HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on Non-macrophage-tropic, T-Tropic R5 Envelopes Is Occluded.
HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on Non-macrophage-tropic, T-Tropic R5 Envelopes Is Occluded.
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HIV-1 R5 巨噬细胞亲性包膜糖蛋白三聚体以高亲和力结合 CD4，而非巨噬细胞亲性 T-Tropic R5 包膜上的 CD4 结合位点被封闭。
DOI：
10.1128/jvi.00841-17
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发表时间：
2018
影响因子：
5.4
通讯作者：
Go
中科院分区：
文献类型：
--
作者：
Quitadamo,Briana;Peters,PaulJ;Repik,Alexander;O'Connell,Olivia;Mou,Zhongming;Koch,Matthew;Somasundaran,Mohan;Brody,Robin;Luzuriaga,Katherine;Wallace,Aaron;Wang,Shixia;Lu,Shan;McCauley,Sean;Luban,Jeremy;Duenas-Decamp,Maria;Go
HIV-1 R5变体利用CCR5作为辅助受体感染T细胞和巨噬细胞。从免疫组织和外周血中传播或衍生的R5病毒在介导巨噬细胞感染方面主要效率低下。相反，高嗜巨噬细胞（maci -tropic） R5病毒主要存在于脑组织中，可在脑脊液中检测到，但即使在疾病晚期，也很少出现在免疫组织或血液中。这些嗜巨噬性R5变异携带包膜糖蛋白（Envs），适应利用巨噬细胞上低水平的CD4诱导感染。然而，目前尚不清楚这种适应是由于Env三聚体对CD4亲和力的增加，还是由三聚体结合后的结构重排介导的，后者增加了对辅助受体结合位点的暴露，促进了导致融合和病毒进入的事件。在这项研究中，我们研究了CD4与亲和性和非亲和性Env三聚体的结合，发现CD4- igg与亲和性R5 Env三聚体有效结合，而与非亲和性三聚体的结合则无法检测到。我们的数据表明，CD4结合位点（CD4bs）在非亲和性R5病毒的Env三聚体上被高度阻断。因此，这些病毒可能通过病毒突触感染T细胞，在那里Env和CD4变得高度集中。这种环境将使高亲和性相互作用克服极低的Env-CD4亲和性。hiv R5变异与T细胞和巨噬细胞上的CD4和CCR5受体结合，引发感染。传播的HIV变异感染T细胞但不感染巨噬细胞，这些病毒株即使在疾病晚期也持续存在于免疫组织中。在这里，我们发现HIV包膜蛋白上CD4的结合位点被免疫组织中复制的病毒所阻断。这种阻断可能阻止抗体结合到该位点并中和病毒，但它使病毒与cd4相互作用难以发生。这类病毒可能通过CD4高度集中的细胞接触从T细胞传播到T细胞，并通过低效率的包膜-CD4结合导致感染。我们的数据与旨在诱导针对包膜蛋白上CD4结合位点的抗体的疫苗高度相关。
HIV-1 R5 variants exploit CCR5 as a coreceptor to infect both T cells and macrophages. R5 viruses that are transmitted or derived from immune tissue and peripheral blood are mainly inefficient at mediating infection of macrophages. In contrast, highly macrophage-tropic (mac-tropic) R5 viruses predominate in brain tissue and can be detected in cerebrospinal fluid but are infrequent in immune tissue or blood even in late disease. These mac-tropic R5 variants carry envelope glycoproteins (Envs) adapted to exploit low levels of CD4 on macrophages to induce infection. However, it is unclear whether this adaptation is conferred by an increased affinity of the Env trimer for CD4 or is mediated by postbinding structural rearrangements in the trimer that enhance the exposure of the coreceptor binding site and facilitate events leading to fusion and virus entry. In this study, we investigated CD4 binding to mac-tropic and non-mac-tropic Env trimers and showed that CD4-IgG binds efficiently to mac-tropic R5 Env trimers, while binding to non-mac-tropic trimers was undetectable. Our data indicated that the CD4 binding site (CD4bs) is highly occluded on Env trimers of non-mac-tropic R5 viruses. Such viruses may therefore infect T cells via viral synapses where Env and CD4 become highly concentrated. This environment will enable high-avidity interactions that overcome extremely low Env-CD4 affinities.IMPORTANCEHIV R5 variants bind to CD4 and CCR5 receptors on T cells and macrophages to initiate infection. Transmitted HIV variants infect T cells but not macrophages, and these viral strains persist in immune tissue even in late disease. Here we show that the binding site for CD4 present on HIV's envelope protein is occluded on viruses replicating in immune tissue. This occlusion likely prevents antibody binding to this site and neutralization of the virus, but it makes it difficult for virus-CD4 interactions to occur. Such viruses probably pass from T cell to T cell via cell contacts where CD4 is highly concentrated and allows infection via inefficient envelope-CD4 binding. Our data are highly relevant for vaccines that aim to induce antibodies targeting the CD4 binding site on the envelope protein.