Vaccine-Induced memory CD4T cells and HIV reservoirs

产品说明：研究疫苗的免疫应答是评价免疫能力和研究参与特异性应答的免疫系统组分的有用方法。在2009年，当H1N1流感流行来袭时，我们调查了一组病毒抑制的HIV感染患者，他们接受了联合抗逆转录病毒治疗（cART），以获得对H1N1/09流感疫苗的免疫应答，发现只有约50%的患者产生了血清学应答。我们集中研究了外周记忆性CD 4 T细胞的一个新的亚群，命名为外周（p）T滤泡辅助细胞（Tfh），因为它们的功能与淋巴结（LN）中的Tfh相似，包括生发中心（GC）-Tfh，其在记忆B细胞和浆细胞的发育、诱导抗体亲和力成熟、体细胞超突变和抗体分泌中起关键作用。我们发现疫苗应答者外周血（PB）中的pTfh显示出疫苗接种后的扩增，并且仅在疫苗应答者中支持来自纯化的自体B细胞的抗原特异性抗体产生。此外，pTfh在表型和功能上不同于非pTfh CD 4 T细胞。我们假设pTfh在功能上与LN Tfh相似，并且它们的损伤导致HIV感染患者的B细胞功能较差和抗体产生缺陷。在淋巴结中，最近发现Tfh隔室高度允许HIV/SIV感染和复制，并且这些细胞在慢性HIV/SIV感染中经历扩增。在初步研究中，我们发现与接受cART的患者的CD 4 T细胞区室中的非pTfh细胞相比，外周血中的pTfh细胞表现出更高频率的诱导型HIV。我们假设像GCTfh一样，CD 4 TCM细胞内的pTfh细胞亚群是HIV感染和复制的优选区室。本申请的一个目的是研究pTfh在HIV感染的不同临床情况下的表型和功能特征 并与淋巴结Tfh进行比较。我们有三个具体目标：1。描述季节性流感疫苗接种后HIV感染患者的pTfh特征。2.纵向表征启动cART的HIV感染患者中的pTfh。3.检查pTfh中的HIV负荷和诱导型HIV，并比较pTfh和LN Tfh隔室中的病毒。这项研究是重要的，因为循环pTfh是容易获得的细胞，可以作为疫苗反应的有希望的生物标志物，并作为操纵抗体反应和HIV储库的治疗靶点。

DESCRIPTION: Study of immune response to vaccines is a useful way to evaluate immune competence and to study components of the immune system involved in the specific response. In 2009, when the H1N1 influenza epidemic struck, we investigated a group of virally suppressed HIV-infected patients on combination antiretroviral therapy (cART) for immune responses to the influenza H1N1/09 vaccine, and found that only about 50% mounted a serologic response. We focused on a novel subset of peripheral memory CD4 T cells designated as peripheral (p) T follicular helper cells (Tfh) because of their functional similaritis to Tfh in lymph nodes (LN), including germinal center (GC)-Tfh, that play a critical role in development of memory B cells and plasma cells, inducing antibody affinity maturation, somatic hypermutation and antibody secretion. We found that the pTfh in peripheral blood (PB) of vaccine responders showed expansion post- vaccination and supported antigen specific antibody production from purified autologous B cells only in vaccine responders. Moreover, pTfh were phenotypically and functionally distinct from non-pTfh CD4 T cells. We hypothesize that the pTfh are functionally similar to LN Tfh, and that their impairment results in poor B cell function and deficient antibody production in HIV infected patients. In lymph nodes The Tfh compartment has recently been found to be highly permissive for HIV/SIV infection and replication and these cells undergo expansion in chronic HIV/SIV infection. In preliminary studies we found the pTfh cells in peripheral blood to manifest higher frequencies of inducible HIV as compared to non-pTfh cells in the CD4 T cell compartment of patients on cART. We hypothesize that like the GCTfh, the pTfh cell subset within the CD4 TCM cells is a preferred compartment for HIV infection and replication. A goal of this application is to investigate phenotypic and functional characteristics of pTfh in different clinical situations of HIV infection and to compare them with lymph node Tfh. We have 3 specific aims: 1. To characterize pTfh in HIV infected patients following seasonal influenza vaccination. 2. To characterize pTfh longitudinally in HIV infected patients initiating cART. 3. To examine HIV burden and inducible HIV in pTfh and to compare viruses in pTfh and LN Tfh compartments. This research is significant as circulating pTfh are easily accessible cells that could emerge as promising biomarkers of vaccine responses and as therapeutic targets for manipulating antibody responses and HIV reservoirs.