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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Available from: Alex Compton, Sep 03, 2015
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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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    ABSTRACT: Tripartite motif-containing protein 22 (TRIM22) is a novel interferon-induced protein that potently inhibits the replication of evolutionarily diverse viruses, including human immunodeficiency virus type 1 (HIV-1). Altered TRIM22 expression is associated with a variety of diseases such as multiple sclerosis, cancer and autoimmune diseases. The factors that influence TRIM22 expression and antiviral activity are largely unknown. We adopted an evolution-guided functional approach to identify potential genetic determinants of TRIM22 function. Evolutionary analysis of TRIM22 from mammals spanning >100 million years of evolution demonstrated that the evolution of TRIM22 has been shaped by ancient and variable positive selection. We showed that positive selection is operating on multiple residues that cluster in putative functional regions and are predicted to be functionally damaging. Interestingly, the second most prevalent TRIM22 single nucleotide polymorphism (SNP) in humans (rs1063303) is located at one of these positively selected residues. We showed that the frequency of rs1063303:G>C varies up to 10-fold between ethnicities. The SNP rs1063303:G>C variant also had an inverse functional impact where it increased TRIM22 expression and decreased the antiviral activity of TRIM22. Together, our data characterizes the extensive genetic variation in TRIM22 and identifies rs1063303:G>C as a highly prevalent SNP that influences its function. This article is protected by copyright. All rights reserved.
    Human Mutation 09/2014; 35(9). DOI:10.1002/humu.22595 · 5.05 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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    Virology 01/2014; 449:224–228. DOI:10.1016/j.virol.2013.11.026 · 3.28 Impact Factor
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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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