Functional Assessment of CTL Anergy in HIV Infection

描述（由申请人提供）：本提案提出了一个关于细胞毒性T淋巴细胞在HIV-1感染的免疫发病机制中的失败的新概念。虽然零散的报道表明，可能存在表位变异引起CTL“拮抗”或能量的例子，但对这一现象的了解甚少，并且无法确定这一过程在多大程度上是零星的或广泛的。我们提出了一个新的假设，并建立了HIV-1表位突变引起应答ctl的能量可能是一个普遍的过程。随着人们对能量的认识不断加深，我们将探讨能量在CTL控制HIV-1中的作用。我们的具体目标是：目的1：证明在hiv -1特异性ctl中诱导能量的表位变异。来自感染者的hiv -1特异性tcr将通过转导正常CD8+ T细胞来产生表型正常的ctl。这些ctl将对来自同一个人的表位变异进行功能筛选，以识别诱导能量的突变体，并使用hiv -1感染的细胞进行确认。目的2：在体内证明能量诱导变异对HIV-1的功能影响。一个带有HIV-1特异性tcr转导的ctl的人源化SCID小鼠模型将通过感染含有表位突变的HIV-1进行能量诱导测试。

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.