CD4 T cells and anti-viral control in SIV infection

描述（由申请人提供）：HIV感染的特点是在感染早期CD4 T细胞大量丢失。这与HIV特异性CD4 T细胞在HIV感染过程中被优先感染和破坏的证明相结合，表明免疫系统产生抗病毒免疫反应以控制HIV的能力在HIV感染的早期就严重受损。最近在小动物模型和初次感染期间接受抗逆转录病毒治疗（ART）的HIV感染者中进行的研究表明，CD4 T细胞的早期丢失可能对抗病毒CDS T细胞反应的产生和维持具有重要意义。CD4 T细胞在CDS介导的HIV感染控制中的确切作用尚未完全阐明。本研究的长期目标是描述CD4 T细胞在产生抗病毒免疫反应中的作用，并确定这些反应如何与感染的持久控制和长期结果相关。本提案的具体目的是：(1)确定早期开始抗逆转录病毒治疗是否可以保存外周和粘膜组织中的CD4 T细胞，以及这种保存是否与抗病毒CDS T细胞反应性质的质变相关(2)检查CDS T细胞反应性质的质变是否与持久的病毒控制和停止抗逆转录病毒治疗后有利的长期结果相关。我们假设早期ART将保存CD4 T细胞，这反过来将导致产生更强、更有效的多功能CDS T细胞反应，这将有助于更好地控制病毒感染。本研究将使用感染SIVmac239并经PMPA和FTC治疗的恒河猴。采用多色流式细胞术和分子技术检测抗逆转录病毒治疗后外周血和粘膜组织中CD4 T细胞的保存程度。SIV特异性CDS T细胞反应将通过使用细胞内染色和多色流式细胞术同时测量多种功能标记来评估。这些研究将为CD4 T细胞在CDS介导的HIV感染控制中的作用提供极有价值的见解，并将有助于开发更好的治疗方法来持久控制HIV感染。

DESCRIPTION (provided by applicant): HIV infection is characterized by an extensive loss of CD4 T cells very early during infection. This coupled with the demonstration that HIV specific CD4 T cell are preferentially infected and destroyed during the course of HIV infection suggests that the ability of the immune system to generate anti-viral immune responses to control HIV is severely compromised very early during HIV infection. Recent studies in small animal modes and HIV infected subjects treated with anti-retroviral therapy (ART) during primary infection indicate that early loss of CD4 T cells may have significant implications for the generation and maintenance of anti-viral CDS T cell responses. The exact role of CD4 T cells in CDS mediated control of HIV infection has not been completely delineated. The long term objectives of this study are to delineate the role of CD4 T cell help in the generation of anti-viral immune responses, and to determine how these responses correlate with durable control of infection and long term outcome. The Specific Aims of this proposal are (1) to determine if early initiation of ART can preserve CD4 T cells in peripheral and mucosal tissues, and if this preservation correlates with qualitative changes in the nature of anti-viral CDS T cell responses (2) to examine if the qualitative differences in the nature of CDS T cell responses correlate with durable viral control and favorable long term outcome after cessation of ART. We hypothesize that early ART will preserve CD4 T cells that in turn will lead to generation of stronger and more effective poly functional CDS T cell responses that will aid in better control of viral infection. Rhesus macaques infected with SIVmac239 and treated with PMPA and FTC will be used in this study. The degree of CD4 T cell preservation in both peripheral and mucosal tissues after ART will be determined using multi-color flow cytometry and molecular techniques. SIV specific CDS T cell responses will be evaluated by measuring multiple functional markers simultaneously using intracellular staining and multi-color flow cytometry. These studies will provide extremely valuable insights into the role of CD4 T cells in CDS mediated control of HIV infection, and will help develop better therapeutic approaches for durable control of HIV infection.