Functional Assessment of CTL Anergy in HIV Infection

描述（由申请方提供）：本提案提出了关于细胞毒性T淋巴细胞在HIV-1感染免疫发病机制中失败的新概念。虽然零散的报道表明可能有表位变异导致CTL“拮抗”或无反应性的例子，但人们对这种现象知之甚少，并且无法确定该过程的散发或广泛程度。我们提出了一个新的假设，并建立了一个案件，HIV-1表位突变导致无能的反应性CTL可能是一个普遍的过程。随着人们对无反应性的了解越来越多，我们将探讨无反应性在CTL控制HIV-1中的作用。我们的具体目标是：目的1：证明表位变异，诱导无反应性的HIV-1特异性CTL。来自感染者的HIV-1特异性TCR将用于通过转导正常的CD 8 + T细胞来产生表型正常的CTL。这些CTL将针对来自相同人的表位变体进行功能性筛选，以鉴定无活力诱导突变体，并使用HIV-1感染的细胞进行确认。目的2：证明体内HIV-1内无活力诱导变体的功能影响。将测试具有HIV-1特异性TCR转导的CTL的人源化SCID小鼠模型通过感染含有表位突变的HIV-1的无反应性诱导。

DESCRIPTION (provided by applicant): This proposal addresses a novel concept regarding the failure of cytotoxic T lymphocytes in the immunopathogenesis of HIV-1 infection. While scattered reports have suggested that there may be examples of epitope variation causing CTL "antagonism" or anergy, the phenomenon has been poorly understood and it has been impossible to determine the degree to which this process is sporadic or widespread. We present a novel hypothesis and build the case that HIV-1 epitope mutation causing anergy of responding CTLs may be a generalized process. Tapping into the growing understanding of anergy in general, we will explore the effect of anergy in CTL control of HIV-1. Our specific aims are: Aim 1: To demonstrate epitope variants that induce anergy in HIV-1-specific CTLs. HIV-1-specific TCRs from infected persons will be used to generate phenotypically normal CTLs by transducing normal CD8+ T cells. These CTLs will be screened functionally against epitope variants from the same persons to identify anergy-inducing mutants, with confirmation using HIV-1-infected cells. Aim 2: To demonstrate the functional impact of anergy-inducing variants within HIV-1 in vivo. A humanized SCID mouse model with HIV-1-specific TCR-transduced CTLs will be tested for anergy induction by infection with HIV-1 containing epitope mutations.