Slow Receptor Binding of the Noncytopathic HIV-2UC1 Envs Is Balanced by Long-Lived Activation State and Efficient Fusion Activity
Slow Receptor Binding of the Noncytopathic HIV-2UC1 Envs Is Balanced by Long-Lived Activation State and Efficient Fusion Activity
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DOI：
10.1016/j.celrep.2020.107749
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发表时间：
2020-06-09
期刊：
影响因子：
8.8
通讯作者：
Herschhorn, Alon
中科院分区：
文献类型：
--
作者：
Harris, Miranda;Ratnapriya, Sneha;Herschhorn, Alon
许多HIV毒株下调感染细胞表面的CD4受体水平，以防止重复感染。相比之下，罕见的HIV-2(UC1)毒株是非细胞病变的，对感染细胞中的CD4表达没有影响，但在外周血单个核细胞(PBMC)中的复制效率仍然与更多的细胞病变毒株一样高。在这里，我们表明，HIV-2(UC1)环境病毒与CD4受体的相互作用表现出缓慢的结合动力学，而解离动力学在细胞病变菌株的范围内。尽管结合亲和力下降了10-100倍，但HIV-2(UC1)env显示出长寿命的激活状态和有效的融合活性。这些观察表明，HIV-2(UC1)env进化成了低亲和力与改进的、容易触发的分子机制之间的平衡，以中介进入。对冷暴露的抗性，类似于许多主要的HIV-1分离株，以及对sCD4中和的抗性表明，HIV-2(UC1)env优先采样封闭的env构象。我们的数据提供了对艾滋病毒进入机制的洞察。
Many HIV strains downregulate the levels of CD4 receptor on the surface of infected cells to prevent super-infection. In contrast, the rare HIV-2(UC1) strain is noncytopathic and has no effect on CD4 expression in infected cells but still replicates as efficiently as more cytopathic strains in peripheral blood mononuclear cells (PBMCs). Here, we show that HIV-2(UC1) Env interactions with the CD4 receptor exhibit slow association kinetics, whereas the dissociation kinetics is within the range of cytopathic strains. Despite the resulting 10-to 100-fold decrease in binding affinity, HIV-2(UC1) Envs exhibit long-lived activation state and efficient fusion activity. These observations suggest that HIV-2(UC1) Envs evolved to balance low affinity with an improved and readily triggerable molecular machinery to mediate entry. Resistance to cold exposure, similar to many primary HIV-1 isolates, and to sCD4 neutralization suggests that HIV-2(UC1 )Envs preferentially sample a closed Env conformation. Our data provide insights into the mechanism of HIV entry.