Nef decreases HIV-1 sensitivity to neutralizing antibodies that target the membrane-proximal external region of TMgp41.
Nef decreases HIV-1 sensitivity to neutralizing antibodies that target the membrane-proximal external region of TMgp41.
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DOI：
10.1371/journal.ppat.1002442
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Pizzato M
中科院分区：
文献类型：
--
作者：
Lai RP;Yan J;Heeney J;McClure MO;Göttlinger H;Luban J;Pizzato M
灵长类慢病毒网是病毒在体内持续复制和加速发展为艾滋病所必需的。在探索Nef增加无细胞病毒体感染性的机制的同时，我们研究了Nef和Env之间的功能联系。由于我们未能检测到Nef对病毒粒子相关Env数量的影响，我们通过检测Nef是否会改变HIV-1对针对Env不同特征的药物的敏感性来寻找质变。Nef对两种靶向TMgp41膜近端外区（MPER）的强效中和单克隆抗体2F5和4E10具有高达50倍的抗性。相比之下，Nef对mper特异性nAb Z13e1、肽抑制剂T20、靶向gp120的nAb和其他试剂对HIV-1的中和作用没有影响。从各种HIV-1和SIV分离株中观察到Nef对2F5和4E10中和的抗性，以及从CCR5和cxcr4 -热带病毒、B枝和C枝病毒或初级分离株中观察到携带Env的HIV-1病毒粒子。一组Nef突变体的功能分析显示，这种活性需要Nef肉豆蔻酰化，但它与其他Nef功能（如增强病毒传染性和下调CD4的能力）在遗传上是可分离的。来自MoMLV的糖基化gag取代了Nef，赋予对2F5和4E10的抗性，表明这种活性在不编码Nef的逆转录病毒中是保守的。考虑到已报道的2F5和4E10对MPER识别的膜依赖性，与Z13e1的膜依赖性相反，这里的数据与Nef在病毒粒子膜背景下改变MPER识别的模型是一致的。事实上，Nef和glycosyated - gag降低了2F5和4E10的病毒粒子捕获效率，而其他nab则没有。这些研究表明，Nef保护慢病毒免受最广泛作用的一类中和抗体的侵害。这一新发现的Nef活性对抗hiv -1免疫和艾滋病发病机制具有重要意义。Nef是灵长类慢病毒表达的致病因子。由表达Nef的细胞产生的HIV-1病毒粒子获得未知的修饰，使它们能够以更高的效率感染新的靶细胞。我们假设Nef可能会改变HIV-1 Env糖蛋白的结构或功能。在这项研究中，我们测试了Nef是否通过结合Env的不同部分来改变HIV-1对几种抑制HIV-1的药物的敏感性。我们发现Nef对两种抗体（2F5和4E10）的中和具有10到50倍的抗性，这两种抗体属于最强大的中和剂之一，对广泛的HIV-1分离物具有活性。我们确定Nef降低了这些抗体对病毒颗粒的识别，这些抗体结合到邻近逆转录病毒膜（MPER）的Env结构域。来自不同HIV-1分离株的Env对这种活性同样敏感，并且来自HIV-1和SIV的Nef蛋白都保留了这种活性。通过保护慢病毒免受作用最广泛的一类中和抗体的侵害，Nef的这种新活性可能对艾滋病的发病机制做出了重大贡献。
Primate lentivirus nef is required for sustained virus replication in vivo and accelerated progression to AIDS. While exploring the mechanism by which Nef increases the infectivity of cell-free virions, we investigated a functional link between Nef and Env. Since we failed to detect an effect of Nef on the quantity of virion-associated Env, we searched for qualitative changes by examining whether Nef alters HIV-1 sensitivity to agents that target distinct features of Env. Nef conferred as much as 50-fold resistance to 2F5 and 4E10, two potent neutralizing monoclonal antibodies (nAbs) that target the membrane proximal external region (MPER) of TMgp41. In contrast, Nef had no effect on HIV-1 neutralization by MPER-specific nAb Z13e1, by the peptide inhibitor T20, nor by a panel of nAbs and other reagents targeting gp120. Resistance to neutralization by 2F5 and 4E10 was observed with Nef from a diverse range of HIV-1 and SIV isolates, as well as with HIV-1 virions bearing Env from CCR5- and CXCR4-tropic viruses, clade B and C viruses, or primary isolates. Functional analysis of a panel of Nef mutants revealed that this activity requires Nef myristoylation but that it is genetically separable from other Nef functions such as the ability to enhance virus infectivity and to downregulate CD4. Glycosylated-Gag from MoMLV substituted for Nef in conferring resistance to 2F5 and 4E10, indicating that this activity is conserved in a retrovirus that does not encode Nef. Given the reported membrane-dependence of MPER-recognition by 2F5 and 4E10, in contrast to the membrane-independence of Z13e1, the data here is consistent with a model in which Nef alters MPER recognition in the context of the virion membrane. Indeed, Nef and Glycosylated-Gag decreased the efficiency of virion capture by 2F5 and 4E10, but not by other nAbs. These studies demonstrate that Nef protects lentiviruses from one of the most broadly-acting classes of neutralizing antibodies. This newly discovered activity for Nef has important implications for anti-HIV-1 immunity and AIDS pathogenesis. Nef is a pathogenic factor expressed by primate lentiviruses. HIV-1 virions produced by cells that express Nef acquire unknown modifications that allow them to infect new target cells with higher efficiency. We hypothesized that Nef might alter the structure or function of the HIV-1 Env glycoproteins. In this study we tested whether Nef alters the sensitivity of HIV-1 to several agents that inhibit HIV-1 by binding to different parts of Env. We found that Nef confers 10 to 50-fold resistance to neutralization by two antibodies (2F5 and 4E10) that belong to one of the most powerful classes of neutralizing agents, which are active against a wide range of HIV-1 isolates. We established that Nef decreases the recognition of the virus particles by these antibodies, which bind to a domain of the Env adjacent to the retroviral membrane (MPER). Env from diverse HIV-1 isolates are equally sensitive to this activity, and Nef proteins derived from both HIV-1 and SIV retain the activity. By protecting lentiviruses from one of the most broadly-acting classes of neutralizing antibodies, this new activity of Nef might make a significant contribution to AIDS pathogenesis.
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