Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, United States of America.
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261, United States of America.
EBioMedicine. 2019 May;43:295-306. doi: 10.1016/j.ebiom.2019.03.077. Epub 2019 Apr 2.
Despite the success of antiretroviral therapy (ART), latent HIV-1 continues to persist in a long-lived population of resting memory CD4 T cells within those who are infected. Finding a safe and effective means to induce latency reversal (LR) during ART to specifically expose this latent HIV-1 cellular reservoir for immune elimination has been a major barrier to a functional cure.
In this study, we test the use of antigen-presenting type 1-polarized, monocyte-derived dendritic cells (MDC1) generated from chronic HIV-1-infected individuals on ART as a means to induce HIV-1 latency reversal in autologous CD4 T cells harboring replication-competent provirus. We use the same MDC1 for ex-vivo generation of autologous HIV-1 antigen-specific CD8 cytotoxic T cells (CTL) and test their effector responses against the MDC1-exposed HIV-1- infected CD4 T cell targets.
MDC1 presentation of either HIV-1 or cytomegalovirus (CMV) antigens to CD4 T cells facilitated HIV-1 LR. This antigen-driven MDC1-mediated LR was sharply diminished with blockade of the CD40L/CD40 'helper' signaling pathway. Importantly, these antigen-presenting MDC1 also activated the expansion of CTL capable of killing the exposed HIV-1-infected targets.
Inclusion of virus-associated MHC class II 'helper' antigens in MDC1-based HIV-1 immunotherapies could serve both as a targeted means to safely unmask antigen-specific CD4 T cells harboring HIV-1, and to support CTL responses that can effectively target the MDC1-exposed HIV-1 cellular reservoir as a functional cure strategy. FUND: This study was supported by the NIH-NAID grants R21-AI131763, U01-AI35041, UM1-AI126603, and T32-AI065380.
尽管抗逆转录病毒疗法（ART）取得了成功，但感染 HIV 的人群中，静息记忆 CD4 T 细胞中仍存在持续存在的潜伏 HIV-1。寻找一种安全有效的方法，在 ART 期间诱导潜伏逆转（LR），专门暴露这种潜伏的 HIV-1 细胞储库，以进行免疫清除，一直是实现功能性治愈的主要障碍。
在这项研究中，我们测试了来自接受 ART 的慢性 HIV-1 感染个体的抗原呈递 1 型极化单核细胞衍生树突状细胞（MDC1），作为诱导携带复制能力前病毒的自体 CD4 T 细胞中 HIV-1 潜伏逆转的一种手段。我们使用相同的 MDC1 体外生成自体 HIV-1 抗原特异性 CD8 细胞毒性 T 细胞（CTL），并测试它们对 MDC1 暴露的 HIV-1 感染 CD4 T 细胞靶标的效应反应。
将 HIV-1 或巨细胞病毒（CMV）抗原呈递给 CD4 T 细胞，MDC1 促进了 HIV-1 LR。这种抗原驱动的 MDC1 介导的 LR 在阻断 CD40L/CD40“辅助”信号通路时明显减弱。重要的是，这些抗原呈递的 MDC1 还激活了能够杀伤暴露的 HIV-1 感染靶标的 CTL 的扩增。
将病毒相关的 MHC 类 II“辅助”抗原纳入基于 MDC1 的 HIV-1 免疫疗法中，既可以作为一种安全的靶向手段，揭示携带 HIV-1 的特异性 CD4 T 细胞，又可以支持 CTL 反应，有效地靶向 MDC1 暴露的 HIV-1 细胞储库，作为功能性治愈策略。
本研究由 NIH-NAID 资助 R21-AI131763、U01-AI35041、UM1-AI126603 和 T32-AI065380 资助。
