Antiretroelement Activity of APOBEC3H Was Lost Twice in Recent Human Evolution

Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
Cell host & microbe (Impact Factor: 12.33). 10/2008; 4(3):249-59. DOI: 10.1016/j.chom.2008.07.005
Source: PubMed


The primate APOBEC3 gene locus encodes a family of proteins (APOBEC3A-H) with various antiviral and antiretroelement activities. Here, we trace the evolution of APOBEC3H activity in hominoids to identify a human-specific loss of APOBEC3H antiviral activity. Reconstruction of the predicted ancestral human APOBEC3H protein shows that human ancestors encoded a stable form of this protein with potent antiviral activity. Subsequently, the antiviral activity of APOBEC3H was lost via two polymorphisms that are each independently sufficient to destabilize the protein. Nonetheless, an APOBEC3H allele that encodes a stably expressed protein is still maintained at high frequency, primarily in African populations. This stable APOBEC3H protein has potent activity against retroviruses and retrotransposons, including HIV and LINE-1 elements. The surprising finding that APOBEC3H antiviral activity has been lost in the majority of humans may have important consequences for our susceptibility to retroviral infections as well as ongoing retroelement proliferation in the human genome.

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Available from: Harmit Singh Malik
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    • "Unstable A3H haplotypes (haplotypes I, III, IV, and VI) carry either a Gly-105, Asn-15, or both in combination with other possible polymorphisms at positions 18, 121, and 178 (35, 36) (Table 1). Unstable A3H haplotype I occurs at the highest population frequency (0.308 – 0.526) (35,36). An Arg-105 and Asn-15 are required for a stable A3H in cells (35). "
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    ABSTRACT: APOBEC3H is a deoxycytidine deaminase that can restrict the replication of HIV-1 in the absence of the viral protein Vif that induces APOBEC3H degradation in cells. APOBEC3H exists in humans as seven haplotypes (I-VII) with different cellular stabilities. Of the three stable APOBEC3H haplotypes (II, V, and VII), haplotypes II and V occur most frequently in the population. Despite APOBEC3H being a bona fide restriction factor, there has been no comparative biochemical characterization of APOBEC3H haplotypes. We characterized the single-stranded (ss)DNA scanning mechanisms that haplotypes II and V use to search their ssDNA substrate for cytosine containing deamination motifs. APOBEC3H haplotype II was able to processively deaminate multiple cytosines in a single enzyme-substrate encounter by using sliding, jumping, and intersegmental transfer movements. In contrast, APOBEC3H haplotype V exhibited diminished sliding and intersegmental transfer abilities, but was able to jump along ssDNA. Due to an Asp or Glu at amino acid 178 differentiating these APOBEC3H haplotypes, the data indicated that this amino acid on helix 6 contributes to processivity. The diminished processivity of APOBEC3H haplotype V did not result in a reduced efficiency to restrict HIV-1 replication in single-cycle infectivity assays, suggesting a redundancy in the contributions of jumping and intersegmental transfer to mutagenic efficiency. Optimal processivity on ssDNA also required dimerization of APOBEC3H through the β2 strands. The findings support a model in which jumping can compensate for deficiencies in intersegmental transfer and suggest that APOBEC3H haplotypes II and V induce HIV-1 mutagenesis efficiently, but by different mechanisms.
    Full-text · Article · Sep 2015 · Journal of Biological Chemistry
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    • "Human apolipoprotein B messenger RNA (mRNA)-editing catalytic polypeptide-like 3 (APOBEC3) gene family encodes cellular cytidine deaminases that play a crucial role in antiretroviral activity by inhibiting replication of retroviruses including HIV-1 (Desimmie et al. 2014; Sheehy et al. 2002). Expression of mRNA for a member of APOBEC3 family, APOBEC3H (A3H), can be detected in various tissues and induced by IFN-α in target cells of HIV-1 infection (Refsland et al. 2010; OhAinle et al. 2006; Harari et al. 2009; Tan et al. 2009), although it is difficult to detect cellular protein expression due to low stability of A3H protein (Dang et al. 2008; OhAinle et al. 2008). "
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    ABSTRACT: Human APOBEC3H (A3H) is a member of APOBEC3 cytidine deaminase family that potently restricts HIV-1 replication. Because A3H is genetically divergent with different intracellular stability and anti-HIV-1 activity in vitro, we investigated a possible association of A3H with susceptibility to HIV-1 infection and disease progression in Japanese populations. A total of 191 HIV-1-infected individuals (HIV group), 93 long-term non-progressors to AIDS (LTNP group) and 421 healthy controls were genotyped for two functional APOBEC3H polymorphisms, rs139292 and rs139297. As compared with the controls, minor allele frequency (MAF) for rs139292 was high in the HIV group (MAF in cases vs. controls; 0.322 vs. 0.263, odds ratio (OR) = 1.33, 95 % confidence interval (95 % CI) = 1.02-1.74, p = 0.035) and low in the LTNP group (0.161 vs. 0.263, OR = 0.54, 95 % CI = 0.36-0.82, p = 0.004, pc = 0.007), whereas the MAF for rs139297 was high in the HIV group (0.367 vs. 0.298, OR = 1.36, 95 % CI = 1.07-1.76, p = 0.017, pc = 0.035). In addition, haplotype analyses revealed that the frequencies of A3H-hapC and -hapA were high (0.322 vs. 0.262, OR = 1.33, 95% CI = 1.02-1.74, p = 0.003) and low (0.634 vs. 0.697, OR = 0.75, 95 % CI = 0.58-0.97, p = 0.002), respectively, in the HIV group, whereas the frequencies of A3H-hapC and -hapB were low (0.161 vs. 0.262, OR = 0.54, 95 % CI = 0.36-0.82, p = 0.00003) and high (0.097 vs. 0.040, OR = 2.55, 95 % CI = 1.40-4.62, p = 0.000008), respectively, in the LTNP group, as compared with those in the controls. These observations suggest that the A3H with low anti-HIV-1 activity, A3H-hapC, is associated with the susceptibility to HIV-1 infection, whereas the A3H producing a stable protein, A3H-hapB, may confer a low risk of disease progression to AIDS.
    Full-text · Article · Feb 2015 · Immunogenetics
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    • "In humans, certain A3H haplotypes influence both the activity of the protein and their subcellular location (OhAinle et al., 2008; Li and Emerman, 2011; Harari et al., 2009). Some of these haplotypes encode a completely inactive A3H, thus promoting retroviral infections in the subjects that display such haplotypes (OhAinle et al., 2008; Li and Emerman, 2011; Harari et al., 2009). In the present study, the haplotype ''GGGGCC'' was significantly more frequently detected in the FIV-and FeLV-uninfected animals, suggesting a possible protective effect of this allelic combination in relation to infection by FIV and FeLV. "
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    ABSTRACT: Feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) are widely distributed retroviruses that infect domestic cats (Felis catus). Restriction factors are proteins that have the ability to hamper retroviruses' replication and are part of the conserved mechanisms of anti-viral immunity of mammals. The APOBEC3 protein family is the most studied class of restriction factors; they are cytidine deaminases that generate hypermutations in provirus DNA during reverse transcription, thus causing hypermutations in the viral genome, hindering virus replication. One of the feline APOBEC3 genes, named APOBEC3H, encodes two proteins (APOBEC3H and APOBEC3CH). In other mammals, APOBEC3H single-nucleotide polymorphisms (SNPs) can alter the stability and cellular localization of the encoded protein, thus influencing its subcellular localization and reducing its anti-viral effect. In cats, the association of APOBEC3H SNPs with susceptibility to retroviral infections was not yet demonstrated. Therefore, this study aimed the investigation on the variability of APOBEC3H and the possible association with FIV/FeLV infections. DNA obtained from whole blood of fifty FIV- and/or FeLV-infected cats and fifty-nine FIV- and/or FeLV-uninfected cats were used as templates to amplify two different regions of the APOBEC3H, with subsequent sequencing and analysis. The first region was highly conserved among all samples, while in the second, six single-nucleotide variation points were identified. One of the SNPs, A65S (A65I), was significantly correlated with the susceptibility to FIV and/or FeLV infections. On the other hand, the haplotype analysis showed that the combination "GGGGCC" was positively correlated with the lack of FIV and/or FeLV infections. Our results indicate that, as previously shown in other mammals, variability of restriction factors may contribute to susceptibility of domestic cats to retroviral infections; however, these results should be confirmed by more extensive analysis and in vitro experiments.
    Full-text · Article · Aug 2014 · Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases
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