Defective interfering particle

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Predicted secondary structure of the Coronavirus SL-III cis-acting replication element, a genomic structure required for BCoV DI RNA replication

In virology, defective interfering particles (DIPs), also known as defective interfering viruses, are spontaneously generated virus mutants in which a critical portion of the particle's genome has been lost due to defective replication. DIPs are derived from and associated with their parent virus, and particles are classed as DIPs if they are rendered non-infectious due to at least one essential gene of the virus being lost or severely damaged as a result of the defection. A DIP can usually still penetrate host cells, but requires another fully functional virus particle (the 'helper' virus) to co-infect a cell with it, in order to provide the lost factors. The existence of DIPs has been known about for decades, and they can occur within nearly every class of both DNA and RNA viruses.

Defection

DIPs are a naturally occurring phenomenon that can also be synthesized for experimental use. They are spontaneously produced by error-prone viral replication, something particularly prevalent in RNA viruses over DNA viruses due to the enzyme used (replicase, or RNA-dependent RNA polymerase.) DI genomes typically retain the termini sequences needed for recognition by viral polymerases, and sequences for packaging of their genome into new particles, but little else. The size of the genomic deletion event can vary greatly, with one such example in a DIP derived from rabies virus exhibiting a 6.1 kb deletion. In another example, the size of several DI-DNA plant virus genomes varied from one tenth of the size of the original genome to one half.

Interference

The particles are considered interfering when they affect the function of the parent virus through competitive inhibition during coinfection. In other words, defective and non-defective viruses replicate simultaneously, but when defective particles increase, the amount of replicated non-defective virus is decreased. The extent of interference depends on the type and size of defection in the genome; large deletions of genomic data allow rapid replication of the defective genome. During the coinfection of a host cell, a critical ratio will eventually be reached in which more viral factors are being used to produce the non-infectious DIPs than infectious particles.

This interfering nature is becoming more and more important for future research on virus therapies. It is thought that because of their specificity, DIPs will be targeted to sites of infection. In one example, scientists have used DIPs to create "protecting viruses", which attenuated the pathogenicity of an influenza A infection in mice to a point that it was no longer lethal.

Pathogenesis

DIPs have been shown to play a role in pathogenesis of certain viruses. One study demonstrates the relationship between a pathogen and its defective variant, showing how regulation of DI production allowed the virus to attenuate its own infectious replication, decreasing viral load and thus enhance its parasitic efficiency by preventing the host from dying too fast. This also provides the virus with more time to spread and infect new hosts. DIP generation is regulated within viruses: the Coronavirus SL-III cis-acting replication element (shown in the image) is a higher-order genomic structure implicated in the mediation of DIP production in bovine coronavirus, with apparent homologs detected in other coronavirus groups. A more in-depth introduction can be found in Alice Huang and David Baltimore's work from 1970.

Types of defective RNA genomes

1. Deletions defections are when a fragment of the template is skipped. Examples of this type of defection can be found in the Resende, et al. 1992 article.
2. Snapbacks defections are when replicase transcribes part of one strand then uses this new strand as a template. The result of this can produce a hairpin. Snapback defections are explored in the Schubert & Lazzarini 1981 article.
3. Panhandle defections are when the polymerase carries a partially made strand and then switches back to transcribe the 5' end, forming the panhandle shape. Panhandle defections in the influenza virus can be found in the Fodor, et al. 1994 article.
4. Compound defections are when both a deletion and snapback defection happens together.
5. Mosaic or complex DI genome, in which the various regions may come from the same helper virus genome but in the wrong order; from different helper genome segments, or could include segments of host RNA. Duplications may also occur.

Recent published work

Recent work has been done by virologists to learn more about the interference in infection of host cells and how DI genomes could potentially work as antiviral agents. The Dimmock & Easton, 2014 article explains that pre-clinical work is being done to test their effectiveness against influenza viruses. DI-RNAs have also been found to aid in the infection of fungi via viruses of the family Partitiviridae for the first time, which makes room for more interdisciplinary work.