The Host Restriction Factor APOBEC3G and Retroviral Vif Protein Coevolve due to Ongoing Genetic Conflict

Compton, Alex A.; Hirsch, Vanessa M.; Emerman, Michael

doi:10.1016/j.chom.2011.11.010

Cited by 96 publications

(161 citation statements)

References 30 publications

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“…23). An excellent recent example is provided by studies on nat- ural simian immunodeficiency virus (SIV) 4 infection of four African green monkey (SIV agm ) subspecies (24). As expected, the Vif protein of each SIV agm strain degrades the APOBEC3G protein of its respective host.…”

Section: Restriction By Hypermutation: Apobec3 Dna Deaminasesmentioning

confidence: 80%

The Restriction Factors of Human Immunodeficiency Virus

Harris

Hultquist

Evans

2012

Journal of Biological Chemistry

244

255

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Cellular proteins called "restriction factors" can serve as powerful blockades to HIV replication, but the virus possesses elaborate strategies to circumvent these barriers. First, we discuss general hallmarks of a restriction factor. Second, we review how the viral Vif protein protects the viral genome from lethal levels of cDNA deamination by promoting APOBEC3 protein degradation; how the viral Vpu, Env, and Nef proteins facilitate internalization and degradation of the virus-tethering protein BST-2/tetherin; and how the viral Vpx protein prevents the premature termination of reverse transcription by degrading the dNTPase SAMHD1. These HIV restriction and counter-restriction mechanisms suggest strategies for new therapeutic interventions. Restriction Factor HallmarksRestriction factors have at least four defining characteristics (see Fig. 1A). First and foremost, a restriction factor must directly and dominantly cause a significant decrease in HIV infectivity. This is often determined by cotransfecting cell lines such as HEK293 and HeLa with a molecular clone of the virus, with or without a plasmid expressing the restriction factor, and measuring the amount and infectivity of virus recovered in the cell culture medium after 1-2 days of incubation. Such assays are ideally done over a range of restriction factor expression, with the highest levels often imposing log-scale drops in viral infectivity (see Fig. 1B). This "single-cycle" assay for viral replication is useful for testing the impact of viral mutations and/or restriction factor variations.Second, if a restriction factor is a true threat to viral replication, then the predecessors of HIV invariably evolved an equally potent counter-restriction mechanism that still exists in the present day virus. For instance, titrating a counter-restriction factor into the aforementioned single-cycle infectivity experiment can result in a full recovery of viral infectivity despite the presence of an active restriction factor (Fig. 1B). Viruses lacking these various countermeasures are able to replicate in some, but not all, cell types depending on the expression level of the relevant restriction factor. Cell lines that support replication are termed "permissive," and those that do not are termed "nonpermissive." This life/death dichotomy has been elegantly exploited to identify several restriction factors and their corresponding viral antagonists.Third, because the interactions between restriction and counter-restriction factors occur through direct protein-protein interactions, the restriction factor often shows signatures of rapid evolution. In general, mutations are maintained in a population only if they confer a selective advantage. If a host species experiences iterative rounds of pathogenic pressure, altered variants of host restriction factors that are no longer susceptible to the pathogen's counteraction mechanism are selected. Over evolutionary time, this results in an overabundance of amino acid substitution mutations in these genes relative to non-amino acid...

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Section: Restriction By Hypermutation: Apobec3 Dna Deaminasesmentioning

confidence: 80%

The Restriction Factors of Human Immunodeficiency Virus

Harris

Hultquist

Evans

2012

Journal of Biological Chemistry

244

255

View full text Add to dashboard Cite

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“…6), providing a possible explanation for why SIVcpz has not crossed between chimpanzees and gorillas more often. Although all gorillas we have examined are homozygous at the site in A3G conferring resistance to SIVcpz, extensive A3G sequence diversity has been observed in other primate species (e.g., rhesus macaques, sooty mangabeys, African green monkeys) (40,41). A3G polymorphism could render certain individuals more susceptible to transmissions of SIVcpz, allowing the virus to gain a foothold in gorillas (19).…”

Section: Sivgor Resulted From a Single Introduction Of Sivcpz From Symentioning

confidence: 96%

“…Previous studies have highlighted the importance of host restriction factors as a barrier to SIV cross-species transmission (39). Among these host restriction factors, A3G has been reported to be one of the most effective (40)(41)(42). In fact, gorilla A3G is resistant to HIV-1 and SIVcpz Vif proteins (Fig.…”

Section: Sivgor Resulted From a Single Introduction Of Sivcpz From Symentioning

confidence: 99%

Origin of the HIV-1 group O epidemic in western lowland gorillas

D’arc

Ayouba

Esteban

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

136

149

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HIV-1, the cause of AIDS, is composed of four phylogenetic lineages, groups M, N, O, and P, each of which resulted from an independent cross-species transmission event of simian immunodeficiency viruses (SIVs) infecting African apes. Although groups M and N have been traced to geographically distinct chimpanzee communities in southern Cameroon, the reservoirs of groups O and P remain unknown. Here, we screened fecal samples from western lowland (n = 2,611), eastern lowland (n = 103), and mountain (n = 218) gorillas for gorilla SIV (SIVgor) antibodies and nucleic acids. Despite testing wild troops throughout southern Cameroon (n = 14), northern Gabon (n = 16), the Democratic Republic of Congo (n = 2), and Uganda (n = 1), SIVgor was identified at only four sites in southern Cameroon, with prevalences ranging from 0.8–22%. Amplification of partial and full-length SIVgor sequences revealed extensive genetic diversity, but all SIVgor strains were derived from a single lineage within the chimpanzee SIV (SIVcpz) radiation. Two fully sequenced gorilla viruses from southwestern Cameroon were very closely related to, and likely represent the source population of, HIV-1 group P. Most of the genome of a third SIVgor strain, from central Cameroon, was very closely related to HIV-1 group O, again pointing to gorillas as the immediate source. Functional analyses identified the cytidine deaminase APOBEC3G as a barrier for chimpanzee-to-gorilla, but not gorilla-to-human, virus transmission. These data indicate that HIV-1 group O, which spreads epidemically in west central Africa and is estimated to have infected around 100,000 people, originated by cross-species transmission from western lowland gorillas.

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“…There are several retroviral restriction factors that operate in parallel in mammals; the most notable are BST-2, TRIM5-␣, SAMHD1, and APOBEC3 (A3) proteins, as well as several other factors that are dependent on an interferon response for expression (3). To persist, retroviruses therefore need to concomitantly develop countermeasures to all these restrictions factors, and these are often in the form of accessory proteins or genetic substitutions at sites of interactions with restriction factors (1,4,5). HIV-1 and HIV-2 are among the retroviruses that have been the most successful at avoiding restriction by the host, whereby BST-2 is defeated by expression of the viral accessory protein Vpu (6,7), SAMHD1 is defeated by Vpx (8,9), A3 (A3F, A3G, A3D, and A3H) is defeated by Vif (10), and TRIM5␣ is defeated by the virus evolving target sequences that avoid its capsid being recognized by this restriction factor (11)(12)(13)(14).…”

mentioning

confidence: 99%

N -Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins

Gerpe

Renner

Bélanger

et al. 2015

J Virol

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Retroviruses are pathogens with rapid infection cycles that can be a source of disease, genome instability, and tumor development in their hosts. Host intrinsic restriction factors, such as APOBEC3 (A3) proteins, are constitutively expressed and dedicated to interfering with the replication cycle of retroviruses. To survive, propagate, and persist, retroviruses must counteract these restriction factors, often by way of virus genome-encoded accessory proteins. Glycosylated Gag, also called glycosylated Pr80 Gag (gPr80), is a gammaretrovirus genome-encoded protein that inhibits the antiretroviral activity of mouse A3 (mA3). Here we show that gPr80 exerts two distinct inhibitory effects on mA3: one that antagonizes deamination-independent restriction and another one that inhibits its deaminase activity. More specifically, we find that the number of N-glycosylated residues in gPr80 inversely correlates with the sensitivity of a gammaretrovirus to deamination by mouse A3 and also, surprisingly, by human A3G. Finally, our work highlights that retroviruses which have successfully integrated into the mouse germ line generally express a gPr80 with fewer glycosylated sites than exogenous retroviruses. This observation supports the suggestion that modulation of A3 deamination intensity could be a desirable attribute for retroviruses to increase genetic diversification and avoid immune detection. Overall, we present here the first description of how gammaretroviruses employ posttranslational modification to antagonize and modulate the activity of a host genome-encoded retroviral restriction factor. IMPORTANCEAPOBEC3 proteins are host factors that have a major role in protecting humans and other mammals against retroviruses. These enzymes hinder their replication and intensely mutate their DNA, thereby inactivating viral progeny and the spread of infection. Here we describe a newly recognized way in which some retroviruses protect themselves against the mutator activity of APOBEC3 proteins. We show that gammaretroviruses expressing an accessory protein called glycosylated Gag, or gPr80, use the host's posttranslational machinery and, more specifically, N-linked glycosylation as a way to modulate their sensitivity to mutations by APOBEC3 proteins. By carefully controlling the amount of mutations caused by APOBEC3 proteins, gammaretroviruses can find a balance that helps them evolve and persist.

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The Host Restriction Factor APOBEC3G and Retroviral Vif Protein Coevolve due to Ongoing Genetic Conflict

Cited by 96 publications

References 30 publications

The Restriction Factors of Human Immunodeficiency Virus

The Restriction Factors of Human Immunodeficiency Virus

Origin of the HIV-1 group O epidemic in western lowland gorillas

N -Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins

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