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

摘要 潜伏的病毒库的持续存在仍然是治愈慢性艾滋病毒感染的障碍。查找 清除和暴露病毒库的有效和无毒的手段一直难以捉摸，被认为是 治愈的主要障碍。由于它们在启动和调节适应性T细胞免疫中起着关键作用， 树突状细胞(DC)一直是癌症和HIV的治疗靶点。我们最新的发现表明 在优化编程的情况下，DC具有刺激潜力，既可以推动HIV特异性细胞毒的扩张 T细胞淋巴细胞(CTL)，并有效诱导HIV潜伏期逆转(LR)，使感染细胞暴露于CTL 锁定目标并予以淘汰。我们已经确定我们产生IL-12p70的特殊类型-1极化 单核细胞来源的DC治疗平台(MDC1)在负载CMV或HIV时可促进HIV LR 免疫原肽，表明HIV细胞储存库的相当大部分包含 在CMV和HIV特异性的CD4+T细胞中。在此，我们提出了基于mdc1的免疫治疗的优化方案。 利用与MHC II类相关的CMV表位以及高度保守的MHC I类限制的策略 HIV多肽作为组合抗原成分设计用于促进CD4+T细胞的暴露 藏匿潜伏的艾滋病毒(“踢”)，并通过艾滋病毒特异性CTL消除它们(“杀”)。在我们建议的研究中，我们 将更深入地挖掘所涉及的机制，我们将转化我们的体外发现来测试这种方法 体内使用人源化的小鼠艾滋病毒感染模型和mdc1免疫疗法。

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.