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

 描述（由申请人提供）： CD 4 + T细胞是HIV-1感染的主要靶细胞，其丧失是HIV-1疾病的标志。然而，滤泡辅助性T（Tfh）细胞，一种专门帮助B细胞形成生发中心（GC）以产生高亲和力类别转换抗体的CD 4 + T细胞的独特亚群，在慢性感染Tfh的患者中扩增。 HIV-1观察到的Tfh细胞扩增不是由于这种细胞类型对HIV-1感染的易感性较低，因为Tfh细胞已被鉴定为HIV-1感染和复制的主要CD 4 + T细胞区室。为什么Tfh细胞更容易复制HIV-1尚不清楚。受感染的Tfh细胞是否有效地恢复到静息记忆状态，成为HIV-1潜伏期的主要储存库也是未知的。我们假设Tfh细胞具有减弱的细胞内在抗病毒免疫，从而使这些细胞更容易受到HIV-1复制的影响。我们还假设一些感染的Tfh细胞存活并恢复到静息记忆状态，成为HIV-1潜伏期的细胞库。为了实现这些假设，我们组建了一个由四名科学家组成的研究团队，他们在细胞内在免疫，Tfh细胞发育，HIV-1发病机制和治疗方面具有互补的专业知识。我们有初步数据显示：（i）Tfh细胞表达显著较低水平的细胞内在抗HIV-1限制因子，包括IFITM 3（干扰素诱导的跨膜蛋白3）和MX2（粘病毒抗性2）比其它CD 4 + T细胞类型更强，这可能归因于转录抑制因子BCL 6的高组成型表达在免疫小鼠中，（B）BCL 6控制记忆性CD 4 + T细胞的发育，和（iii）BCL 6控制CXCR 5 + Tfh细胞的发育。根据这些初步调查结果，我们有三个具体目标要确定：（1）Tfh细胞是否具有减弱的细胞内在抗HIV-1免疫（目标1），（2）HIV-1患者的Tfh相对于非Tfh CD 4 + T细胞中IFITM 3和MX2的水平及其与潜伏感染的Tfh相对于非Tfh CD 4 + T细胞的频率的关系（目标2），以及（3）BCL 6是否控制Tfh细胞存活，以及BCL 6功能的消除是否诱导杀死来自HIV-1患者的长寿命潜伏感染的Tfh细胞（目的3）。与 最终目标是确定和消除感染患者中的HIV-1储库，我们建议利用大量HIV-1患者来识别和表征细胞储库 在HIV-1患者中。我们的研究结果将提供有关HIV-1潜伏期如何建立和维持的见解，并可能导致新的治疗干预措施，用于HIV-1的功能性治愈。

 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.