HIV-1 Vpu Mediates HLA-C Downregulation.
HIV-1 Vpu Mediates HLA-C Downregulation.
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DOI：
10.1016/j.chom.2016.04.005
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发表时间：
2016-05-11
影响因子：
30.3
通讯作者：
Carrington M
中科院分区：
文献类型：
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作者：
Apps R;Del Prete GQ;Chatterjee P;Lara A;Brumme ZL;Brockman MA;Neil S;Pickering S;Schneider DK;Piechocka-Trocha A;Walker BD;Thomas R;Shaw GM;Hahn BH;Keele BF;Lifson JD;Carrington M
许多病原体通过下调感染细胞表面的人类白细胞抗原分子来逃避细胞毒性T淋巴细胞(CTL)，但人类白细胞抗原的缺失可触发NK细胞介导的溶解。HIV-1被认为通过Nef介导的对HLA-A和-B的下调而不是对HLA-C分子的下调来破坏CTL，同时保留对NK细胞的抑制。我们发现，与实验室适应的NL4-3病毒相比，大多数主要的HIV-1克隆，包括传播的方正病毒，都下调了HLA-C的表达。人类白细胞抗原C的减少是由病毒VPU介导的，并在体外降低了人类白细胞抗原C限制的CTL在CD4+细胞中抑制病毒复制的能力。HLAA/B不受VPU的影响，HIV-1原代克隆下调HLAC的能力不同，可能是对CTL或NK细胞通过HLAC主导免疫压力的反应。HIV-2还通过不同的机制抑制人类白细胞抗原-C的表达，强调了人类白细胞抗原-C对艾滋病毒施加的免疫压力。这种病毒免疫逃避为CTL和NK细胞在抗HIV免疫反应中的作用提供了新的线索。
Many pathogens evade cytotoxic T lymphocytes (CTLs) by downregulating HLA molecules on infected cells, but the loss of HLA can trigger NK cell-mediated lysis. HIV-1 is thought to subvert CTLs while preserving NK cell inhibition by Nef-mediated downregulation of HLA-A and -B but not HLA-C molecules. We find that HLA-C is downregulated by most primary HIV-1 clones, including transmitted founder viruses, in contrast to the laboratory-adapted NL4-3 virus. HLA-C reduction is mediated by viral Vpu and reduces the ability of HLA-C restricted CTLs to suppress viral replication in CD4+ cells in vitro. HLA-A/B are unaffected by Vpu, and primary HIV-1 clones vary in their ability to downregulate HLA-C, possibly in response to whether CTLs or NK cells dominate immune pressure through HLA-C. HIV-2 also suppresses HLA-C expression through distinct mechanisms, underscoring the immune pressure HLA-C exerts on HIV. This viral immune evasion casts new light on the roles of CTLs and NK cells in immune responses against HIV.