The case for transmissible antivirals to control population-wide infectious disease

Notton, Timothy; Sardanyés, Josep; Weinberger, Ariel D.; Weinberger, Leor S.

doi:10.1016/j.tibtech.2014.06.006

Cited by 29 publications

(19 citation statements)

References 47 publications

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“…TIPs would theoretically replicate faster than the wild-type virus and therefore outcompete the virus hindering spread and transmission. TIPs would have the advantage of being active only in organisms already infected with the wild-type virus due to their dependence on a helper virus to replicate 118,119 . Although still in the exploratory phase, it remains to be determined how TIPs would impact virus persistence, the generation of adaptive mutations and the generation of new infectious viruses by complementation.…”

Section: Use As Antivirals and Vaccine Adjuvantsmentioning

confidence: 99%

Defective viral genomes are key drivers of the virus–host interaction

2019

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Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are beginning to appreciate the surprising versatility of viral genomes and how replicationcompetent and -defective virus variants can provide means for adaptation, immune escape and virus perpetuation. This Review summarizes current knowledge of the types of defective viral genomes generated during the replication of RNA viruses and the functions that they carry out. We highlight the universality and diversity of defective viral genomes during infections and discuss their predicted role in maintaining a fit virus population, their impact on human and animal health, and their potential to be harnessed as antiviral tools. Review ARticleNATuRe MicRoBiology extinction interfere with replication of a wild-type viral genome 29,30 . Hypermutations and mutations leading to frame shifts also result in defective viruses 31 (Fig. 1a). One example is mutations introduced by the cellular protein APOBEC3G into pro-retroviruses 32 . APOBEC3G deaminates deoxycytidine nucleotides in the viral DNA, leading to hypermutations that interfere with the ability of the viral genome to integrate into the host genome and replicate. Interestingly, in opposition to an interfering activity for these mutated pro-viruses, it has been proposed that defective proviruses enhance fitness and that complementation among them drives viral persistence and pathogenesis 33,34 .Deletions. The genomic viral species most commonly referred to as DVGs are truncated viral genomes resulting from large internal deletions occurring during viral replication. Deletion DVGs tend to bear single large truncations that remove several or all essential genes required for self-propagation while retaining 5′ and 3′ ends as well as other RNA structural elements required for polymerase binding, replication and/or packaging [35][36][37] . Multiple variants also exist, including DVGs that can be described as 'mosaic' in that they appear to be the result of multiple recombination and rearrangement events, including deletions, insertions, duplications and even inversions of parts of the genome [38][39][40] (Fig. 1b). Copy-backs.Copy-back and snap-back DVGs are rearranged genomes in which a sequence is duplicated in reverse complement to create theoretical stem-like structures (panhandle structures for copy-back DVGs or hairpin structures for snap-back DVGs) 41-43 . Copy-back DVGs have been reported in many negative-sense (ns) RNA viruses and are generated from the 5′ end of the genome in a process that produces DVGs with complementary 3′ and 5′ termini 44,45 . If the complementary region of the DVG comprises almost the entire sequence, the DVG can be further characterized as a snap-back DVG 43 (Fig. 1c). Copy-back DVGs are predicted to be generated when the viral RNA-dependent RNA polymerase (RdRP) detaches from the template and reattaches to the nascent strand, copying back the end of the genome 42,46 .

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Section: Use As Antivirals and Vaccine Adjuvantsmentioning

confidence: 99%

Defective viral genomes are key drivers of the virus–host interaction

2019

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“…This competition results in a reduced accumulation of the wild-type virus, a process known as interference [13,[16][17][18][19][20][21][22][23][24][25]. The interest in DIs has been revitalized in recent years mainly for three reasons: (i) they may be involved in triggering antiviral immunity during acute viral replication [26], (ii) they negatively impact the biotechnological production of vaccines and viral vectors [27], and (iii) their possible application as transmissible antivirals to control viral infections at the host-population level [28], the so-called therapeutic interfering particles.…”

Section: Introductionmentioning

confidence: 99%

Nonlinear trade-offs allow the cooperation game to evolve from Prisoner's Dilemma to Snowdrift

Chao

Elena

2017

Proc. R. Soc. B.

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The existence of cooperation, or the production of public goods, is an evolutionary problem. Cooperation is not favoured because the Prisoner's Dilemma (PD) game drives cooperators to extinction. We have re-analysed this problem by using RNA viruses to motivate a model for the evolution of cooperation. Gene products are the public goods and group size is the number of virions co-infecting the same host cell. Our results show that if the trade-off between replication and production of gene products is linear, PD is observed. However, if the trade-off is nonlinear, the viruses evolve into separate lineages of ultra-defectors and ultra-cooperators as group size is increased. The nonlinearity was justified by the existence of real viral ultra-defectors, known as defective interfering particles, which gain a nonlinear advantage by being smaller. The evolution of ultra-defectors and ultra-cooperators creates the Snowdrift game, which promotes high-level production of public goods.

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“…The safety and ethical implications of transmissible, integrating therapies are important considerations that have been addressed extensively by Notton et al, [ 93 ], but we briefly summarize the main points here.…”

Section: Generating De Novo Interference For Therapymentioning

confidence: 99%

Exploiting Genetic Interference for Antiviral Therapy

2016

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Rapidly evolving viruses are a major threat to human health. Such viruses are often highly pathogenic (e.g., influenza virus, HIV, Ebola virus) and routinely circumvent therapeutic intervention through mutational escape. Error-prone genome replication generates heterogeneous viral populations that rapidly adapt to new selection pressures, leading to resistance that emerges with treatment. However, population heterogeneity bears a cost: when multiple viral variants replicate within a cell, they can potentially interfere with each other, lowering viral fitness. This genetic interference can be exploited for antiviral strategies, either by taking advantage of a virus’s inherent genetic diversity or through generating de novo interference by engineering a competing genome. Here, we discuss two such antiviral strategies, dominant drug targeting and therapeutic interfering particles. Both strategies harness the power of genetic interference to surmount two particularly vexing obstacles—the evolution of drug resistance and targeting therapy to high-risk populations—both of which impede treatment in resource-poor settings.

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The case for transmissible antivirals to control population-wide infectious disease

Cited by 29 publications

References 47 publications

Defective viral genomes are key drivers of the virus–host interaction

Defective viral genomes are key drivers of the virus–host interaction

Nonlinear trade-offs allow the cooperation game to evolve from Prisoner's Dilemma to Snowdrift

Exploiting Genetic Interference for Antiviral Therapy

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