HIV-1 adaptation to low levels of CCR5 results in V3 and V2 loop changes that increase envelope pathogenicity, CCR5 affinity and decrease susceptibility to Maraviroc
HIV-1 adaptation to low levels of CCR5 results in V3 and V2 loop changes that increase envelope pathogenicity, CCR5 affinity and decrease susceptibility to Maraviroc
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DOI：
10.1016/j.virol.2016.03.010
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发表时间：
2016-06-01
期刊：
影响因子：
3.7
通讯作者：
Joshi, Anjali
中科院分区：
文献类型：
--
作者：
Garg, Himanshu;Lee, Raphael T. C.;Joshi, Anjali
人群中CCR5水平的变异可能影响病毒的进化、适应度和HIV疾病的进程。我们之前证明了细胞表面CCR5水平直接影响HIV包膜介导的旁观者细胞凋亡。在这项研究中，我们试图了解HIV在低水平CCR5存在下的进化，模拟宿主固有的限制性CCR5水平。在表达低水平CCR5的T细胞系中，HIV-1的适应导致了两种特异性突变；N302Y和E172K。N302Y突变导致低CCR5表达细胞中病毒复制加速、Maraviroc IC50增加和包膜介导的旁观者凋亡增加。B亚型序列分析显示N302Y在CXCR4病毒中比在CCR5病毒中多表达。考虑到个体之间CCR5水平的可变性，我们的研究结果对病毒进化、MVC易感性以及HIV发病机制具有重要意义。(C) 2016 Elsevier Inc.版权所有。
Variability in CCR5 levels in the human population is suggested to affect virus evolution, fitness and the course of HIV disease. We previously demonstrated that cell surface CCR5 levels directly affect HIV Envelope mediated bystander apoptosis. In this study, we attempted to understand HIV evolution in the presence of low levels of CCR5, mimicking the limiting CCR5 levels inherent to the host. HIV-1 adaptation in a T cell line expressing low levels of CCR5 resulted in two specific mutations; N302Y and E172K. The N302Y mutation led to accelerated virus replication, increase in Maraviroc IC50 and an increase in Envelope mediated bystander apoptosis in low CCR5 expressing cells. Analysis of subtype B sequences showed that N302Y is over-represented in CXCR4 tropic viruses in comparison to CCR5 tropic isolates. Considering the variability in CCR5 levels between individuals, our findings have implications for virus evolution, MVC susceptibility as well as HIV pathogenesis. (C) 2016 Elsevier Inc. All rights reserved.