Antigen-specific ‘kick and kill’ of the latent HIV reservoir using dendritic cells

摘要 潜伏病毒库的持续存在仍然是治愈慢性HIV感染的障碍。找到一个 清除和暴露病毒储库的有效且无毒的方法一直是难以捉摸的， 治愈的主要障碍由于它们在启动和调节适应性T细胞免疫中的关键作用， 树突状细胞（DC）已经成为癌症和HIV的治疗靶点。我们最新的发现表明， 通过最佳编程，DC具有刺激潜力，既可以驱动HIV特异性细胞毒性药物的扩张， T细胞淋巴细胞（CTL），并有效地诱导HIV潜伏期逆转（LR），使受感染的细胞暴露于CTL 锁定目标和消灭我们已经确定，我们的专门IL-12 p70生产型1极化 单核细胞衍生的DC治疗平台（MDC 1）在负载CMV或HIV时可促进HIV LR 免疫原性肽，这表明HIV细胞库的相当大的组成部分被包含 CMV-和HIV特异性CD 4 + T细胞之间。在这里，我们提出了基于MDC 1的免疫疗法的优化 利用MHC II类相关CMV表位沿着高度保守的MHC I类限制性 HIV肽作为组合抗原成分，设计用于促进CD 4 + T细胞暴露 携带潜伏的HIV（“踢”）和它们被HIV特异性CTL消除（“踢”）。在我们提出的研究中， 我们将更深入地研究所涉及的机制，我们将把我们的体外研究结果转化为测试这种方法， 使用HIV感染的人源化小鼠模型和MDC 1免疫疗法在体内进行。

ABSTRACT The persistence of the latent viral reservoir remains a hurdle for the cure of chronic HIV infection. Finding an effective and non-toxic means to purge and expose the viral reservoir has been elusive and is considered a major barrier to the cure. Because of their pivotal role in the initiation and regulation of adaptive T cell immunity, dendritic cells (DC) have been a therapeutic target for both cancer and HIV. Our most recent findings show that with optimal programming, DC have the provocative potential to both drive expansion of HIV-specific cytotoxic T cell lymphocytes (CTL), and to effectively induce HIV latency reversal (LR) to expose the infected cells for CTL targeting and elimination. We have determined that our specialized IL-12p70-producing type-1 polarized monocyte derived DC therapeutic platform (MDC1) can facilitate HIV LR when loaded with either CMV or HIV immunogenic peptides, suggesting that a considerable component of the HIV cellular reservoir is contained among CMV- and HIV specific CD4+ T cells. Here we propose the optimization of MDC1-based immunotherapy strategy that utilizes MHC class II associated CMV epitopes along with highly conserved MHC class I restricted HIV peptides as combined antigenic components designed to facilitate both the exposure of CD4+ T cells harboring latent HIV (the ‘kick’) and their elimination by HIV specific CTL (the ‘kill’). In our proposed studies we will dig deeper into the mechanisms involved, and we will translate our in vitro findings to test this approach in vivo using a humanized mouse model of HIV infection and MDC1 immunotherapy.