Mechanisms of HIV-1-Specific CD4+ T Cell Dysfunction

描述(由申请人提供)：人们认为HIV-1特异性的CD4+T细胞对于在慢性感染者体内控制HIV-1复制是重要的。然而，不受控制的慢性HIV-1感染的特点是缺乏强烈的HIV-1特异性CD4+T细胞增殖反应。我们发现在HIV-1复制不受抑制的情况下，产生细胞因子的CD4+T细胞的频率和增殖之间存在不一致。然而，HIV-1特异性增殖功能障碍背后的机制尚不清楚，但它可能是多因素的，可能涉及无能、细胞死亡或CD4+T细胞分化缺陷。需要检验的假设是，HIV-1复制导致HLV-1特异性T细胞无能、激活诱导细胞死亡(AICD)和CD4+T细胞成熟缺陷，所有这些都可能导致观察到的增殖缺陷。将采取以下具体目标：(1)确定在病毒活跃复制的受试者中存在的HIV-1特异性CD4+T细胞是否在功能上无能，如果是，则检查在这种情况下T细胞低反应的潜在机制。(2)确定在活动性复制的受试者中存在的HIV-1特异性CD4+T细胞是否在体外刺激后死亡，并确定激活诱导细胞死亡(AICD)或直接细胞溶解在丧失HIV-1特异性CD4+T细胞增殖中所起的作用。(3)检测HIV-1特异性CD4+T细胞的分化或成熟状态，并将T细胞成熟状态与T细胞功能状态联系起来。

DESCRIPTION (provided by applicant): It is thought that HIV-1-specific CD4+ T cells are important for the in vivo control of HIV-1 replication in chronically infected individuals. However, the hallmark of uncontrolled, chronic HIV-1 infection is the absence of strong HIV-1-specific CD4+ T cell proliferative responses. We have shown a discordance between the frequency of cytokine producing CD4+ T cells and proliferation in the setting of unchecked HIV-1 replication. However, the mechanism behind the HIV-1-specific proliferation dysfunction remains unclear but it is mosl likely multifactorial and may involve anergy, cell death, or defects in CD4+ T cell differentiation. The hypothesis to be tested is that HIV-1 replication results in HlV-1-specific T cell anergy, activation induced ceL death (AICD), and CD4+ T cell maturational defects, all of which may contribute to the observed proliferative defect. The following specific aims will be undertaken: (1) To determine if HIV-1-specific CD4+ T cells present in subjects with active viral replication are functionally anergic, and if so, to examine the mechanisms underlying T cell hypo-responsiveness in this setting. (2) To determine if HIV-1-specific CD4+ T cells present in subjects with active replication are dying after in vitro stimulation and to determine the role that activation induced cell death (AICD) or direct cytolysis play in the loss of HIV-1-specific CD4+ T cell proliferation. (3) To examine the differentiation or maturation states of HIV-1-specific CD4+ T cells and to relate T cell maturation state to T cell functional capacity in subjects with and without active viral replication.