Cadena Cristhian, Stavrou Spyridon, Manzoni Tomaz, Iyer Shilpa S, Bibollet-Ruche Frederic, Zhang Weiyu, Hahn Beatrice H, Browne Edward P, Ross Susan R
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL, 60612, USA.
Retrovirology. 2016 Jun 30;13(1):45. doi: 10.1186/s12977-016-0280-y.
Humans encode seven APOBEC3 proteins (A-H), with A3G, 3F and 3H as the major factors restricting HIV-1 replication. HIV-1, however, encodes Vif, which counteracts A3 proteins by chaperoning them to the proteasome where they are degraded. Vif polymorphisms found in HIV-1s isolated from infected patients have varying anti-A3G potency when assayed in vitro, but there are few studies demonstrating this in in vivo models. Here, we created Friend murine leukemia viruses encoding vif alleles that were previously shown to differentially neutralize A3G in cell culture or that were originally found in primary HIV-1 isolates. Infection of transgenic mice expressing different levels of human A3G showed that these naturally occurring Vif variants differed in their ability to counteract A3G during in vivo infection, although the effects on viral replication were not identical to those seen in cultured cells. We also found that the polymorphic Vifs that attenuated viral replication reverted to wild type only in A3G transgenic mice. Finally, we found that the level of A3G-mediated deamination was inversely correlated with the level of viral replication. This animal model should be useful for studying the functional significance of naturally occurring vif polymorphisms, as well as viral evolution in the presence of A3G.
人类编码七种载脂蛋白B mRNA编辑酶催化多肽样蛋白3（APOBEC3）蛋白（A - H），其中A3G、3F和3H是限制HIV - 1复制的主要因素。然而，HIV - 1编码病毒感染因子（Vif），它通过将A3蛋白伴侣转运至蛋白酶体使其降解来对抗A3蛋白。从感染患者分离出的HIV - 1中发现的Vif多态性在体外检测时具有不同的抗A3G效力，但在体内模型中证明这一点的研究很少。在这里，我们构建了编码Vif等位基因的弗氏鼠白血病病毒，这些等位基因先前已显示在细胞培养中能差异中和A3G，或者最初是在原发性HIV - 1分离株中发现的。对表达不同水平人类A3G的转基因小鼠进行感染表明，这些天然存在的Vif变体在体内感染期间对抗A3G的能力有所不同，尽管对病毒复制的影响与在培养细胞中观察到的并不相同。我们还发现，减弱病毒复制的多态性Vif仅在A3G转基因小鼠中恢复为野生型。最后，我们发现A3G介导的脱氨基水平与病毒复制水平呈负相关。这个动物模型对于研究天然存在的Vif多态性的功能意义以及在存在A3G的情况下病毒的进化应该是有用的。
