteins that facilitate cell exit, such as the agnoprotein or VP4.[19] In some
cases high levels of encapsidated virus result in cell lysis, releasing the
virions.[15]
Viral proteinsEdit
Tumor antigensEdit
The large tumor antigen plays a key role in regulating the viral life cycle by
binding to the viral origin of DNA replication where it promotes DNA synthesis.
Also as the polyomavirus relies on the host cell machinery to replicate the host
cell needs to be in s-phase for this to begin. Due to this, large T-antigen also
modulates cellular signaling pathways to stimulate progression of the cell cycle by
binding to a number of cellular control proteins.[22] This is achieved by a two
prong attack of inhibiting tumor suppressing genes p53 and members of the
retinoblastoma (pRB) family,[23] and stimulating cell growth pathways by binding
cellular DNA, ATPase-helicase, DNA polymerase α association, and binding of
transcription preinitiation complex factors.[24] This abnormal stimulation of the
cell cycle is a powerful force for oncogenic transformation.[citation needed]
The small tumor antigen protein is also able to activate several cellular pathways
that stimulate cell proliferation. Polyomavirus small T antigens commonly target
protein phosphatase 2A (PP2A),[25] a key multisubunit regulator of multiple
pathways including Akt, the mitogen-activated protein kinase (MAPK) pathway, and
the stress-activated protein kinase (SAPK) pathway.[26][27] Merkel cell
polyomavirus small T antigen encodes a unique domain, called the LT-stabilization
domain (LSD), that binds to and inhibits the FBXW7 E3 ligase regulating both
cellular and viral oncoproteins.[28] Unlike for SV40, the MCV small T antigen
directly transforms rodent cells in vitro.[29]
The middle tumor antigen is used in model organisms developed to study cancer, such
as the MMTV-PyMT system where middle T is coupled to the MMTV promoter. There it
functions as an oncogene, while the tissue where the tumor develops is determined
by the MMTV promoter.[citation needed]
Capsid proteinsEdit
The polyomavirus capsid consists of one major component, major capsid protein VP1,
and one or two minor components, minor capsid proteins VP2 and VP3. VP1 pentamers
form the closed icosahedral viral capsid, and in the interior of the capsid each
pentamer is associated with one molecule of either VP2 or VP3.[5][30] Some
polyomaviruses, such as Merkel cell polyomavirus, do not encode or express VP3.[31]
The capsid proteins are expressed from the late region of the genome.[5]
AgnoproteinEdit
The agnoprotein is a small multifunctional phospho-protein found in the late coding

part of the genome of some polyomaviruses, most notably BK virus, JC virus, and
SV40. It is essential for proliferation in the viruses that express it and is
thought to be involved in regulating the viral life cycle, particularly replication
and viral exit from the host cell, but the exact mechanisms are unclear.[32][33]
TaxonomyEdit
The polyomaviruses are members of group I (dsDNA viruses). The classification of

polyomaviruses has been the subject of several proposed revisions as new members of
the group are discovered. Formerly, polyomaviruses and papillomaviruses, which
share many structural features but have very different genomic organizations, were
classified together in the now-obsolete family Papovaviridae.[34] (The name
Papovaviridae derived from three abbreviations: Pa for Papillomavirus, Po for
Polyomavirus, and Va for "vacuolating.")[35] The polyomaviruses were divided into
three major clades (that is, genetically-related groups): the SV40 clade, the avian
clade, and the murine polyomavirus clade.[36] A subsequent proposed
reclassification by the International Committee on Taxonomy of Viruses (ICTV)
recommended dividing the family of Polyomaviridae into three genera:[37]
Genus Orthopolyomavirus (type species SV40)

Genus Wukipolyomavirus (type species KI polyomavirus)
Genus Avipolyomavirus (type species Avian polyomavirus)
The current ICTV classification system recognises six genera and 117 species, of
which five could not be assigned a genus. This system retains the distinction
between avian and mammalian viruses, grouping the avian subset into the genus
Gammapolyomavirus. The six genera are:[3]
Alphapolyomavirus
Betapolyomavirus
Deltapolyomavirus
Epsilonpolyomavirus
Gammapolyomavirus
Zetapolyomavirus
The following species are unassigned to a genus:[3]
Centropristis striata polyomavirus 1

Rhynchobatus djiddensis polyomavirus 1
Sparus aurata polyomavirus 1
Trematomus bernacchii polyomavirus 1
Trematomus pennellii polyomavirus 1
Description of additional viruses is ongoing. These include the sea otter

polyomavirus 1[38] and Alpaca polyomavirus[39] Another virus is the giant panda
polyomavirus 1.[40] Another virus has been described from sigmodontine rodents.[41]
Another - tree shrew polyomavirus 1 - has been described in the tree shrew.[42]
Human polyomavirusesEdit
Most polyomaviruses do not infect humans. Of the polyomaviruses cataloged as of
2017, a total of 14 were known with human hosts.[4] However, some polyomaviruses
are associated with human disease, particularly in immunocompromised individuals.
MCV is highly divergent from the other human polyomaviruses and is most closely
related to murine polyomavirus. Trichodysplasia spinulosa-associated polyomavirus
(TSV) is distantly related to MCV. Two viruses—HPyV6 and HPyV7—are most closely
related to KI and WU viruses, while HPyV9 is most closely related to the African
green monkey-derived lymphotropic polyomavirus (LPV).[citation needed]
A fourteenth virus has been described.[43] Lyon IARC polyomavirus is related to

raccoon polyomavirus.[citation needed]
List of human polyomavirusesEdit
The following 14 polyomaviruses with human hosts had been identified and had their
genomes sequenced as of 2017:[4]
Species Proposed genus Virus name Abbreviation NCBI RefSeq Year
of discovery Clinical correlate (if any) References
Human polyomavirus 5 Alpha Merkel cell polyomavirus MCPyV
NC_010277 2008 Merkel cell cancer[5] [44][11][45]
Human polyomavirus 8 Alpha Trichodysplasia spinulosa polyomavirus TSPyV
NC_014361 2010 Trichodysplasia spinulosa[5] [46][47]
Human polyomavirus 9 Alpha Human polyomavirus 9 HPyV9 NC_015150
2011 None known [48]
Human polyomavirus 12 Alpha Human polyomavirus 12 HPyV12 NC_020890
2013 None known [49]
Human polyomavirus 13 Alpha New Jersey polyomavirus NJPyV
NC_024118 2014 None known [50]
Human polyomavirus 1 Beta BK polyomavirus BKPyV NC_001538 1971
Polyomavirus-associated nephropathy; haemorrhagic cystitis[5] [51]
Human polyomavirus 2 Beta JC polyomavirus JCPyV NC_001699 1971
Progressive multifocal leukoencephalopathy[5] [52]
Human polyomavirus 3 Beta KI polyomavirus KIPyV NC_009238 2007 None
known [53]
Human polyomavirus 4 Beta WU polyomavirus WUPyV NC_009539 2007 None
known [14]
Human polyomavirus 6 Delta Human polyomavirus 6 HPyV6 NC_014406
2010 HPyV6 associated pruritic and dyskeratotic dermatosis (H6PD)[54]
[31]
Human polyomavirus 7 Delta Human polyomavirus 7 HPyV7 NC_014407
2010 HPyV7-related epithelial hyperplasia[54][55][56] [31]
Human polyomavirus 10 Delta MW polyomavirus MWPyV NC_018102 2012
None known [57][58][59]
Human polyomavirus 11 Delta STL polyomavirus STLPyV NC_020106 2013
None known [60]
Human polyomavirus 14 Alpha Lyon IARC polyomavirus LIPyV NC_034253.1
2017 None known [61][62]
Deltapolyomavirus contains only the four human viruses shown in the above table.
The Alpha and Beta groups contain viruses that infect a variety of mammals. The
Gamma group contains the avian viruses.[4] Clinically significant disease
associations are shown only where causality is expected.[5][63]
Antibodies to the monkey lymphotropic polyomavirus have been detected in humans

suggesting that this virus - or a closely related virus - can infect humans.[64]
Clinical relevanceEdit
All the polyomaviruses are highly common childhood and young adult infections.[65]
Most of these infections appear to cause little or no symptoms. These viruses are
probably lifelong persistent among almost all adults. Diseases caused by human
polyomavirus infections are most common among immunocompromised people; disease
associations include BK virus with nephropathy in renal transplant and non-renal
solid organ transplant patients,[8][9] JC virus with progressive multifocal
leukoencephalopathy,[10] and Merkel cell virus (MCV) with Merkel cell cancer.[11]
SV40Edit
Main article: SV40
SV40 replicates in the kidneys of monkeys without causing disease, but can cause
cancer in rodents under laboratory conditions. In the 1950s and early 1960s, well
over 100 million people may have been exposed to SV40 due to previously undetected
SV40 contamination of polio vaccine, prompting concern about the possibility that
the virus might cause disease in humans.[66][67] Although it has been reported as
present in some human cancers, including brain tumors, bone tumors, mesotheliomas,
and non-Hodgkin's lymphomas,[68] accurate detection is often confounded by high
levels of cross-reactivity for SV40 with widespread human polyomaviruses.[67] Most
virologists dismiss SV40 as a cause for human cancers.[66][69][70]
DiagnosisEdit
The diagnosis of polyomavirus almost always occurs after the primary infection as
it is either asymptomatic or sub-clinical. Antibody assays are commonly used to
detect presence of antibodies against individual viruses.[71] Competition assays
are frequently needed to distinguish among highly similar polyomaviruses.[72]
In cases of progressive multifocal leucoencephalopathy (PML), a cross-reactive

antibody to SV40 T antigen (commonly Pab419) is used to stain tissues directly for
the presence of JC virus T antigen. PCR can be used on a biopsy of the tissue or
cerebrospinal fluid to amplify the polyomavirus DNA. This allows not only the
detection of polyomavirus but also which sub type it is.[73]
There are three main diagnostic techniques used for the diagnosis of the
reactivation of polyomavirus in polyomavirus nephropathy (PVN): urine cytology,
quantification of the viral load in both urine and blood, and a renal biopsy.[71]
The reactivation of polyomavirus in the kidneys and urinary tract causes the
shedding of infected cells, virions, and/or viral proteins in the urine. This
allows urine cytology to examine these cells, which if there is polyomavirus
inclusion of the nucleus, is diagnostic of infection.[74] Also as the urine of an
infected individual will contain virions and/or viral DNA, quantitation of the
viral load can be done through PCR.[75] This is also true for the blood.
Renal biopsy can also be used if the two methods just described are inconclusive or
if the specific viral load for the renal tissue is desired. Similarly to the urine
cytology, the renal cells are examined under light microscopy for polyomavirus
inclusion of the nucleus, as well as cell lysis and viral partials in the extra
cellular fluid. The viral load as before is also measure by PCR.[citation needed]
Tissue staining using a monoclonal antibody against MCV T antigen shows utility in
differentiating Merkel cell carcinoma from other small, round cell tumors.[76]
Blood tests to detect MCV antibodies have been developed and show that infection
with the virus is widespread although Merkel cell carcinoma patients have
exceptionally higher antibody responses than asymptomatically infected persons.[7]
[77][78][79]
Use in tracing human migrationEdit
The JC virus offers a promising genetic marker for human evolution and migration.
[80] It is carried by 70–90 percent of humans and is usually transmitted from
parents to offspring. This method does not appear to be reliable for tracing the
recent African origin of modern humans.[citation needed]
HistoryEdit
Murine polyomavirus was the first polyomavirus discovered, having been reported by
Ludwik Gross in 1953 as an extract of mouse leukemias capable of inducing parotid
gland tumors.[81] The causative agent was identified as a virus by Sarah Stewart
and Bernice Eddy, after whom it was once called "SE polyoma".[82][83][84] The term
"polyoma" refers to the viruses' ability to produce multiple (poly-) tumors (-oma)
under certain conditions. The name has been criticized as a "meatless linguistic
sandwich" ("meatless" because both morphemes in "polyoma" are affixes) giving
little insight into the viruses' biology; in fact, subsequent research has found
that most polyomaviruses rarely cause clinically significant disease in their host
organisms under natural conditions.[85]
Dozens of polyomaviruses have been identified and sequenced as of 2017, infecting

mainly birds and mammals. Two polyomaviruses are known to infect fish, the black
sea bass[86] and gilthead seabream.[87] A total of fourteen polyomaviruses are
known to infect humans.[4]
References
External links
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Adenoviridae
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"ad5", "ad26", "ad35", and "ad48" redirect here. For the years, see AD 5, AD 26, AD
35, and AD 48. For other uses, see AD-5 (disambiguation), AD26 (disambiguation),
and AD 35 (disambiguation).
Adenoviruses (members of the family Adenoviridae) are medium-sized (90–100 nm),

nonenveloped (without an outer lipid bilayer) viruses with an icosahedral
nucleocapsid containing a double-stranded DNA genome.[2] Their name derives from
their initial isolation from human adenoids in 1953.[3]
Adenoviruses
Adenovirus 4.jpg
Transmission electron micrograph of two adenovirus particles
(unranked):
Virus
Realm:
Varidnaviria
Kingdom:
Bamfordvirae
Phylum:
Preplasmiviricota
Class:
Tectiliviricetes
Order:
Rowavirales
Family:
Adenoviridae
Genera
Atadenovirus
Aviadenovirus
Ichtadenovirus
Mastadenovirus
Siadenovirus
Testadenovirus
Adenovirus D26 structural model at atomic resolution[1]
They have a broad range of vertebrate hosts; in humans, more than 50 distinct
adenoviral serotypes have been found to cause a wide range of illnesses, from mild
respiratory infections in young children (known as the common cold) to life-
threatening multi-organ disease in people with a weakened immune system.[2]
VirologyEdit
ClassificationEdit
This family contains the following genera:[4]
Atadenovirus
Aviadenovirus
Ichtadenovirus
Mastadenovirus (including all human adenoviruses)
Siadenovirus
Testadenovirus
DiversityEdit
In humans, currently there are 88 human adenoviruses (HAdVs) in seven species

(Human adenovirus A to G):[5]
A: 12, 18, 31
B: 3, 7, 11, 14, 16, 21, 34, 35, 50, 55
C: 1, 2, 5, 6, 57[6]
D: 8, 9, 10, 13, 15, 17, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33,
36, 37, 38, 39, 42, 43, 44, 45, 46, 47, 48, 49, 51, 53, 54, 56,[7] 58, 59, 60, 62,
63,[8] 64, 65, 67, 69,[9] 70, 71, 72, 73, 74, 75
E: 4
F: 40, 41[10]
G: 52[11]
Different types/serotypes are associated with different conditions:[12]
respiratory disease (mainly species HAdV-B and C)

conjunctivitis (HAdV-B and D)
gastroenteritis (HAdV-F types 40, 41, HAdV-G type 52)
obesity or adipogenesis (HAdV-A type 31, HAdV-C type 5, HAdV-D types 9, 36, 37)
[13]
All these types are called Human mastadenovirus A–G by the ICTV, because all are
members of the genus Mastadenovirus.
StructureEdit
The structure of adenovirus. 1 = penton capsomers, 2 = hexon capsomers, and 3=

viral genome (linear dsDNA)
Adenoviruses are medium-sized (90–100 nm).[2] The virions are composed of one
linear piece of double-stranded DNA inside an icosahedral capsid. 240 hexon
proteins make up the bulk of the capsid, while twelve penton bases cap the
icosahedron's corners. The penton bases are associated with protruding fibers that
aid in attachment to the host cell via the receptor on its surface.[14]
In 2010, the structure of the human adenovirus was solved at the atomic level,
making it the largest high-resolution model ever. The virus is composed of around 1
million amino acid residues and weighs around 150 MDa.[15][16]
GenomeEdit
Main article: Adenovirus genome
Schematic diagram of the linear adenovirus genome, showing Early genes (E) and Late
genes (L).
The adenovirus genome is linear, non-segmented double-stranded (ds) DNA that is

between 26 and 48 Kbp.[2] This allows the virus to theoretically carry 22 to 40
genes. Although this is significantly larger than other viruses in its Baltimore
group, it is still a very simple virus and is heavily reliant on the host cell for
survival and replication. An interesting feature of this viral genome is that it
has a terminal 55 kDa protein associated with each of the 5' ends of the linear
dsDNA. These are used as primers in viral replication and ensure that the ends of
the virus' linear genome are adequately replicated.[citation needed]
ReplicationEdit
Adenoviruses possess a linear dsDNA genome and are able to replicate in the nucleus
of vertebrate cells using the host's replication machinery.[2] Entry of
adenoviruses into the host cell involves two sets of interactions between the virus
and the host cell.[2] Most of the action occurs at the vertices. Entry into the
host cell is initiated by the knob domain of the fiber protein binding to the cell
receptor.[2] The two currently established receptors are: CD46 for the group B
human adenovirus serotypes and the coxsackievirus/adenovirus receptor (CAR) for all
other serotypes.[2] There are some reports suggesting MHC molecules and sialic acid
residues functioning in this capacity as well. This is followed by a secondary
interaction, where a motif in the penton base protein (see capsomere) interacts
with an integrin molecule. It is the co-receptor interaction that stimulates entry
of the adenovirus. This co-receptor molecule is αV integrin. Binding to αv integrin
results in endocytosis of the virus particle via clathrin-coated pits. Attachment
to αV integrin stimulates cell signaling and thus induces actin polymerization,
which facilitates clathrin-mediated endocytosis, and results in virion's entry into
the host cell within an endosome.[17]
Once the virus has successfully gained entry into the host cell, the endosome
acidifies, which alters virus topology by causing capsid components to disband. The
capsid is destabilized and protein VI, which is one of the capsid constituents (see
Adenovirus genome) is released from it.[18] These changes, as well as the toxic
nature of the pentons, destroy the endosome, resulting in the movement of the
virion into the cytoplasm.[2] With the help of cellular microtubules, the virus is
transported to the nuclear pore complex, whereby the adenovirus particle
disassembles. Viral DNA is subsequently released, which can enter the nucleus via
the nuclear pore.[19] After this the DNA associates with histone molecules already
present in the nucleus, which allows it to interact with the host cell
transcription machinery[citation needed]. Then, viral gene expression can occur,
without integrating the viral genome into host cell chromosomes,[20] and new virus
particles can be generated.
The adenovirus life cycle is separated by the DNA replication process into two
phases: an early and a late phase.[2] In both phases, a primary transcript that is
alternatively spliced to generate monocistronic mRNAs compatible with the host's
ribosome is generated, allowing for the products to be translated.[citation needed]
The early genes are responsible for expressing mainly non-structural, regulatory
proteins.[2] The goal of these proteins is threefold: to alter the expression of
host proteins that are necessary for DNA synthesis; to activate other virus genes
(such as the virus-encoded DNA polymerase); and to avoid premature death of the
infected cell by the host-immune defenses (blockage of apoptosis, blockage of
interferon activity, and blockage of MHC class I translocation and expression).
Some adenoviruses under specialized conditions can transform cells using their
early gene products. E1A (binds Retinoblastoma tumor suppressor protein) has been
found to immortalize primary cells in vitro allowing E1B (binds p53 tumor
suppressor) to assist and stably transform the cells. Nevertheless, they are
reliant upon each other to successfully transform the host cell and form tumors.
E1A is mostly intrinsically disordered protein and contains CR3 domain which is
critical for transcriptional activation.[21]
DNA replication separates the early and late phases. Once the early genes have
liberated adequate virus proteins, replication machinery, and replication
substrates, replication of the adenovirus genome can occur. A terminal protein that
is covalently bound to the 5' end of the adenovirus genome acts as a primer for
replication. The viral DNA polymerase then uses a strand displacement mechanism, as
opposed to the conventional Okazaki fragments used in mammalian DNA replication, to
replicate the genome.
The late phase of the adenovirus lifecycle is focused on producing sufficient

quantities of structural protein to pack all the genetic material produced by DNA
replication.[2] Once the viral components have successfully been replicated, the
virus is assembled into its protein shells and released from the cell as a result
of virally induced cell lysis.[2]
Multiplicity reactivationEdit
Adenovirus is capable of multiplicity reactivation (MR)[22] (Yamamoto and Shimojo,

1971). MR is the process by which two, or more, virus genomes containing lethal
damage interact within the infected cell to form a viable virus genome. Such MR was
demonstrated for adenovirus 12 after virions were irradiated with UV light and
allowed to undergo multiple infection of host cells.[22] In a review, numerous
examples of MR in different viruses were described, and it was suggested that MR is
a common form of sexual interaction that provides the survival advantage of
recombinational repair of genome damages.[23]
EpidemiologyEdit
TransmissionEdit
Adenoviruses are unusually stable to chemical or physical agents and adverse pH

conditions, allowing for prolonged survival outside of the body and water.
Adenoviruses are spread primarily via respiratory droplets, however they can also
be spread by fecal routes. Research into the molecular mechanisms underlying
adenoviral transmission provide empirical evidence in support of the hypothesis
that coxsackievirus/adenovirus receptors (CARs) are needed to transport
adenoviruses into certain naive/progenitor cell types.[24]
HumansEdit
Main article: Adenovirus infection
Humans infected with adenoviruses display a wide range of responses, from no

symptoms at all to the severe infections typical of Adenovirus serotype 14.
AnimalsEdit
See also: DA2PPC Vaccine
Bat adenovirus TJM (Bt-AdV-TJM) is a novel species of the Mastadenovirus genus
isolated from Myotis and Scotophilus kuhlii in China.[25] It is most closely
related to the tree shrew and canine AdVs.[26]
Two types of canine adenoviruses are well known, type 1 and 2. Type 1 (CAdV-1)
causes infectious canine hepatitis, a potentially fatal disease involving
vasculitis and hepatitis. Type 1 infection can also cause respiratory and eye
infections. CAdV-1 also affects foxes (Vulpes vulpes and Vulpes lagopus) and may
cause hepatitis and encephalitis. Canine adenovirus 2 (CAdV-2) is one of the
potential causes of kennel cough. Core vaccines for dogs include attenuated live
CAdV-2, which produces immunity to CAdV-1 and CAdV-2. CAdV-1 was initially used in
a vaccine for dogs, but corneal edema was a common complication.[27]
Squirrel adenovirus (SqAdV) is reported to cause enteritis in red squirrels in

Europe, while gray squirrels seem to be resistant. SqAdV is most closely related to
the adenovirus of guinea pigs (GpAdV).
Adenovirus in reptiles is poorly understood, but research is currently in progress.
Adenoviruses are also known to cause respiratory infections in horses, cattle,

pigs, sheep, and goats. Equine adenovirus 1 can also cause fatal disease in
immunocompromised Arabian foals, involving pneumonia and destruction of pancreatic
and salivary gland tissue.[27] Tupaia adenovirus (TAV) (tree shrew adenovirus 1)
has been isolated from tree shrews.
Otarine adenovirus 1 has been isolated from sea lions (Zalophus californianus).[28]
The fowl adenoviruses are associated with many disease conditions in domestic fowl
like inclusion body hepatitis, hydropericardium syndrome,[29] Egg drop syndrome,
Quail bronchitis, Gizzard erosions and many respiratory conditions. They have also
been isolated from wild black kites (Milvus migrans).[30]
Titi monkey adenovirus was isolated from a colony of monkeys.[31]

PreventionEdit
Main article: Adenovirus vaccine
Currently there is a vaccine for adenovirus type 4 and 7 for US military personnel
only. US military personnel are the recipients of this vaccine because they may be
at a higher risk of infection.[citation needed] The vaccine contains a live virus,
which may be shed in stool and lead to transmission. The vaccine is not approved
for use outside of the military, as it has not been tested in studied in the
general population or on people with weakened immune systems.[32]
In the past, US military recruits were vaccinated against two serotypes of

adenovirus, with a corresponding decrease in illnesses caused by those serotypes.
That vaccine is no longer manufactured. The U.S. Army Medical Research and Materiel
Command announced on 31 October 2011 that a new adenovirus vaccine, which replaces
the older version that has been out of production for over a decade, was shipped to
basic training sites on 18 October 2011. More information is available here.[33]
Prevention of adenovirus, as well as other respiratory illnesses, involves frequent

hand washing for more than 20 seconds, avoiding touching the eyes, face, and nose
with unwashed hands, and avoiding close contact with people with symptomatic
adenovirus infection. Those with symptomatic adenovirus infection are additionally
advised to cough or sneeze into the arm or elbow instead of the hand, to avoid
sharing cups and eating utensils, and to refrain from kissing others. Chlorination
of swimming pools can prevent outbreaks of conjunctivitis caused by adenovirus.[32]
DiagnosisEdit
Diagnosis is from symptoms and history. Tests are only necessary in very serious
cases. Tests include blood tests, eyes, nose or throat swabs, stool sample tests,
and chest x-rays.[34] In the laboratory, adenovirus can be identified with antigen
detection, polymerase chain reaction (PCR), virus isolation and serology. Even if
adenovirus is found to be present, it may not be the cause of any symptoms. Some
immunocompromised individuals can shed the virus for weeks and show no symptoms.
[35]
InfectionsEdit
Main article: Adenovirus infection
Most infections with adenovirus result in infections of the upper respiratory

tract. Adenovirus infections often present as conjunctivitis, tonsillitis (which
may look exactly like strep throat and cannot be distinguished from strep except by
throat culture), an ear infection, or croup.[36] Adenoviruses types 40 and 41 can
also cause gastroenteritis.[37] A combination of conjunctivitis and tonsillitis is
particularly common with adenovirus infections.
Some children (especially the youngest) can develop adenovirus bronchiolitis or

pneumonia, both of which can be severe. In babies, adenoviruses can also cause
coughing fits that look almost exactly like whooping cough. Adenoviruses can also
cause viral meningitis or encephalitis. Rarely, adenovirus can cause hemorrhagic
cystitis (inflammation of the urinary bladder—a form of urinary tract infection—
with blood in the urine).
Most people recover from adenovirus infections by themselves, but people with
immunodeficiency sometimes die of adenovirus infections, and—rarely—even previously
healthy people can die of these infections.[38] This may be because sometimes
adenoviral infection can lead to cardiac disorders. For example, in one study, some
cardiac samples of patients with dilated cardiomyopathy were positive for presence
of adenovirus type 8.[39]
Adenoviruses are often transmitted by expectoration (e.g. aerosols), but they can
also be transmitted by contact with an infected person, or by virus particles left
on objects such as towels and faucet handles. Some people with adenovirus
gastroenteritis may shed the virus in their stools for months after getting over
the symptoms. The virus can be passed through water in swimming pools that are not
sufficiently chlorinated.
As with many other illnesses, good handwashing practice is one way to inhibit the
person-to-person transmission of adenoviruses. Heat and bleach will kill
adenoviruses on objects.[citation needed]
TreatmentEdit
There are no proven antiviral drugs to treat adenoviral infections, so treatment is

largely directed at the symptoms (such as acetaminophen for fever). The antiviral
drug cidofovir has helped certain of those patients who had severe cases of
illness; the number helped and to what degree, and the particular complications or
symptoms it helped with, and when and where this happened, were not given in the
source.[40] A doctor may give antibiotic eyedrops for conjunctivitis, while
awaiting results of bacterial cultures, and to help prevent secondary bacterial
infections. Currently, there is no adenovirus vaccine available to the general
public, but a vaccine is available for the United States military for Types 4 and
7.
Use in gene therapy and vaccinationEdit
Gene therapyEdit
Adenoviruses have long been a popular viral vector for gene therapy due to their
ability to affect both replicating and non-replicating cells, accommodate large
transgenes, and code for proteins without integrating into the host cell genome.
[20] More specifically, they are used as a vehicle to administer targeted therapy,
[41] in the form of recombinant DNA or protein. This therapy has been found
especially useful in treating monogenic disease (e.g. cystic fibrosis, X-linked
SCID, alpha1-antitrypsin deficiency) and cancer.[20] In China, oncolytic adenovirus
is an approved cancer treatment.[42] Specific modifications on fiber proteins are
used to target Adenovirus to certain cell types;[43] a major effort is made to
limit hepatotoxicity and prevent multiple organ failure. Adenovirus dodecahedron
can qualify as a potent delivery platform for foreign antigens to human myeloid
dendritic cells (MDC), and that it is efficiently presented by MDC to M1-specific
CD8+ T lymphocytes.[44]
Adenovirus has been used for delivery of CRISPR/Cas9 gene editing systems, but high
immune reactivity to viral infection has posed challenges in use for patients.
VaccinesEdit
Further information: Viral vector vaccine
Modified (recombinant) adenovirus vectors, including replication incompetent types,

can deliver DNA coding for specific antigens.[45]
Adenovirus have been used to produce viral vector COVID-19 vaccines. "In four
candidate COVID-19 vaccines... Ad5... serves as the 'vector' to transport the
surface protein gene of SARS-CoV-2".[46] The goal is to genetically express the
spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
A replication-deficient chimpanzee adenovirus vaccine vector (ChAdOx1) is used by
the Oxford–AstraZeneca COVID-19 vaccine that has been approved for use.[47][48] The
Janssen COVID-19 vaccine uses modified recombinant adenovirus type-26 (Ad26).[49]
Recombinant adenovirus type-5 (Ad5) are being used by Ad5-nCoV,[50] ImmunityBio and
UQ-CSL V451. The Gam-COVID-Vac (aka Sputnik-V) product is innovative because an
Ad26 based vaccine is used on the first day and an Ad5 vaccine is used on day 21.
[49] Another one is ChAd-SARS-CoV-2-S; the vaccine reportedly prevented mice that
were genetically modified to have human ACE2 (hACE2) receptors, presumably
receptors that allow virus-entry into the cells, from being infected with SARS-CoV-
2.[51][52]
Possible issues with using Adenovirus as vaccine vectors include: the human body
develops immunity to the vector itself, making subsequent booster shots difficult
or impossible.[53] In some cases, people have pre-existing immunity to
Adenoviruses, making vector delivery ineffective.[54]
HIV infection concernsEdit
Learn more
This section needs more medical references for verification or relies too heavily
on primary sources. (April 2021)
The use of Ad5 vaccines for COVID-19 worried researchers who had experience with
two failed trials of an Ad5 vaccine, Phambili and STEP, due to the increased risk
for uncircumcised male patients of contracting HIV-1 via unprotected anal sex.[55]
At the time, it was concluded that heightened risk of HIV reception may be observed
for any Ad5-based vector vaccine.[56] In October 2020, these researchers wrote in
The Lancet: "On the basis of these findings, we are concerned that use of an Ad5
vector for immunisation against SARS-CoV-2 could similarly increase the risk of
HIV-1 acquisition among men who receive the vaccine."[57][58] Vaccines using other
technologies would not be affected, but Sputnik V, Convidecia and ImmunityBio's
hAd5 would.[59] Two studies found that Ad5-specific CD4 T cells are more
susceptible to HIV infection than CD4 T cells specific to certain other vectors,
such as Cytomegalovirus[60] and Canarypox.[61]
By comparison, a Science article reported that China had approved CanSino's Ebola
vaccine based on an Ad5 vector. It was tested in Sierra Leone, which had high HIV
prevalence, making it more likely for such problems to be detected. CanSino's CEO
said "we haven't seen anything with the Ebola vaccine" and speculated that HIV
susceptibility might be limited to Ad5 vaccines which produced HIV proteins. In
research reported in The Lancet in May, the company's researchers acknowledged the
possibility, called it "controversial" and said they would watch for it in the
company's COVID-19 vaccine candidate's trials.[46][50] It is not known to what
extent LGBT discrimination in Sierra Leone could have contributed to masking a
possible causal link in the Ebola vaccine trial; while the Step trial enrolled
mainly homosexual and bisexual men, the Phambili trial enrolled mainly heterosexual
men and women and still found an apparent connection.[citation needed]
See also
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Anelloviridae is a family of viruses. They are classified as vertebrate viruses and

have a non-enveloped capsid, which is round with isometric, icosahedral symmetry
and has a triangulation number of 3.
Anelloviridae
(unranked):
Virus
Realm:
incertae sedis
Kingdom:
incertae sedis
Phylum:
incertae sedis
Class:
incertae sedis
Order:
incertae sedis
Family:
Anelloviridae
The name is derived from Italian anello 'ring', referring to the circular genome of
anelloviruses.
GenomeEdit
The genome is not segmented and contains a single molecule of circular, negative-
sense, single-stranded DNA. The complete genome is 3000–4000 nucleotides long.[1]
They also contain a non-coding region with one to two 80–110 nt sequences that
contain high GC content, forming a secondary structure of stems and loops.[2] The
genome has ORFs and a high degree of genetic diversity.[3]
Although the mechanism of replication has not been studied heavily, anelloviridae
appears to use the rolling circle mechanism where first ssDNA is converted to
dsDNA. It requires a host polymerase for replication to occur as the genome itself
does not encode for a viral polymerase and, as a result, anelloviridae must
replicate inside the cell's nucleus.[4]
Anelloviridae also have two main open reading frames, ORF1 and ORF2. They initiate
at two different AUG codons.[5] Additional ORFs can be formed as well. These ORFs
may overlap partially. [2]
ORF1 is thought to encode the putative capsid protein and replication-associated

protein of anelloviruses. The specific role of these replication-associated
proteins are still being studied.[6]
ORF2 is thought to either encode a protein with phosphatase activity (TTMVs) or a

peptide that suppresses the NF- κ {\displaystyle \kappa } \kappa B pathways (TTVs).
[7] It was seen to have a highly conserved motif in the N-terminal part.
ClinicalEdit
Anellovirus species are highly prevalent and genetically diverse. Their virome has
been present in most humans. They enter in the cell early in life and replicate
persistently.[8] This happens in the first month of life. It remains debated
whether or not the first infection is symptomatic or not, however. They are
probably repressed by host immunity, as the anelloviruses increase during host
immunosuppression.[5]
The overall prevalence in the general population is over 90% and has been found in
all continents.[2] They cause chronic human viral infections that have not yet been
associated with disease. There is also no evidence of viral clearance following
infection.[5] At least 200 different species are present in humans and animals.[9]
It has been shown that there are multiple methods of transmission such as saliva
droplets and maternal or sexual routes.[2]
TaxonomyEdit
Most genera has a name pattern of a certain (Greek, Arabic or Hebrew)

letter+torquevirus with the exception of gyrovirus, as Alphatorquevirus (where
torque means necklace) is one of the first genera to represent the family. The
family contains the following genera:[10]
Aleptorquevirus
Alphatorquevirus
Betatorquevirus
Chitorquevirus
Dalettorquevirus
Deltatorquevirus
Epsilontorquevirus
Etatorquevirus
Gammatorquevirus
Gimeltorquevirus
Gyrovirus
Hetorquevirus
Iotatorquevirus
Kappatorquevirus
Lambdatorquevirus
Mutorquevirus
Nutorquevirus
Omegatorquevirus
Omicrontorquevirus
Pitorquevirus
Psitorquevirus
Rhotorquevirus
Sigmatorquevirus
Tautorquevirus
Tettorquevirus
Thetatorquevirus
Upsilontorquevirus
Wawtorquevirus
Xitorquevirus
Zayintorquevirus
Zetatorquevirus
References
External links
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"Parvo", "parvovirus", and "parvo virus" redirect here. For the dog disease, see
canine parvovirus. For the cat disease, see feline parvovirus. For the pig disease,
see porcine parvovirus. For the human disease caused by parvovirus B19, see fifth
disease.
Parvoviruses are a family of animal viruses that constitute the family

Parvoviridae. They have linear, single-stranded DNA (ssDNA) genomes that typically
contain two genes encoding for a replication initiator protein, called NS1, and the
protein the viral capsid is made of. The coding portion of the genome is flanked by
telomeres at each end that form into hairpin loops that are important during
replication. Parvovirus virions are small compared to most viruses, at 23–28
nanometers in diameter, and contain the genome enclosed in an icosahedral capsid
that has a rugged surface.
Parvoviridae
Electron micrograph of canine parvovirus
Electron micrograph of canine parvovirus
(unranked):
Virus
Realm:
Monodnaviria
Kingdom:
Shotokuvirae
Phylum:
Cossaviricota
Class:
Quintoviricetes
Order:
Piccovirales
Family:
Parvoviridae
Genera
See text
Parvoviruses enter a host cell by endocytosis, travelling to the nucleus where they
wait until the cell enters its replication stage. At that point, the genome is
uncoated and the coding portion is replicated. Viral messenger RNA (mRNA) is then
transcribed and translated, resulting in NS1 initiating replication. During
replication, the hairpins repeatedly unfold, are replicated, and refold to change
the direction of replication to progress back and forth along the genome in a
process called rolling hairpin replication that produces a molecule containing
numerous copies of the genome. Progeny ssDNA genomes are excised from this
concatemer and packaged into capsids. Mature virions leave the cell by exocytosis
or lysis.
Parvoviruses are believed to be descended from ssDNA viruses that have circular
genomes that form a loop because these viruses encode a replication initiator
protein that is related to NS1 and have a similar replication mechanism. Another
group of viruses called bidnaviruses appear to be descended from parvoviruses.
Within the family, three subfamilies, 26 genera, and 126 species are recognized.
Parvoviridae is the sole family in the order Piccovirales, which is the sole order
in the class Quintoviricetes. This class is assigned to the phylum Cossaviricota,
which also includes papillomaviruses, polyomaviruses, and bidnaviruses.
A variety of diseases in animals are caused by parvoviruses. Notably, the canine

parvovirus and feline parvovirus cause severe disease in dogs and cats,
respectively. In pigs, the porcine parvovirus is a major cause of infertility.
Human parvoviruses are less severe, the two most notable being parvovirus B19,
which causes a variety of illnesses including fifth disease in children, and human
bocavirus 1, which is a common cause of acute respiratory tract illness, especially
in young children. In medicine, recombinant adeno-associated viruses (AAV) have
become an important vector for delivering genes to the cell nucleus during gene
therapy.
Animal parvoviruses were first discovered in the 1960s, including minute virus of
mice, which is frequently used to study parvovirus replication. Many AAVs were also
discovered during this time period and research on them over time has revealed
their benefit as a form of medicine. The first pathogenic human parvovirus to be
discovered was parvovirus B19 in 1974, which became associated with various
diseases throughout the 1980s. Parvoviruses were first classified as the genus
Parvovirus in 1971 but were elevated to family status in 1975. They take their name
from the Latin word parvum, meaning 'small' or 'tiny', referring to the small size
of the virus's virions.
GenomeEdit
Parvoviruses have linear, single-stranded DNA (ssDNA) genomes that are about 4–6
kilobases (kb) in length. The parvovirus genome typically contains two genes,
termed the NS/rep gene and the VP/cap gene.[1] The NS gene encodes the non-
structural (NS) protein NS1, which is the replication initiator protein, and the VP
gene encodes the viral protein (VP) that the viral capsid is made of. NS1 contains
an HUH superfamily endonuclease domain near its N-terminus, containing both site-
specific binding activity and site-specific nicking activity, and a superfamily 3
(SF3) helicase domain toward the C-terminus. Most parvoviruses contain a
transcriptional activation domain near the C-terminus that upregulates
transcription from viral promoters as well as alternate or overlapping open reading
frames that encode a small number of supporting proteins involved in different
aspects of the viral life cycle.[2]
The coding portion of the genome is flanked at each end by terminal sequences about
116–550 nucleotides (nt) in length that consist of imperfect palindromes folded
into hairpin loop structures. These hairpin loops contain most of the cis-acting
information required for DNA replication and packaging and act as hinges during
replication to change the direction of replication. When the genome is converted to
double-stranded forms, replication origin sites are created involving sequences in
and adjacent to the hairpins.[2][3]
Genomic DNA strands in mature virions may be positive-sense or negative-sense. This

varies from species to species as some have a preference for packaging strands of
one polarity, others package varying proportions, and others package both sense
strands at equal proportions. These preferences reflect the efficiency with which
progeny strands are synthesized, which in turn reflects the efficiency of specific
replication origin sites.[2] The 3′-end (usually pronounced "three prime end") of a
negative sense strand, and the 5′-end (usually pronounced "five prime end") of a
positive sense strand, is called the left end, and the 5′-end of the negative sense
strand, and the 3′-end of a positive sense strand, is called the right end.[2][4]
[5]
StructureEdit
Schematic diagram of a Parvoviridae virion
A diagram of the canine parvovirus's capsid, containing 60 monomers of the capsid
protein.
Parvovirus virions are 23–28 nanometers (nm) in diameter and consist of the genome
enclosed inside a capsid that is icosahedral in shape with a rugged surface. The
capsid is composed of 60 structurally equivalent polypeptide chains derived from
the C-terminal end of a VP protein's sequence, interlocking extensively to form an
icosahedron with 60 asymmetric, superficial triangular units. These units have 3-
fold radial symmetry at two vertices and 5-fold radial symmetry at one, with 2-fold
radial symmetry at the line opposite of the 5-fold vertex and a 2/5 circular fold
wall surrounding the point of the 5-fold vertex. Twenty 3-fold vertices, thirty 2-
fold lines, and twelve 5-fold vertices exist per capsid, the latter corresponding
to the 12 vertices of the icosahedron.[2]
Typical features of the capsid surface include depressions at each 2-fold axis,
elevated protrusions surrounding the 3-fold axes, and raised cylindrical
projections made of five beta-barrels[6] surrounded by canyon-like depressions at
the 5-fold axes. Each of these cylinders potentially contains an opening to connect
the exterior of the capsid to the interior, which mediates entry and exit of the
genome. About 20 nucleotides from the 5′-end of the genome may remain exposed
outside of the capsid carrying a copy of NS1 bound to the 5′-end, which is a result
of how the genome is synthesized and packaged.[2]
Varying sizes of the VP protein are expressed for different parvoviruses, the
smaller ones, VP2–5, being expressed at a higher frequency than the large size,
VP1. The smaller VPs share a common C-terminus with different N-terminus lengths
due to truncation. For VP1, the N-terminus is extended to contain regions important
in the replication cycle, and it is incorporated into the capsid, typically 5–10
per capsid, with the common C-terminus responsible for assembling capsids.[1][2]
Each VP monomer contains a core beta-barrel structure called the jelly roll motif
of eight strands arranged in two adjacent antiparallel beta sheets, labeled CHEF
and BIDG after the individual strands, the latter forming the interior surface of
the capsid. Individual beta strands are connected by loops that have varying
length, sequence, and conformation, and most of these loops extend toward the
exterior surface, giving parvoviruses their unique, rough surface. Related
parvoviruses share their surface topologies and VP protein folds to a greater
degree than their sequence identities, so the structure of the capsid and capsid
protein are useful indicators of phylogeny.[1][2]
Life cycleEdit
Parvoviruses enter cells by endocytosis, using a variety of cellular receptors to

bind to the host cell. In endosomes, many parvoviruses undergo a change in
conformation so that the phospholipase A2 (PLA2) domain on the VP1 N-termini are
exposed so the virion can penetrate lipid bilayer membranes. Intracellular
trafficking of virions varies, but virions ultimately arrive to the nucleus, inside
of which the genome is uncoated from the capsid. Based on studies of minute virus
of mice (MVM), the genome is ejected from the capsid in a 3′-to-5′ direction from
one of the openings in the capsid, leaving the 5′-end of the DNA attached to the
capsid.[2]
Parvoviruses lack the ability to induce cells into their DNA replication stage,
called S-phase, so they must wait in the nucleus until the host cell enters S-phase
on its own. This makes cell populations that divide rapidly, such as fetal cells,
an excellent environment for parvoviruses. Adeno-associated viruses (AAV) are
dependent on helper viruses, which may be an adenovirus or a herpesvirus, since
coinfection alters the cellular environment to allow for replication.[2] In the
absence of coinfection, AAV's genome is integrated into the host cell's genome
until coinfection occurs.[7] Infected cells that enter S-phase are forced to
synthesize viral DNA and cannot leave S-phase. Parvoviruses establish replication
foci in the nucleus that grow progressively larger as infection progresses.[8]
Once a cell enters S-phase and the genome is uncoated, a host DNA polymerase uses
the 3′-end of the 3′ hairpin as a primer to synthesize a complementary DNA strand
for the coding portion of the genome, which is connected to the 5′-end of the 5′
hairpin.[3][7][9] Messenger RNA (mRNA) that encodes NS1 is then transcribed from
the genome by the DNA polymerase, capped and polyadenylated, and translated by host
ribosomes to synthesize NS1.[2][5][10] If proteins are encoded in multiple co-
linear frames, then alternative splicing, suboptimal translation initiation, or
leaky scanning may be used to translate different gene products.[2]
Parvoviruses replicate their genome via rolling hairpin replication, a

unidirectional, strand displacement form of DNA replication that is initiated by
NS1. Replication begins once NS1 binds to and makes a nick in a replication origin
site in the duplex DNA molecule at the end of one hairpin. Nicking releases the 3′-
end of the nicked strand as a free hydroxyl (-OH) to prime DNA synthesis[2] with
NS1 remaining attached to the 5′-end.[7] The nick causes the adjacent hairpin to
unfold into a linear, extended form. At the 3′-OH, a replication fork is
established using NS1's helicase activity, and the extended telomere is replicated
by the DNA polymerase.[10][11] The two telomere strands then refold back in on
themselves to their original configurations, which repositions the replication fork
to switch templates to the other strand and move in the opposite direction toward
the other end of the genome.[12][13]
Parvoviruses vary in whether the termini are similar or the same, called
homotelomeric parvoviruses, or different, called heterotelomeric parvoviruses. In
general, homotelomeric parvoviruses, such as AAV and B19, replicate both ends of
their genome through the aforementioned process, called terminal resolution, and
their hairpin sequences are contained within larger (inverted) terminal repeats.
Heterotelomeric viruses, such as minute virus of mice (MVM), replicate one end by
terminal resolution and the other end via an asymmetric process called junction
resolution[2][14] so that the correct orientation of the telomere can be copied.
[15]
During asymmetric junction resolution, the duplex extended-form telomeres refold in

on themselves into a cruciform shape. A replication origin site on the lower strand
of the right arm of the cruciform is nicked by NS1, leading to the lower arm of the
cruciform unfolding into its linear extended form. A replication fork established
at the nick site moves down the extended lower arm to copy the lower arm's
sequence. The two strands of the lower arm then refold to reposition the
replication fork to go back toward the other end, displacing the upper strand in
the process.[16]
The back and forth, end-to-end pattern of rolling hairpin replication produces a
concatemer containing multiple copies of the genome.[2][3] NS1 periodically makes
nicks in this molecule and, through a combination of terminal resolution and
junction resolution, individual strands of the genome are excised from the
concatemer.[9][13] Excised genomes may either be recycled for further rounds of
replication or packaged into progeny capsids.[7] Translation of mRNA containing VP
proteins leads to the accumulation of capsid proteins in the nucleus that assemble
into these empty capsids.[8]
Genomes are encapsidated at one of the capsid's vertices through a portal,[2]

potentially the one opposite the portal used to expel the genome.[5] Once complete
virions have been constructed, they may be exported from the nucleus to the
exterior of the cell before disintegration of the nucleus. Disruption of the host
cell environment may also occur later on in the infection. This results in cell
lysis via necrosis or apoptosis, which releases virions to the outside of the cell.
[2][8]
EvolutionEdit
Parvoviruses are believed to be descended from ssDNA viruses that have a circular
genome that forms a loop and which replicate via rolling circle replication, which
is similar to rolling hairpin replication. These circular ssDNA viruses encode a
replication initiator protein that is related to and possesses many of the same
characteristics as the replication initiator protein of parvoviruses, such as the
HUH endonuclease domain and the SF3 helicase domain.[17] In contrast to these other
replication initiator proteins, NS1 shows only vestigial traces of being able to
perform ligation, which is a key part of rolling circle replication.[8] The
Bidnaviridae family, which are also linear ssDNA viruses, appear to be descended
from a parvovirus that had its genome integrated into the genome of a polinton, a
type of DNA transposon related to viruses in the realm Varidnaviria.[17]
Based on phylogenetic analysis of the SF3 helicase, parvoviruses split into two
branches early in their evolutionary history, one of which contains viruses
assigned to the subfamily Hamaparvovirinae. The other branch split into two
sublineages that constitute the other two subfamilies, Densovirinae and
Parvovirinae.[18] Parvoviruses in the Hamaparvovirinae lineage are likely all
heterotelomeric, Densovirinae are exclusively homotelomeric, and Parvovirinae
varies.[2] Telomere sequences have significant complexity and diversity, suggesting
that many species have co-opted them to perform additional functions.[7][10]
Parvoviruses are also considered to have high rates of genetic mutations and
recombinations.[2][9]
ClassificationEdit
Parvoviruses constitute the family Parvoviridae. The family is the sole family in
the order Piccovirales, which is the sole order in the class Quintoviricetes. The
class Quintoviricetes belongs to the phylum Cossaviricota, which also includes
papillomaviruses, polyomaviruses, and bidnaviruses. Cossaviricota is included in
the kingdom Shotokuvirae, which is assigned to the realm Monodnaviria. Parvoviridae
belongs to Group II: ssDNA viruses in the Baltimore classification system, which
groups viruses together based on their manner of mRNA synthesis. Within
Parvoviridae, three subfamilies, 26 genera, and 126 species are recognized as of
2020 (-virinae denotes subfamily and -virus denotes genus):[18][19]
Densovirinae (11 genera, 21 species)
Aquambidensovirus (3 species)
Blattambidensovirus (1 species)
Diciambidensovirus (1 species)
Hemiambidensovirus (2 species)
Iteradensovirus (5 species)
Miniambidensovirus (1 species)
Muscodensovirus (1 species)
Pefuambidensovirus (1 species)
Protoambidensovirus (2 species)
Scindoambidensovirus (3 species)
Tetuambidensovirus (1 species)
Hamaparvovirinae (5 genera, 21 species)
Brevihamaparvovirus (2 species)
Chaphamaparvovirus (16 species)
Hepanhamaparvovirus (1 species)
Ichthamaparvovirus (1 species)
Penstylhamaparvovirus (1 species)
Parvovirinae (10 genera, 84 species)
Amdoparvovirus (5 species)
Artiparvovirus (1 species)
Aveparvovirus (3 species)
Bocaparvovirus (28 species)
Copiparvovirus (7 species)
Dependoparvovirus (11 species)
Erythroparvovirus (7 species)
Loriparvovirus (1 species)
Protoparvovirus (15 species)
Tetraparvovirus (6 species)
Parvoviruses are assigned to the same species if they share at least 85% of their
protein sequence identities. Species are grouped together in a genus based on
phylogeny of the NS1 and SF3 helicase domains, as well as similarity of NS1
sequence identity and coverage. If these criteria aren't satisfied, then genera can
still be established provided that common ancestry is supported. The three
subfamilies are distinguished based on phylogeny of the SF3 helicase domain, which
corresponds to host range: viruses in Densovirinae infect invertebrates, viruses in
Hamaparvovirinae infect invertebrates and vertebrates, and viruses in Parvovirinae
infect vertebrates.[18]
DiseaseEdit
Child with Fifth disease
In humans, the most prominent parvoviruses that cause disease are parvovirus B19
and human bocavirus 1. B19 infection is often asymptomatic but can manifest in a
variety of ways, including Fifth disease with its characteristic rash in children,
persistent anemia in immunocompromised persons and in people who have underlying
hemoglobinopathies,[20] transient aplastic crises, hydrops fetalis in pregnant
women, and arthropathy. Human bocavirus 1 is a common cause of acute respiratory
tract infection, especially in young children, wheezing being a common symptom.
Other parvoviruses associated with different diseases in humans include human
parvovirus 4 and human bufavirus, though the manner by which these viruses cause
disease is unclear.[6]
Carnivore-infecting viruses in the genus Protoparvovirus, in contrast to human

parvoviruses, are more life-threatening.[2] Canine parvovirus causes severe illness
in dogs, the most common symptom being hemorrhagic enteritis, with up to a 70%
mortality rate in pups but usually less than 1% in adults.[21] Feline parvovirus, a
closely related virus,[22] likewise causes severe illness in cats along with
panleukopenia.[23][24] In pigs, porcine parvovirus is a major cause of infertility
as infection frequently leads to death of the fetus.[25]
Use in medicineEdit
Adeno-associated viruses have become an important vector for gene therapy aimed at
treating genetic diseases, such as those caused by a single mutation. The
recombinant AAV (rAAV) contains a viral capsid but lacks a complete viral genome.
Instead, the typical nucleic acid packaged into the capsid contains a promoter
region, the gene of interest, and a terminator region, all contained within two
inverted terminal repeats derived from the viral genome. rAAV essentially acts as a
container that can traverse the cell membrane and deliver its nucleic acid cargo to
the nucleus.[26][27]
HistoryEdit
Parvoviruses were discovered relatively late in comparison to other prominent virus

families, potentially due to their small size. In the late 1950s[28] and 1960s,[29]
a variety of animal parvoviruses were discovered, including minute virus of mice,
[30] which has since been used extensively to study rolling hairpin replication.
[31] Many AAVs were also discovered during this time period[32] and research on
them led to their first usage in gene therapy in the 1980s. Over time, improvements
in aspects such as vector design led to certain AAV gene therapy products reaching
clinical efficacy in 2008 and being approved in the following years.[27]
In 1974, the first pathogenic human parvovirus was discovered by Yvonne Cossart, et
al. When testing for the hepatitis B virus's surface antigen, one serum sample gave
anomalous results and with electron microscopy was shown to contain a virus
resembling animal parvoviruses. This virus was named B19 after the coding of the
serum sample, number 19 in panel B.[20][33] B19 was later recognized as a species
by the International Committee on Taxonomy of Viruses (ICTV) in 1985, and
throughout the 1980s it increasingly became associated with various diseases.[33]
In the ICTV's first report in 1971, parvoviruses were grouped together in the genus
Parvovirus.[30][32] They were elevated to the rank of family in 1975 and remained
unassigned to higher taxa until 2019, when they were assigned to higher taxa up to
the highest rank, realm.[34] The family was reorganized in 2019, departing from the
"traditional" invertebrate-vertebrate distinction between Densovirinae and
Parvovirinae and instead distinguishing the subfamilies based on helicase
phylogeny, leading to the establishment of a new subfamily, Hamaparvovirinae.[18]
EtymologyEdit
Parvoviruses take their name from Latin parvus or parvum, meaning small or tiny,
referring to the small size of parvovirus virions compared to most other viruses.
[2][20] In the family name Parvoviridae, -viridae is the suffix used for virus
families.[35] The order Piccovirales takes the first part of its name from the
Italian word piccolo, meaning small, and the second part is the suffix used for
virus orders. The class Quintoviricetes takes the first part of its name from the
Galician word quinto, meaning fifth, referring to fifth disease (erythema
infectiosum) caused by parvovirus B19, and viricetes, the suffix used for virus
classes.[17]
References
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Circovirus is a genus of viruses, in the family Circoviridae. Birds (such as
pigeons[1] and ducks[2]) and pigs[3] serve as natural hosts, though dogs have been
shown to be infected as well.[4] It is a single stranded DNA virus (ssDNA). There
are 49 species in this genus. Some members of this genus cause disease: PCV-1 is
non pathogenic, while PCV-2 causes postweaning multisystemic wasting syndrome
(PMWS).[5][6]
Circovirus
Circovirus virion.jpg
(unranked):
Virus
Realm:
Monodnaviria
Kingdom:
Shotokuvirae
Phylum:
Cressdnaviricota
Class:
Arfiviricetes
Order:
Cirlivirales
Family:
Circoviridae
Genus:
Circovirus
TaxonomyEdit
The following species are recognized:
Barbel circovirus
Bat associated circovirus 1
Beak and feather disease virus
Bear circovirus
Canary circovirus
Canine circovirus
Chimpanzee associated circovirus 1
Civet circovirus
Duck circovirus
Elk circovirus
European catfish circovirus
Finch circovirus
Goose circovirus
Gull circovirus
Human associated circovirus 1
Mink circovirus
Mosquito associated circovirus 1
Penguin circovirus
Pigeon circovirus
Porcine circovirus 1
Raven circovirus
Rodent associated circovirus 1
Starling circovirus
Swan circovirus
Tick associated circovirus 1
Tick associated circovirus 2
Whale circovirus
Zebra finch circovirus
StructureEdit
Viruses in Circovirus are non-enveloped, with icosahedral and round geometries, and
T=1 symmetry. The diameter is around 17 nm. Genomes are circular and non-segmented.
[5]
The virions of Circoviruses are surprisingly small, with diameters ranging from 17
up to 22 nm.[7]
Genus Structure Symmetry Capsid Genomic arrangement Genomic
segmentation
Circovirus Icosahedral T=1 Non-enveloped Circular Monopartite
Life cycleEdit
Viral replication is nuclear. Entry into the host cell is achieved by penetration.
Replication follows the ssDNA rolling circle model. DNA templated transcription,
with some alternative splicing mechanism is the method of transcription. The virus
exits the host cell by nuclear egress, and nuclear pore export. Birds and pigs
serve as the natural host. Transmission routes are fecal-oral and parental.[5]
Genus Host details Tissue tropism Entry details Release details
Replication site Assembly site Transmission
Circovirus Birds; pigs None Cell receptor endocytosis Budding
Nucleus Nucleus Horizontal; oral-fecal
References
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Additionally, the species Iguanid herpesvirus 2 is currently unassigned to a genus

See Herpesvirales#Taxonomy for information on taxonomic history, phylogenetic

All members of the Herpesviridae share a common structure; a relatively large,

All herpesviruses are nuclear-replicating—the viral DNA is transcribed to mRNA

Chromatin dynamics regulate the transcription competency of entire herpes virus

Reactivation of latent viruses has been implicated in a number of diseases (e.g.

The three mammalian subfamilies – Alpha-, Beta- and Gamma-herpesviridae – arose

In addition to the herpesviruses considered endemic in humans, some viruses

In animal virology, the best known herpesviruses belong to the subfamily

Content is available under CC BY-SA 3.0 unless otherwise noted.

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Individual papillomavirus types tend to be highly adapted to replication in a

A few reports have identified papillomaviruses in smaller rodents, such as Syrian

Four papillomaviruses are known to infect birds: Fringilla coelebs papillomavirus

The evolution of papillomaviruses is thought to be slow compared to many other

It is believed that papillomaviruses generally co-evolve with a particular species

The papillomavirus genome is a double-stranded circular DNA molecule ~8,000 base

The viral capsid consists of 72 capsomeres of which 12 are five-coordinated and 60

Papillomaviruses replicate exclusively in keratinocytes. Keratinocytes form the

After successful infection of a keratinocyte, the virus expresses E1 and E2

The differentiation of keratinocytes can be mimicked in vitro by exposing cultured

Recently, transient high-yield methods for producing HPV pseudoviruses carrying

Structure of Sap97 PDZ3 bound to the C-terminal peptide of HPV18 E6[58]

E6 is a 151 amino-acid peptide that incorporates a type 1 motif with a consensus

E6 is of particular interest because it appears to have multiple roles in the cell

Since the expression of E6 is strictly required for maintenance of a malignant

In most papillomavirus types, the primary function of the E7 protein is to

L1 spontaneously self-assembles into pentameric capsomers. Purified capsomers can

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Structure and genomeEdit

Polyomaviruses are non-enveloped double-stranded DNA viruses with circular genomes

The agnoprotein is a small multifunctional phospho-protein found in the late coding

The polyomaviruses are members of group I (dsDNA viruses). The classification of

Genus Orthopolyomavirus (type species SV40)

The following species are unassigned to a genus:[3]

Centropristis striata polyomavirus 1

Description of additional viruses is ongoing. These include the sea otter

A fourteenth virus has been described.[43] Lyon IARC polyomavirus is related to

Antibodies to the monkey lymphotropic polyomavirus have been detected in humans

In cases of progressive multifocal leucoencephalopathy (PML), a cross-reactive

Dozens of polyomaviruses have been identified and sequenced as of 2017, infecting

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Adenoviruses (members of the family Adenoviridae) are medium-sized (90–100 nm),

Adenovirus D26 structural model at atomic resolution[1]

This family contains the following genera:[4]

In humans, currently there are 88 human adenoviruses (HAdVs) in seven species

Different types/serotypes are associated with different conditions:[12]

respiratory disease (mainly species HAdV-B and C)

The structure of adenovirus. 1 = penton capsomers, 2 = hexon capsomers, and 3=

The adenovirus genome is linear, non-segmented double-stranded (ds) DNA that is

The late phase of the adenovirus lifecycle is focused on producing sufficient

Adenovirus is capable of multiplicity reactivation (MR)[22] (Yamamoto and Shimojo,

Adenoviruses are unusually stable to chemical or physical agents and adverse pH

Humans infected with adenoviruses display a wide range of responses, from no

Squirrel adenovirus (SqAdV) is reported to cause enteritis in red squirrels in

Adenovirus in reptiles is poorly understood, but research is currently in progress.