HIV 1 SPECIFIC CD4 CELLS IN DISEASE PATHOGENESIS

描述(改编自《调查者摘要》)：艾滋病毒的比较 感染其他获得保护性免疫的病毒疾病， 揭示了HIV-1感染最明显的缺陷是缺乏 病毒特异性的CD4辅助细胞功能。沃克博士的实验室最近 在一组人类免疫缺陷病毒的子集中发现了强大的HIV特异性的CD4增殖反应 病毒载量极低的长期非进展型(LTNP)，提供 确凿的证据表明，艾滋病毒可以引起这种反应。这个 研究人员假设HIV患者的CD4辅助细胞功能丧失 感染者由于这些细胞的激活和耗尽在 伴随初次感染的病毒血症高峰期。此外， 他们推测，有效的抗病毒疗法可能能够恢复这些 反应，而这些细胞的持久性是 维持无症状状态以及B细胞对 病毒蛋白。另一种假说认为，树突状细胞是一种 导致CD4辅助T细胞选择性死亡的关键因素。致信地址 后一种假设，私家侦探将利用相当大的 拉尔夫·斯坦曼博士在树突状细胞领域的互补专业知识 以及约翰·摩尔博士在体液免疫领域的研究。的集体目标 IRPG将学习如何对HIV-1产生更好的抵抗力。这个 调查人员特别建议a)确定增殖剂 低病毒载量和高病毒载量LTNP对HIV-1 p24和gp160的应答，快速 进度指标和最近的血清转化器；b)确定组合 在血清转换时或期间进行抗逆转录病毒治疗 慢性感染可恢复HIV-1特异性增殖反应；c) 根据细胞因子的产生和靶点定义辅助细胞的反应 表位，使用呈递HIV-1和CD4T细胞的树突状细胞簇作为 用于克隆HIV特异的CD4细胞系的来源；d)确定APC的作用 在维持艾滋病毒特异性辅助细胞功能方面；和e)确定 通过树突状细胞呈递感染性病毒是否会导致 T辅助细胞选择性死亡。

DESCRIPTION (Adapted from the Investigator's Abstract): A comparison of HIV infection to other viral diseases in which protective immunity is achieved, reveals that the most glaring defect in HIV-1 infection is the lack of virus-specific CD4 helper cell function. Dr. Walker's laboratory recently identified vigorous HIV-specific CD4 proliferative responses in a subset of long-term non-progressors (LTNP) with extremely low viral loads, providing conclusive evidence that such responses can be elicited by HIV. The investigators hypothesize that CD4 helper cell function is lost in HIV infected persons due to activation and depletion of these cells during the period of peak viremia which accompanies primary infection. Furthermore, they hypothesize that potent antiviral therapy may be able to restore these responses, and the persistence of these cells is a key factor in the maintenance of both the asymptomatic state as well as B cell responses to viral proteins. An additional hypothesis states that dendritic cells are a key factor in leading to selective death of CD4 helper T-cells. To address this latter hypothesis, the P.I. will draw upon the considerable complementary expertise of Dr. Ralph Steinman in the area of dendritic cells and Dr. John Moore in the area of humoral immunity. The collective goal of the IRPG is to learn to generate better resistance to HIV-1. The investigators specifically propose to a) determine the proliferative response to HIV-1 p24 and gp160 in LTNP with low and high viral loads, rapid progressors, and recent seroconvertors; b) determine whether combination antiretroviral therapy administered at the time of seroconversion or during chronic infection can restore HIV-1 specific proliferative responses; c) define helper cell responses in terms of cytokine production and target epitopes, using dendritic cell clusters presenting HIV-1 and CD4 T cells as a source for cloning HIV-specific CD4 cell lines; d) define the role of APC in maintenance of HIV-specific helper cell function; and e) determine whether presentation of infectious virions via dendritic cells leads to selective death of T helper cells.