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.

Download full-text


Available from: Alex Compton
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Sep 2014 · Human Mutation
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jan 2014 · Virology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There are seven members of the APOBEC3 family in humans (APOBEC3A through APOBEC3H) that have antiviral activity against retroviruses and/or retroelements. To determine whether variants in APOBEC3 genes in human populations have altered antiviral activity, we identified and functionally tested novel single nucleotide variants (SNVs) in APOBEC3 genes present in the 1000 Genome Project dataset. We found that common variants minor allele frequency (>1%) of APOBEC3A, C, F, and G do not affect protein function. However, we found that two common novel polymorphisms in APOBEC3D decrease antiviral activity against HIV-1, and one polymorphism decreases activity against Alu retrotransposons. We characterized the diversity of APOBEC3 genes in three human populations and find significant evidence that APOBEC3D has evolved under purifying selection in recent human history. These data suggest that the activity of APOBEC3D has been maintained in human populations for a cellular function in host defense.
    Full-text · Article · Jun 2013 · Virology
Show more