Division of Microbiology and Immunology, Yerkes National Primate Research Center, and Emory Vaccine Center Emory University, Atlanta, Georgia, United States of America.
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
PLoS Pathog. 2020 Sep 17;16(9):e1008821. doi: 10.1371/journal.ppat.1008821. eCollection 2020 Sep.
MHC-I-restricted, virus-specific cytotoxic CD8+ T cells (CTLs) may control human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication via the recognition and killing of productively infected CD4+ T cells. Several studies in SIV-infected macaques suggest that CD8+ T cells may also decrease virus production by suppressing viral transcription. Here, we show that non-HIV-specific, TCR-activated non-cytolytic CD8+ T cells suppress HIV transcription via a virus- and MHC-independent immunoregulatory mechanism that modulates CD4+ T cell proliferation and activation. We also demonstrate that this CD8+ T cell-mediated effect promotes the survival of infected CD4+ T cells harboring integrated, inducible virus. Finally, we used RNA sequencing and secretome analyses to identify candidate cellular pathways that are involved in the virus-silencing mediated by these CD8+ T cells. This study characterizes a previously undescribed mechanism of immune-mediated HIV silencing that may be involved in the establishment and maintenance of the reservoir under antiretroviral therapy and therefore represent a major obstacle to HIV eradication.
MHC-I 限制性、病毒特异性细胞毒性 CD8+ T 细胞（CTL）可能通过识别和杀伤感染性 CD4+ T 细胞来控制人类免疫缺陷病毒（HIV）和猴免疫缺陷病毒（SIV）的复制。几项 SIV 感染猕猴的研究表明，CD8+ T 细胞也可能通过抑制病毒转录来降低病毒产生。在这里，我们表明非 HIV 特异性、TCR 激活的非细胞毒性 CD8+ T 细胞通过一种与病毒和 MHC 无关的免疫调节机制抑制 HIV 转录，该机制调节 CD4+ T 细胞的增殖和激活。我们还证明，这种 CD8+ T 细胞介导的效应促进了携带整合诱导病毒的感染 CD4+ T 细胞的存活。最后，我们使用 RNA 测序和分泌组分析鉴定了参与这些 CD8+ T 细胞介导的病毒沉默的候选细胞途径。这项研究描述了一种以前未描述的免疫介导的 HIV 沉默机制，它可能参与了在抗逆转录病毒治疗下病毒库的建立和维持，因此代表了 HIV 根除的主要障碍。
