Research Trends in Virology (Vol 2)

Chapter - 12

HIV/AIDS: Overview and Clinical implications

Mattychris Eregbulem Enyichukwu1*; Esan Emmanuel Ehima2; Eze Jennifer Chinemerem3; Sadjere Onome Cyril4;
Chukwuemeka Chinonso Esther5; Rinji Joseph Kamji6; Kehinde Joan Abayomi7; Nnaji Odaiaku Judith 3; Chikelu
Kizito Umeh3; Chinecherem Anselem Ezeibekwe3; Janefrances Ayogu3; Ihechukwu Christian Uzoukwu3;
Joshua Oluwatobi Owolabi8

1
Department of Medical Laboratory Science, University of Jos, Plateau State, Nigeria.
2
Department of Medical Laboratory Science, University of Benin, Benin City, Edo State, Nigeria
3
Department of Medical Laboratory Science, University of Nigeria Enugu Campus, Enugu State Nigeria
4
Department of Medical Laboratory Science, Niger Delta University, Yenagoa, Bayelsa State, Nigeria.
5
General Medicine, Kursk State Medical University, Kursk, Russia.
6
Department of Medical Laboratory Science, University of Jos, Jos, Plateau State, Nigeria.
7
Department of Medical Laboratory Science, Usmanu Danfodiyo University, Sokoto State, Nigeria.
8
Department of Medical Laboratory Science, University of Lagos, Lagos State, Nigeria.

DOI: https://doi.org/10.23005/ed.book.1211

ABSTRACT
The Human Immunodeficiency Virus (HIV) pandemic is without a doubt the most significant public health disaster
of our day. It is a complex mashup of various epidemics that have spread inside and between different nations and
areas of the world. Our knowledge of the virus's replication, manipulation, and concealment in an infected individual
has grown as a result of research. Though preventative measures have increased and our knowledge of etiology and
transmission dynamics has deepened, a protective vaccination or treatment are still unattainable. In some contexts,
antiretroviral therapy has changed Acquired Immunodeficiency Syndrome (AIDS) from a terminal illness to a chronic,
treatable condition. In those regions of the world that continue to suffer a disproportionate burden of new HIV
infections and are most impacted by rising morbidity and mortality, this transition has yet to be realized. An update
on HIV-related epidemiology, etiology, treatment, and preventative initiatives is given in this chapter.

Key words: Human Immunodeficiency Virus; Acquired Immunodeficiency Syndrome; Morbidity; Mortality;

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INTRODUCTION
HIV is a lentivirus of a member of the retrovirus family. The infection of this virus is asymptomatic and produces no
physical abnormal sign but its progression and development causes AIDS. AIDS (Acquired Immunodeficency
Syndrome) being the final stage of HIV infection during which time infection and cancer frequently arise.1

Details of the origin of HIV remain unclear; however, a lentivirus that is genetically similar to HIV has been found in
'chimpanzees' in Western equatorial Africa. This virus known as 'Simian Immunodeficiency Virus' (SIV) does not
really cause disease in chimpanzees.

AIDS, however is a ‘zoonosis,’ an-infection that is shared by humans and lower vertebrate animals. The practice of
hunting, butchering and eating the meat of chimpanzees may have allowed transmission of the virus to humans
probably in the late 19th Century or early 20th Century.2,3

There are 3 common theories how this ‘zoonosis’ took place and how SIV became HIV in humans: The 'Hunters'
theory, The Oral Polio Vaccine (OPV) theory, and The Contaminated needle theory.4,5 Four of the earliest known
instances of HIV infection are as follows: A plasma sample taken in 1959 from an adult male living in what is now
known as Democratic Republic of Congo, Lymph node sample taken in I960 from an adult female also from the
Democratic Republic of Congo.

HIV found in tissue sample from an American" teenager who died in St. Louis in 1969. HIV found in tissue sample
from a Norwagen sailor who died about 1976. 1998 analysis of the plasma sample from 1959 suggested that HIV-1
was introduced into humans about the 1940's or the early 1950’s.6 HIV tends to have its origin from Simian
Immunodefeciency Virus (SIV), a lentivirus that affects monkeys. It is now accepted that HIV is a descendant of SIV
because certain strains of SIV bear a very close resemblance to HIV-1 and HIV-2 being major types of HIV. Two
types of SIVs were identified as:
SIVcpz from chimpanzees which strain corresponds with HIV-1, SIVm from Sooty Mangabey (also known
as the white collared monkey) which strain corresponds to HIV-2 being indigenous- to West African.7-9
In June 1981, the Centre for Disease Control (CDC), reported an unexplained cluster of immunodeficient
homosexual men residing in Los Angelis signaling recognition of an epidemic. As events unfolded, the cause of this
epidemic, a Human Retrovirus-Human Immunodeficiency Virus (HIV) was first isolated in 1983 and was reported by
Luc Montagnier of Pasteur Institute in Paris, France.10

The biology of HIV/retroviruses

The genome of retroviruses consists of RNA (Ribonucleic Acid) and DNA (Deoxyribonucleic acid). HIV-1
and HIV-2, the agents that cause AIDS are retroviruses being member of the Lentivirus family. The retroviruses can
be divided into endogenous and exogenous retroviruses, the former being normal constituent of cells 10.

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 Genetic studies have led to a general classification system for HIV which is based on the degree of similarity
in viral gene sequence. Two major classes of HIV exist: HIV-1 and HIV-2.
It has been known for some years that different laboratory strains of HIV show considerable diversities of
nucleotide sequence which may result in antigenic variation providing a means where by the virus can escape humoral
and cellular immune control.
HIV mutates extensively and attempts have been made to characterize and sequence HIV isolates. By and
large, 3 genetically and immunogenetically distinct viruses are recognized.10 These are HIV type 1, HIV type-2 and
HIVtype-1 group O.
HIV type 1 and HIV type 2 are different mainly, in that, HIV type 2 possess a gene called VPU which is
absent in HIV-1. This gene accounts for the difference in incubation period between these two viruses.11
HIV group O is characterized by the difference between the nucleotide sequence of the C2V3 region and that
of other groups.12 The virus also differs from others by its weak reactivity with the commonly used ELISA (Enzyme
Linked Immunosorbent Assay) testing kit.12

The Morphology of HIV

Outside of a human cell, HIV exists as rough spherical particle (sometimes called virions). The surface of
each particle is studded with lots of little spikes or knobs. In size, HIV is estimated to be about 100 - 150 billionth of
a metre in diameter. It is about one seventieth of the diameter of a human CD4 white blood cell. However, they can
be seen clearly using an electron microscope.13 HIV particle surround themselves with a coat of fatty material known
as the viral envelope (or membrane) projecting from this are around 72 little spikes or knobs which are formed from
the protein gp120 and gp41. Just below the viral envelope is a layer called the MATRIX which is made from the
protein p17.The viral core (or capsid - bullet shaped) is made from p24. Inside the core are 3 enzymes required for
HIV replication, Known as: Reverse transcriptase, Intergrase, Protease.

Figure 1: Schematic diagram of a retrovirus showing the envelope

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 Figure 2: Schematic diagram of retrovirus showing the inner proteins

Also held within the core is the HIV genetic material consisting of 2 identical strands of RNA. Almost all organisms
including most viruses show their genetic material on long strand of DNA but retroviruses are exceptional hence, their
genes are composed of RNA (Ribonucleic Acid).13
HIV has just nine (9) genes (compared to more than 500genes in a bacterium and about 20,000 - 25,000 in a
human). Three (3) genes that exist in HIV are: gag, pol and Env
carry information needed to make structural protein for new virus particles. And other six (6) genes are: tat, rev, nef,
ViF, Vpv and Vpu code proteins that control the ability of HIV in infecting a cell, produce new copies of virus or
cause disease.13
Chessbrough 14, maintains that progress in this study of HIV has given the following structures: An envelope;
A capsid (shell); A core. The viral particle is a small – 120mm in diameter sphere composed of central conical core
of protein and 2 strands of genomic RNA. The envelope is a lipid bi-layer membrane surrounding the virus, it is
derived from the host and contain some host proteins. The bilayer is covered by knob - like projection or spikes of the
gp120 glycoprotein. This protein is anchored unto their envelope by the gp41 kd glycoprotein. The knobs or spikes
are used to attach the virus to its host cell (Boylston, 1988). The capsid is a protein coat which surrounds the core of
the virus. It is made of protein gp17. The capsid shows cosahedra semetry.14 The core is a conical dense central mass
of the virus, having: Two identical single strands of viral RNA; Structural proteins; The enzyme - reverse transcriptase
and other enzymes.14
The main core protein p25 HIV, is the only human lentivirus known.
Lentivirus constitute a specific sub family of retrovirus. Unique to all retroviruses is DNA polymerase, reverse
transcriptase, which allow the virus to encode RNA message into double strand DNA. The unique morphologic
character of HIV is a cylindrical nucleoid in the mature virion.
The virus contains 3 genes required for a replicating retrovirus. Thus the group associated gene (gag), the
polymerase gene (PoL) and the envelope gene (Env).
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However, several additional open frames found by sequence analysis of HIV genome are of great importance in the
genome, hence are important in the usual pathogenesity of the virus. One unique product the trans-activator (Eat)
protein, functions in‘trans-activation’ whereby a viral gene product is involved in transcriptional activation of other
viral genes. The trans-activation in HIV is highly efficient and may account in part for the virulent nature of HIV
infection.
In contrast, the negative regulatory factor gene (net) appears to down regulate virus expression. It slows
down the transcription of the viral genome and may therefore, be responsible for HIV dormancy in infected cell for a
long period.15,16

Pathogenesity of HIV
It is not clear how much some of the pathology of AIDS is directly due to the virus and how much is caused
by the immune system itself. There are numerous models which have been suggested to explain how HIV causes
Immune Deficiency.1,2 Some of the immune abnormalities in HIV infection include: altered cytokine expression,
decreased NK (natural killer) cell function, decreased humoral and proliferative response to an antigen and mitogens,
decreased MHC II (Major Histocompatibility expression) decreased chemotaxis depletion of CD4 cells, Lymphopenia
and polyclonal B- cell activation.
The pathophysiology of AIDS is complex, as is the case with all syndromes. Ultimately, HIV causes AIDS
by depleting CD4-T helper lymphocytes. This weakens the immune system and allows opportunistic-infections, and
that the mechanism of CD4+ T cell depletion differs in the acute and chronic phases. During the acute phase, HIV
induced cell lysis, and kill the infected cells by cytotoxicity, these T cells accounts for CD8+ cell depletion, although
apoptosis may also be a factor. During the chronic phase, the consequences of generalized immune activation coupled
with the gradual loss of the ability of the immune system to generate new T cells appear (or account for the slow
decline in CD4+ T cell number).
CD4+ T cells in mucosal tissue remain depleted throughout the infection, although enough remain to initially
ward off life threatening infection.12 The virus, though entering through which ever route does act primarily on:
 Lymphorecticular system:
CD4-1 T helper cells,
CD4-I- macrophages
CD4+ monocytes,
Certain endothelial cells
 General nervous system:
 Microglia cell of the nervous system:
Astrocytes
Oligodendrocyte
Neurons- indirectly by the action of cytokines and the gp-120
The cardinal feature of HIV infection begins when-a virus particle encounters a cell with a high affinity
receptor for the virus. A specific high affinity binding reaction occurs between the virus envelop glycoprotein and the
cluster differentiation for molecules.17
Clinical manifestation of HIV
Most people infected with HIV do not know that they have become infected, because they do not feel ill
immediately after infection. However, somepeople at the time of “Sero-conversion” (development of Antibodies to
HIV and usually takes place between 6weeks after HIV infection has happened) develop “acute retroviral syndrome”
which is a glandular fever-like illness with fever, rash, joint pains and enlarged lymph nodes WHO/UNAIDS, 2011).
Whether symptoms or not, the person is already highly infected. After HIV has caused progressive to symptoms
deterioration of the immune system, increase susceptibility to infection now leads to symptoms.
HIV infection is asymptomatic and produces no abnormal physical signs in over half of the affected subjects.
That the time of infection to the development of full blown AIDS ranges from a few months to years with a mean
period of 8-10 years. The length of time of infection, varies with individual if not or course of treatment, signs of HIV
related illness shows between 5-10 years, but the time between infection and diagnosis of AIDS is between 10-15
years or longer.
The symptoms of AIDS are primarily the result of conditions that do not normally develop in individual with
healthy immune system, Ernest, (2009). Some infections are naturally taken care of by healthy immune system, but
reverse is the case in HIV individuals, because of damages caused by the virus to the immune system.
Opportunistic infections are common in people with AIDS. HIV affects nearly every organ, system, hence,
people with AIDS have an increased risk of developing various cancers, such as Kaposi’s sarcoma, cervical cancer
and cancer of the immune system known as lymphomas. Additionally, victims also do have systemic symptoms of
infection like fevers, sweats, (particularly at night), swollen glands, chills, weakness, and weight loss, specific
opportunistic infections presented by AIDS patients being partly dependent on the prevalence of these infection in
the patients geographical area.12
According to Chessbrough14, the earliest stage of the infection (HIV) is generally asymptomatic. At this stage,
though the virus is present in the blood or tissue cells, there is no clinically observable symptom but serological test
is however positive. The duration of the incubation period depends on the patient's immune system and the type of
virus contracted.14
During the window period when the virus can be isolated from infected cells while antibodies are absent in
peripheral blood, no symptom is observable. As the infection progresses, the individual may suffer a range of condition
including, fatigue persistent cough, fever, profuse sweating at night, diarrhoea and drastic loss of weight, secondary
cancers such as Kaposi's Sarcoma and tumours.14
HIV infection is staged on the basis of certain signs, symptoms, and cancers grouped by World Health
Organization WHO, thus:
Primary HIV infection: May be asymptomatic or experienced as acute retroviral syndrome.
Clinical State 1: asymptomatic or generalized swelling of the lymph nodes.
Clinical stage 2: includes minor weight loss, minor subcutaneous manifestations, and recurrent upper
respiratory tract infection.
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 Clinical stage 3: include unexplained diarrhoea, unexplained chronic fever, oral candidiasis or leukoplasia,
sever bacterial infection, pulmonary Tuberculosis (T.B.) and acute necrotising inflammation in the mouth. Some
persons may have AIDS in this stage.
Clinical stage 4: include about 22 opportunistic infections or cancers related to HIV, here, all the victims
have developed AIDS. Most of these conditions of opportunistic infection can be treated easily in patients not infected.
2.9.0 ANTIRETROVIRAL THERAPY DRUGS FOR HIV AND AIDS
Antiretroviral therapy aims to:
Reduce the detectable viral load of HIV RNA as low as possible, ideally to below the current level of
detection of 50 copies/ml; Maintain this level of suppression for as long as possible and to prevent opportunistic
infections occurring, improve the quality to prolong the life of HIV infected persons.17
“No cure or effective vaccine for HIV infection, the primary treatment remains abstinence practice”18 and
attempt to reduce intra-venous (IV) drug use and discourage sharing of needle have helped in some areas. HIV is
treated with three (3) classes of antiretroviral drugs (ART) thus:
Protease inhibitors (PIs), these inhibit the action of HIV enzyme called PROTEASE. This class include:
Ritonavir; Saquinivir; Indinavir; Amprevir; Nelfinavir; Lopinavir.
Nucleoside Reserve Transcriptase Inhibitors (NRTIS), which include: Abacavir (ABC); Zidovudine (AZT);
Didanosine (ddi); Zalcitabine (ddc); Lamivudine (3TC); Stavudine(d4T).
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI); includes: Afavirenz; Delavidine and Nevirpine both
inhibit the action of RT (Reverse transcriptase.18
Notwithstanding, each drug has unique side effect and in addition, treatment with combination of these drugs
leads to additional side effects including a "fat-redistribution condition" called "Lipodystrophy".17,18 Because of HIV
rapid resistance to any single treatment, a combination therapy is used - HAART (Highly Active Antiretroviral
therapy) necessary for effective suppression of the virus hence, combination of 3 or more RT (reverse transcriptase)
and protease inhibitors decrease-mortality rate from HIV, for instance in the US and other industrial states, since its
inception in 1996.17 Though HAART is expensive and not common in areas of high prevalence.
HAART does not eradicate HIV but 'Halts' viral replication, hence; help immune system to reconstitute
itself, levels of the free virus in the blood becomes undetectable; however, the virus is still present in reservoirs best
known of which is a "Latent" reservoir in a subject of helper T-cell called- “Resting memory T cells”. Viruses do stay
or persist in latent state in these cells with a long life span due to their role in allowing the immune system to respond
readily to previously encountered infection. These "Latently" infected cells represent major barriers to "curring" the
infection.18 Treatment with HAART decreases opportunistic diseases and side effects, breaking of the dosage increases
risk of "drug resistance virus and viral replication resumes.
2.9.1 Discontinuation of HAART
ART (Antiretroviral therapy) is initiated when CD4 count of a patient is 200cells per micro litre of blood
which is coinciding with establishment of symptomatic disease.17

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 Several years ago, it was thought that HIV eradication was theoretically possible if HAART was able to
control viral replication for a period of 2-3 years. More recent data shows that there is still ongoing "low level HIV
replication", even when plasma HIV RNA is below the current level of detection (i.e. below 50 copies/ml) Which
result in some "reseeding" of lymphocytes.17
Recent data shows that there is a clinically significant immune reconstitutions starting from 6 months after HAART
has been initiated, and continuing as long as HIV replication is suppressed (Meech, 2007) and current evident shows
that the damaged immune system is capable of some restoration provided HIV replication is controlled.
CONCLUSION
Ever since its discovery, way back in 1983, HIV has always been a big challenge to the medical fraternity.
Advancements in the diagnosis of HIV infection have come to a level where most of the centres are well equipped
even in developing and economically constrained nations. After the introduction of HAART in 1995, the availability
and affordability has improved globally. HAART though has been successful in reducing the mortality, the cause of
concern is the long-term toxic consequences and the increase in non-AIDS related conditions in HIV infected
population receiving HAART.

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