Targeting latently infected Tfh cells to achieving a functional cure of HIV-1

 描述(由申请人提供)： 项目摘要/摘要CD4T细胞是HIV-1感染的主要靶点，它们的丢失是HIV-1疾病的一个标志。然而，滤泡辅助T细胞(TFH)，一种不同的CD4T细胞亚群，专门帮助B细胞形成生发中心(GC)，用于产生高亲和力的类转换抗体，在慢性感染的患者中扩张。 HIV-1。观察到的TFH细胞的扩张并不是由于这种细胞类型对HIV-1感染的易感性较低，因为TFH细胞已被确定为HIV-1感染和复制的主要CD4T细胞亚群。为什么TFH细胞更允许HIV-1复制，目前尚不清楚。被感染的Tfh细胞是否有效地恢复到静止的记忆状态，成为HIV-1潜伏期的主要储存库也是未知的。我们假设TFH细胞削弱了细胞固有的抗病毒免疫，从而使这些细胞更容易复制HIV-1。我们还假设，一些受感染的TFH细胞存活并恢复到静止的记忆状态，成为HIV-1潜伏期的细胞储存库。为了探索这些假说，我们组成了一个研究小组，由四名在细胞内源性免疫、TFH细胞发育、HIV-1发病机制和治疗方面具有互补专业知识的科学家组成。我们的初步数据显示：(I)Tfh细胞表达细胞固有的抗HIV-1限制因子，包括IFITM3(干扰素诱导的跨膜蛋白3)和MX2(粘病毒耐药2)，这可能归因于Tfh细胞中转录抑制因子BCL6(B细胞淋巴瘤6)的高结构性表达，(Ii)BCL6控制记忆CD4 T细胞的发育，以及(Iii)BCL6控制免疫小鼠CXCR5 Tfh细胞的发育。基于这些初步发现，我们有三个具体目标来确定：(1)Tfh细胞是否削弱了细胞固有的抗HIV-1免疫(Aim 1)，(2)HIV-1患者Tfh与非Tfh CD4 T细胞中IFITM3和MX2的水平及其与潜伏感染Tfh与非Tfh CD4 T细胞的频率的关系(Aim 2)，以及(3)BCL6是否控制Tfh细胞的存活以及BCL6功能的取消是否导致HIV-1患者长期潜伏感染的Tfh细胞被杀伤(Aim 3)。与 我们的最终目标是确定和消除感染患者中的HIV-1宿主，我们建议利用大量的HIV-1患者来识别和表征细胞宿主 在HIV-1患者中。我们的结果将为HIV-1潜伏期是如何建立和维持的提供洞察力，并可能导致针对HIV-1的功能性治愈的新的治疗干预措施。

 DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT CD4+ T cells are the major target for HIV-1 infection, and their loss is a hallmark of HIV-1 disease. However, follicular helper T (Tfh) cells, a distinct subset of CD4+ T cells that are specialized in helping B cells to form germinal centers (GCs) for generation of high-affinity class-switched antibodies, expand in patients chronically infected with HIV-1. The observed Tfh cell expansion is not due to a lower susceptibility of this cell type to HIV-1 infection, as Tfh cells have been identified as a major CD4+ T cell compartment for HIV-1 infection and replication. Why Tfh cells are more permissive of HIV-1 replication is unknown. Whether infected Tfh cells efficiently revert back to a resting memory state to become a major reservoir of HIV-1 latency is also unknown. We hypothesize that Tfh cells have weakened cell-intrinsic antiviral immunity, thereby rendering these cells more susceptible to HIV-1 replication. We also hypothesize that some infected Tfh cells survive and revert back to a resting memory state and become cellular reservoirs of HIV-1 latency. To pursue these hypotheses, we formed a research team consisting of four scientists with complementary expertise in cell-intrinsic immunity, Tfh cell development, HIV-1 pathogenesis, and therapy. We have Preliminary Data showing that (i) Tfh cells express significantly lower levels of cell-intrinsic anti-HIV-1 restricton factors including IFITM3 (interferon-induced transmembrane protein 3) and MX2 (myxovirus resistance 2) than other CD4+ T cell types, which may be attributed to the high constitutive expression of the transcriptional repressor BCL6 (B cell lymphoma 6) in Tfh cells, (ii) BCL6 controls development of memory CD4+ T cells, and (iii) BCL6 controls development of CXCR5+ Tfh cells in immunized mice. Based on these preliminary findings, we have three Specific Aims to determine: (1) whether Tfh cells have weakened cell-intrinsic anti-HIV-1 immunity (Aim 1), (2) the levels of IFITM3 and MX2 in Tfh versus non-Tfh CD4+ T cells from HIV-1 patients and their relationships with the frequency of latently- infected Tfh versus non-Tfh CD4+ T cells (Aim 2), and (3) whether BCL6 controls Tfh cell survival and whether abrogation of BCL6 function induces killing of the long-lived latently infected Tfh cells from HIV-1 patients (Aim 3). With the ultimate goal of defining and eliminating HIV-1 reservoirs in infected patients, we propose to take advantage of a large cohort of HIV-1 patients to identify and characterize cellular reservoirs in HIV-1 patients. Our results will provide insights into how HIV-1 latency is established and maintained, and may lead to new therapeutic interventions for a functional cure of HIV-1.