Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Cell Rep. 2020 Mar 17;30(11):3766-3777.e6. doi: 10.1016/j.celrep.2020.02.100.
Disruption of cyclophilin A (CypA)-capsid interactions affects HIV-1 replication in human lymphocytes. To understand this mechanism, we utilize human Jurkat cells, peripheral blood mononuclear cells (PBMCs), and CD4 T cells. Our results show that inhibition of HIV-1 infection caused by disrupting CypA-capsid interactions is dependent on human tripartite motif 5α (TRIM5α), showing that TRIM5α restricts HIV-1 in CD4 T cells. Accordingly, depletion of TRIM5α in CD4 T cells rescues HIV-1 that fail to interact with CypA, such as HIV-1-P90A. We found that TRIM5α binds to the HIV-1 core. Disruption of CypA-capsid interactions fail to affect HIV-1-A92E/G94D infection, correlating with the loss of TRIM5α binding to HIV-1-A92E/G94D cores. Disruption of CypA-capsid interactions in primary cells has a greater inhibitory effect on HIV-1 when compared to Jurkat cells. Consistent with TRIM5α restriction, disruption of CypA-capsid interactions in CD4 T cells inhibits reverse transcription. Overall, our results reveal that CypA binding to the core protects HIV-1 from TRIM5α restriction.
环孢素 A（CypA）-衣壳相互作用的破坏会影响人类淋巴细胞中的 HIV-1 复制。为了理解这种机制，我们利用人类 Jurkat 细胞、外周血单核细胞（PBMC）和 CD4 T 细胞。我们的结果表明，破坏 CypA-衣壳相互作用对 HIV-1 感染的抑制作用依赖于人类三肽基 5α（TRIM5α），表明 TRIM5α 限制了 CD4 T 细胞中的 HIV-1。因此，CD4 T 细胞中 TRIM5α 的耗竭可挽救无法与 CypA 相互作用的 HIV-1，例如 HIV-1-P90A。我们发现 TRIM5α 与 HIV-1 核心结合。破坏 CypA-衣壳相互作用不能影响 HIV-1-A92E/G94D 感染，这与 TRIM5α 与 HIV-1-A92E/G94D 核心结合的丧失有关。与 Jurkat 细胞相比，原代细胞中 CypA-衣壳相互作用的破坏对 HIV-1 的抑制作用更大。与 TRIM5α 限制一致，CD4 T 细胞中 CypA-衣壳相互作用的破坏抑制逆转录。总的来说，我们的结果表明 CypA 与核心的结合保护 HIV-1 免受 TRIM5α 的限制。
