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

Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA.
Cell host & microbe (Impact Factor: 12.33). 01/2012; 11(1):91-8. DOI: 10.1016/j.chom.2011.11.010
Source: PubMed


APOBEC3G (A3G) is a host cytidine deaminase that inhibits retroviruses. HIV and related primate lentiviruses encode Vif, which counteracts A3G by inducing its degradation. This Vif-mediated A3G inhibition is species specific, suggesting that the A3G-Vif interaction has evolved as primate lentiviruses have adapted to their hosts. We examined the evolutionary dynamics of the A3G-Vif interaction within four African green monkey (AGM) subspecies, which are each naturally infected with a distinct simian immunodeficiency virus (SIV). We identified single amino acid changes within A3G in two AGM subspecies that render it resistant to Vif proteins, except for Vif from the viruses that naturally infect these subspecies. Moreover, experimental infection of AGMs shows that Vif can rapidly adapt to these arising Vif-resistant A3G genotypes. These data suggest that despite being generally nonpathogenic in its natural host, SIV infection selects for Vif-resistant forms of A3G in AGM populations, driving Vif counterevolution and functional divergence.

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    • "Several host restriction factors have been shown to undergo balancing selection in primates, including human TRIM5α and primate OAS1 (Newman et al. 2006; Alex A. Compton, Vanessa M. Hirsch 2012; Ferguson et al. 2012). Moreover, a recent genome-wide scan of two ethnic populations identified TRIM22 as one of 60 'extreme' genes undergoing balancing selection in humans (Andrés et al. 2009). "
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    Human Mutation 09/2014; 35(9). DOI:10.1002/humu.22595 · 5.14 Impact Factor
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    • "Vif targets A3G for proteasomal degradation , suppressing hypermutations and allowing persistent infection . The A3G–Vif interaction is thus a remarkable example of the evolutionary arms race between retroviruses and their hosts (Compton et al., 2012) and a promising target of intervention (Dapp et al., 2012; Harris and Liddament, 2004). Indeed, several candidate drug molecules targeting the A3G–Vif axis are currently under development (Cen et al., 2010; Dapp et al., 2012; Ejima et al., 2011; Nathans et al., 2008). "
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    ABSTRACT: The contest between the host factor APOBEC3G (A3G) and the HIV-1 protein Vif presents an attractive target of intervention. The extent to which the A3G–Vif interaction must be suppressed to tilt the balance in favor of A3G remains unknown. We employed stochastic simulations and mathematical modeling of the within-host dynamics and evolution of HIV-1 to estimate the fraction of progeny virions that must incorporate A3G to render productive infection unsustainable. Using three different approaches, we found consistently that a transition from sustained infection to suppression of productive infection occurred when the latter fraction exceeded ~0.8. The transition was triggered by A3G-induced hypermutations that led to premature stop codons compromising viral production and was consistent with driving the basic reproductive number, R0, below unity. The fraction identified may serve as a quantitative guideline for strategies targeting the A3G–Vif axis.
    Virology 01/2014; 449:224–228. DOI:10.1016/j.virol.2013.11.026 · 3.32 Impact Factor
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    • "Many APOBEC3 genes, including APOBEC3G, APOBEC3H, and APOBEC3D, which was called " APOBEC3DE " in earlier papers, have evolved under positive selection for millions of years in primates (Duggal et al., 2011; OhAinle et al., 2008; Sawyer et al., 2004). At least one APOBEC3 gene within an Old World monkey species has acquired population-specific polymorphisms in recent history that allow host evasion from lentiviral infection (Compton et al., 2012), suggesting that APOBEC3s may have rapidly evolved in recent primate history as well. Within humans, several APOBEC3s are known to have common polymorphisms that render them defective. "
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    Virology 06/2013; 443(2). DOI:10.1016/j.virol.2013.05.016 · 3.32 Impact Factor
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