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

摘要 病毒特异性CD8T细胞对HIV-1和SIV具有很强的抗病毒活性。尽管有丰富的 CD8T细胞反应，这些都不能完全抑制病毒复制。这很可能是因为 发生在CD4+T细胞中的大多数病毒复制集中在 例如次级淋巴组织和肠道组织中的B细胞滤泡。病毒式传播 水库研究表明，SIV和HIV的大部分复制可能发生在肠道 黏膜：ART阻断后，病毒复发的位置、丰度和表型 被感染的细胞还没有被很好地理解。然而，新出现的数据表明，CD4T细胞， 除髓系细胞外，淋巴(LN)和肠道中也是重要的贡献者。因此， 需要开发方法来降低粘膜组织以及LN中的病毒载量， 并更全面地了解非淋巴组织中病毒库的来源。CAR T细胞 可以是免疫控制的有效媒介，这些正在被探索作为艾滋病毒的治疗方法。我们 已经开发并开始测试一种针对HIV/SIV的汽车。在这项研究中，我们开发了 并建议测试表达HIV靶向CAR和CCR9的自体T细胞， 一种将细胞定位于肠粘膜的分子。我们将检验我们的假设 靶向肠道粘膜和B细胞滤泡的HIV特异性T细胞将导致 艾滋病毒的持久缓解。我们提出了两个目的来检验这一假设。目标1：确定 体内定位、持久性和抗病毒疗效及其对肠粘膜、淋巴系统的影响 SIV感染的ART猕猴体内的组织和其他组织病毒库抑制了恒河猴 输注自体CAR/CCR9T细胞。目的2：确定联合治疗是否 同时使用肠道和淋巴滤泡归巢的CAR T细胞在促进 SIV在抗逆转录病毒药物治疗中断后持续缓解。如果成功，这项工作 可能导致一种免疫疗法，导致对艾滋病毒的长期抑制。

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.