Natural polymorphisms in human APOBEC3H and HIV-1 Vif combine in primary T lymphocytes to affect viral G-to-A mutation levels and infectivity.
Natural polymorphisms in human APOBEC3H and HIV-1 Vif combine in primary T lymphocytes to affect viral G-to-A mutation levels and infectivity.
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DOI：
10.1371/journal.pgen.1004761
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发表时间：
2014-11
期刊：
影响因子：
4.5
通讯作者：
Harris RS
中科院分区：
文献类型：
--
作者：
Refsland EW;Hultquist JF;Luengas EM;Ikeda T;Shaban NM;Law EK;Brown WL;Reilly C;Emerman M;Harris RS
HIV - 1的Vif蛋白通过降解宿主编码的DNA胞嘧啶脱氨酶APOBEC3家族的若干成员来实现病毒复制。宿主APOBEC3基因和病毒vif基因的多态性都有可能影响个体间病毒复制的程度。七个人类APOBEC3基因中遗传多样性最高的是APOBEC3H，它有七种已知的单倍型。过表达研究表明，这些变体中的一部分表达稳定且有活性的蛋白质，而其他变体编码的蛋白质半衰期短，几乎没有抗病毒活性（如果有的话）。我们证明这些稳定/不稳定表型是原代CD4 + T淋巴细胞中内源性APOBEC3H蛋白的固有特性，并以取决于感染病毒的Vif蛋白自然变异的方式赋予对HIV - 1感染的不同抗性。对于APOBEC3H降解功能低下但完全能够抵消APOBEC3D、APOBEC3F和APOBEC3G的HIV - 1，在表达稳定APOBEC3H的淋巴细胞中易受限制和超突变影响，但在表达不稳定APOBEC3H的淋巴细胞中则不然。相反，具有超功能Vif的HIV - 1既能抵消稳定的APOBEC3H蛋白，也能抵消所有其他内源性APOBEC3蛋白，并能高水平复制。我们还发现APOBEC3H蛋白水平在感染时会被诱导升高10倍以上。最后，我们发现稳定/不稳定APOBEC3H单倍型的全球分布与一个关键的超/低功能Vif氨基酸残基的分布相关。这些数据综合起来强烈表明，稳定的APOBEC3H单倍型是体内阻碍HIV - 1复制的屏障，Vif能够适应这些限制压力，并且尚未达到进化平衡。
APOBEC3酶通过抑制逆转录元件（包括HIV - 1）的传播来保护细胞，其方式是阻断逆转录并使单链DNA复制中间体中的胞嘧啶发生突变。HIV - 1的Vif通过标记APOBEC3蛋白使其被蛋白酶体降解来抵消这种限制。APOBEC3H是该蛋白家族中多样性最高的成员。人类有七种不同的APOBEC3H单倍型，其中三种在强制过表达时产生稳定的蛋白质，四种产生不稳定的蛋白质。在这里，我们研究了具有不同单倍型的供体中内源性APOBEC3H的稳定性表型，并探讨了这些稳定性差异以及病毒的自然多样性如何共同决定HIV - 1的感染性。我们发现内源性APOBEC3H单倍型产生稳定或不稳定的蛋白质，并且稳定的APOBEC3H在病毒感染期间被诱导，它限制具有自然发生的低功能但不限制具有超功能Vif等位基因的分离株的复制。我们还发现稳定APOBEC3H等位基因的全球分布与能够介导其降解的HIV - 1 Vif等位基因的流行率相关，这强烈表明病毒的Vif蛋白能够适应受感染个体的APOBEC3H限制潜力。因此，人类APOBEC3H单倍型和病毒Vif等位基因的组合可能有助于解释在疾病进展和病毒传播中观察到的一些差异。
The Vif protein of HIV-1 allows virus replication by degrading several members of the host-encoded APOBEC3 family of DNA cytosine deaminases. Polymorphisms in both host APOBEC3 genes and the viral vif gene have the potential to impact the extent of virus replication among individuals. The most genetically diverse of the seven human APOBEC3 genes is APOBEC3H with seven known haplotypes. Overexpression studies have shown that a subset of these variants express stable and active proteins, whereas the others encode proteins with a short half-life and little, if any, antiviral activity. We demonstrate that these stable/unstable phenotypes are an intrinsic property of endogenous APOBEC3H proteins in primary CD4+ T lymphocytes and confer differential resistance to HIV-1 infection in a manner that depends on natural variation in the Vif protein of the infecting virus. HIV-1 with a Vif protein hypo-functional for APOBEC3H degradation, yet fully able to counteract APOBEC3D, APOBEC3F, and APOBEC3G, was susceptible to restriction and hypermutation in stable APOBEC3H expressing lymphocytes, but not in unstable APOBEC3H expressing lymphocytes. In contrast, HIV-1 with hyper-functional Vif counteracted stable APOBEC3H proteins as well as all other endogenous APOBEC3s and replicated to high levels. We also found that APOBEC3H protein levels are induced over 10-fold by infection. Finally, we found that the global distribution of stable/unstable APOBEC3H haplotypes correlates with the distribution a critical hyper/hypo-functional Vif amino acid residue. These data combine to strongly suggest that stable APOBEC3H haplotypes present as in vivo barriers to HIV-1 replication, that Vif is capable of adapting to these restrictive pressures, and that an evolutionary equilibrium has yet to be reached. The APOBEC3 enzymes protect cells by inhibiting the spread of retroelements, including HIV-1, by blocking reverse transcription and mutating cytosines in single-stranded DNA replication intermediates. HIV-1 Vif counteracts restriction by marking APOBEC3 proteins for proteasomal degradation. APOBEC3H is the most diverse member of this protein family. Humans have seven distinct APOBEC3H haplotypes with three producing stable and four producing unstable proteins upon forced overexpression. Here, we examine the stability phenotype of endogenous APOBEC3H in donors with different haplotypes and address how these stability differences, as well as natural viral diversity, combine to determine HIV-1 infectivity. We found that endogenous APOBEC3H haplotypes yield stable or unstable proteins and that stable APOBEC3H is induced during viral infection and restricts the replication of isolates with naturally occurring hypo-functional but not hyper-functional Vif alleles. We also found that the global distribution of stable APOBEC3H alleles correlates with the prevalence of HIV-1 Vif alleles capable of mediating its degradation, strongly suggesting that the viral Vif protein is capable of adapting to the APOBEC3H restriction potential of an infected individual. Thus, the combination of human APOBEC3H haplotypes and virus Vif alleles may help account for some of the observed disparities in disease progression and virus transmission.
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影响因子：
64.8
作者：
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影响因子：
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影响因子：
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