PLoS Genet：科学家揭示为何某些人群对HIV-1天生免疫

  长期以来研究者们一直很好奇为何HIV-1可以使某些个体快速致病，难以使另外一些人群感染，近日，发表在国际杂志PLoS Genetics上的一篇研究报告中，来自明尼苏达大学的研究人员通过开展一项HIV-1的遗传突变及其感染细胞的相关研究，揭示了HIV-1的致命弱点，为开发治疗HIV-1感染的新型疗法提供了一定的希望。

  HIV-1可以通过入侵个体机体中的T淋巴细胞，拦截细胞中自我制造的分子机器，进而来破坏受感染的宿主细胞，从而使得感染个体对其它疾病更加易感。在众多的抗病毒防御机制中有一种名为APOBEC3s的蛋白，其可以阻断HIV-1复制的能力，然而HIV-1有一种自我抵御的机制，即利用名为Vif的蛋白破坏APOBEC3s。

  研究者推测，对HIV-1的不同易感性或许和个体免疫系统中的遗传突变直接相关，研究者在文章中发现，HIV-1的感染可以增强APOBEC3H的产生（APOBEC3H是APOBEC3s的一种），这就显示APOBEC3H或许是HIV-1反击的关键；利用分离功能性诱变技术，研究人员发现，不同个体机体中存在不同潜力的APOBEC3H，同时还携带有一些表达稳定的蛋白质。如果感染性病毒存在微弱的Vif蛋白时，那么稳定性的突变就会有效限制HIV-1复制的能力。

  研究者Refsland指出，本文研究中揭示了病毒和人类宿主之间的竞争，结果显示病毒并不能完全在宿主体内完全展现自己复制的能力；利用蛋白质Vif和APOBEC3之间的多面性关系，研究人员下一步计划揭示如何阻断Vif对APOBEC3的失活作用。

  目前研究人员表示，我们可以推测一种阻断Vif结合APOBEC3的药物，这或许才是真正杀灭HIV的途径，而且我们必须设计出在感染个体中激活该路径的方法，那么诸如这样的路径或许就可以真正抑制病毒的复制进而抑制其感染。（转化医学网360zhyx.com）

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转化医学网推荐的原文摘要：

Natural Polymorphisms in Human APOBEC3H and HIV-1 Vif Combine in Primary T Lymphocytes to Affect Viral G-to-A Mutation Levels and Infectivity
PLoS Genetics DOI: 10.1371/journal.pgen.1004761
Refsland EW, Hultquist JF, Luengas EM, Ikeda T, Shaban NM, et al.
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.