Double-Negative T cells in SIV and HIV Infections

描述（由申请人提供）：许多非洲非人类灵长类动物，包括黑白眉猴，是SIV的天然宿主，并与各自的SIV共同进化了至少3万年。对自然宿主物种中SIV感染的研究在两个基本方面极大地影响了我们对艾滋病发病机制的看法。首先，预防疾病进展并不需要抑制病毒复制，因为尽管病毒血症水平很高，天然SIV宿主仍然没有临床症状。其次，在慢性感染期间，没有艾滋病与低水平的全身免疫激活有关。Sodora实验室已经建立了一个siv感染的白眉猴队列，这些白眉猴意外地出现了严重的CD4+ T细胞耗损（CD4血液水平<80细胞/毫升），但仍然没有发展为艾滋病。这些“CD4-低”的动物挑战了目前的范式，即非常低的CD4+ T细胞计数与长期生存不相容。siv感染的CD4-低水平白眉猴引起的关键问题是：这些黑白眉猴是如何在CD4+ T细胞如此少的情况下维持表面上正常的T辅助细胞功能的？在本提案中，我们将验证CD3+CD4- cd8 -双阴性（DN） T细胞在CD4-低SIV感染的黑白眉鸟中提供基本的T辅助细胞功能，从而维持正常的免疫系统，而在人类/猕猴致病性HIV/SIV感染后CD4+ T细胞耗竭期间，DN T细胞功能是次优化的。由于缺乏CD4受体，DN T细胞固有地抵抗SIV感染。除了研究这些细胞在黑白眉鸥中的功能外，我们还将研究在人类和猕猴的致病性HIV和SIV感染过程中，DN T细胞作为辅助细胞的潜力。在之前的研究中，我们已经证明，在cd4 -低siv感染的黑白眉猴中，DN T细胞：(i)在感染之前和之后的外周血中都存在相对较高的水平

DESCRIPTION (provided by applicant): Numerous African non-human primates, including the sooty mangabeys, are natural hosts of SIV and have co- evolved with their respective SIVs for at least 30,000 years. Studies of SIV infections in natural host species have dramatically influenced the way we think about AIDS pathogenesis in two fundamental ways. First, prevention of disease progression does not require suppression of virus replication, as natural SIV hosts remain free of clinical signs despite high levels of viremia. Second, the absence of AIDS correlates with low levels of systemic immune activation during chronic infection. The Sodora laboratory has established a cohort of SIV-infected mangabeys that unexpectedly developed severe CD4+ T cell depletion (CD4 blood levels are <80 cells/ul) but still do not progress to AIDS. These "CD4-low" animals challenge the current paradigm that very low CD4+ T cell counts are not compatible with long term survival. The key unanswered question that the SIV-infected CD4-low mangabey cohort invokes is: How do these sooty mangabeys maintain ostensibly normal T helper cell function with so few CD4+ T cells? In this proposal we will test the hypothesis that CD3+CD4-CD8- double-negative (DN) T cells provide basic T helper cell functions in CD4-low SIV-infected sooty mangabeys, allowing for maintenance of a normal immune system, whereas DN T cell function is sub- optimal during the CD4+ T cell depletion that follows pathogenic HIV/SIV infections in humans/macaques. DN T cells are inherently resistant to SIV infection due to the absence of the CD4 receptor. In addition to studying the function of these cells in sooty mangabeys, we will investigate the potential for DN T cells to function as helper cells during pathogenic HIV and SIV infections of humans and macaques. In previous studies, we have demonstrated that in CD4-low SIV-infected sooty mangabeys, DN T cells: (i) Are present at relatively high levels in peripheral blood both prior to and following an SIV infection; (ii) Can be SIV specific and produce cytokines in response to SIV peptide stimulation; (iii) Principally exhibit a central memory T cell phenotype; and (iv) Produce Th1, Th2 and Th17 cytokines. These preliminary data indicate that the DN T cells provide helper T cell like function that could assist in immune responses against both SIV and opportunistic pathogens in CD4-low mangabeys. The specific aims of the proposal will assess phenotype and function of DN T cells in SIV-infected mangabeys as well as in two pathogenic infections, SIV-infected macaques and HIV infected humans (Aim 1), as well as the ability of DN T cells to make antigen specific responses in immunized mangabeys (Aim 2). Ultimately, this work will provide the basic evaluations necessary to determine if a future immune therapeutic intervention to increase function of DN T cells during pathogenic HIV/SIV infections is possible. We envision that immune therapeutic approaches improving DN T cell function may provide a 'Functional Cure' in which HIV-infected individuals will achieve a non-pathogenic state that is similar to what we have documented in SIV-infected natural hosts.