Targeting HIV-specific CAR T cells to the gut for the durable remission of HIV

摘要 病毒特异性CD 8 T细胞对HIV-1和SIV发挥有效的抗病毒活性。尽管丰富 CD 8 T细胞反应，这些都不能完全抑制病毒复制。这可能是由于 大多数病毒复制发生在CD 4 + T细胞集中在特定区域， B细胞滤泡是指淋巴组织中的B细胞滤泡，如次级淋巴组织和肠组织中的B细胞滤泡。病毒 储库研究表明，大多数SIV和HIV复制可能发生在肠道， 粘膜：ART中断后，复发病毒的位置、丰度和表型 受感染的细胞还不太清楚。然而，新的数据表明，CD 4 T细胞， 淋巴结（LN）和肠中的髓样细胞是重要的贡献者。因此，在本发明中， 需要开发降低粘膜组织以及LN中病毒载量的方法， 并更全面地了解非淋巴组织中病毒储库的来源。CAR T细胞 可能是免疫控制的有效介质，这些正在被探索作为艾滋病毒治疗。我们 已经开发并开始测试针对HIV/SIV的CAR。在这项研究中，我们开发了 并提出测试经工程改造以表达HIV靶向CAR和CCR 9的自体T细胞， 一种将细胞定位到肠粘膜的分子。我们将测试我们的假设， 将HIV特异性T细胞靶向肠粘膜以及B细胞滤泡，将导致 艾滋病的持久缓解。我们提出了两个目标来检验假设。目标1：确定 体内定位、持久性和抗病毒效力以及对肠粘膜、淋巴 SIV感染ART抑制恒河猴中的组织和其他组织病毒储库 输注自体CAR/CCR 9 T细胞。目的2：确定联合治疗是否 使用肠和淋巴滤泡归巢CAR T细胞在促进免疫应答方面具有上级优势。 抗逆转录病毒药物治疗中断后SIV持续缓解。如果成功，这项工作 可能会产生一种免疫疗法，从而长期抑制艾滋病毒。

Abstract Virus-specific CD8 T cells exert potent antiviral activity against HIV-1 and SIV. Despite abundant CD8 T cell responses, these are unable to fully suppress virus replication. This is likely due to the majority of viral replication occurring in CD4+ T cells concentrated in specific areas in the body, such as B-cell follicles in secondary lymphoid tissues and in intestinal tissues. Viral reservoir studies indicate that the majority of SIV and HIV replication may occur in the intestinal mucosa: After ART interruption, the location, abundance, and phenotype of recrudescing virally infected cells are not well understood. However, emerging data suggest that both CD4 T cells, as well as myeloid cells, in lymph node (LN) and the intestine are important contributors. Thus, there is a need to develop methods to reduce viral load in mucosal tissues, as well as in LN, and to more fully understand the source of viral reservoirs in non-lymphoid tissues. CAR T cells can be potent mediators of immune control and these are being explored as an HIV therapy. We have developed and begun testing an HIV/SIV targeting CAR. In this study, we have developed and propose to test autologous T cells engineered to express the HIV-targeting CAR and CCR9, a molecule that will target cells to the intestinal mucosa. We will test our hypothesis that targeting HIV-specific T cells to the intestinal mucosa, as well as B cell follicles, will lead to durable remission of HIV. We propose two aims to test the hypothesis. Aim 1: to determine the in vivo localization, persistence and antiviral efficacy and impact on intestinal mucosa, lymphoid tissue, and other tissue viral reservoirs in SIV infected ART suppressed rhesus macaques infused with autologous CAR/CCR9 T cells. Aim 2: to determine whether combination therapy using both intestine- and lymphoid follicle-homing CAR T cells is superior in promoting sustained remission of SIV after antiretroviral drug treatment interruption. If successful, this work may lead to an immunotherapy that leads to long-term suppression of HIV.