Abstract
APOBEC3 (A3) family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that A3D, A3F, and A3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human A3H is polymorphic and can be categorized into three phenotypes: stable, intermediate, and unstable. However, the anti-viral effect of endogenous A3H in vivo has yet to be examined. Here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable A3H robustly affects HIV-1 fitness in vivo. In contrast, the selection pressure mediated by intermediate A3H is relaxed. Intriguingly, viral genomic RNA sequencing reveled that HIV-1 frequently adapts to better counteract stable A3H during replication in humanized mice. Molecular phylogenetic analyses and mathematical modeling suggest that stable A3H may be a critical factor in human-to-human viral transmission. Taken together, this study provides evidence that stable variants of A3H impose selective pressure on HIV-1.
Highlights
Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) enzymes are cellular single-stranded DNA cytosine deaminases that are encoded in mammals [1,2]
Human APOBEC3 family proteins are known as intrinsic defenses against human immunodeficiency virus type 1 (HIV-1), whereas HIV-1 viral infectivity factor (Vif) counteracts APOBEC3-mediated anti-viral action
Together with phylogenetic analyses and mathematical modeling, we conclude that APOBEC3H is a critical determinant of HIV-1 replication within infected individuals and we propose that it may be a factor in human-to-human HIV-1 transmission
Summary
Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) enzymes are cellular single-stranded DNA cytosine deaminases that are encoded in mammals [1,2]. Gene duplication is a hallmark of the genes that are under evolutionary selective pressures [3], and the seven primate A3 genes have been positively selected during evolution [4], These observations suggest that primate A3 proteins play crucial roles in primates including humans. Previous studies including ours have demonstrated that A3D, A3F, and A3G, which are endogenously expressed in human CD4+ T cells, are restriction factors potently controlling HIV-1 replication in human CD34+ hematopoietic stem cell (HSC)-transplanted humanized mouse models [9,10,11,12]. To antagonize the anti-viral effect of A3 proteins, HIV-1 encodes a protein named viral infectivity factor (Vif). Vif orchestrates cellular ubiquitin ligase complex and degrades anti-viral A3 proteins via ubiquitin/proteasomedependent pathway in infected cells [2,13]
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