Article

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: 12.19). 01/2012; 11(1):91-8. DOI: 10.1016/j.chom.2011.11.010
Source: PubMed

ABSTRACT 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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    • "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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    • "Recently, a study of four African Green Monkey subspecies, which can be infected with divergent strains of SIV, highlighted that even in nonpathogenic infection there is ongoing evolution of simian APOBEC3G in the absence of ongoing disease. In response to these changes, both natural isolates from long-term infected individuals and viruses from experimentally infected individuals adapt to retarget the host restriction factor.59 These studies highlight the ongoing conflict between virus and host, and may contribute to the species specificity of closely related retroviruses. "
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