Double-Negative T cells in SIV and HIV Infections

SIV 和 HIV 感染中的双阴性 T 细胞

• 批准号: 8472130
• 负责人: Donald L Sodora
• 金额: $ 63.02万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472130
• 关键词: Acquired Immunodeficiency Syndrome; Address; African; Am 80; Animals; Antigens; Biopsy; Blood; CD28 gene; CD3 Antigens; CD4 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell physiology; Cells; Cercocebus; Cercocebus atys; Chronic; Clinical; Collaborations; Data; Disease; Disease Outcome; Disease Progression; Evaluation; Exhibits; Flow Cytometry; Future; Gene Expression Profile; Genes; Goals; HIV; HIV Infections; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune response; Immune system; Immunization; Individual; Infection; Interleukin-7; Keyhole Limpet Hemocyanin; Laboratories; Macaca; Macaca mulatta; Maintenance; Mature T-Lymphocyte; Mediating; Memory; Modeling; Monkeys; Pathogenesis; Patients; Peptides; Phenotype; Poly I-C; Prevention; Primates; Resistance; SIV; Signal Pathway; T memory cell; T-Cell Depletion; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF6 gene; Testing; Th1 Cells; Th2 Cells; Therapeutic; Therapeutic Intervention; Thymus Gland; Undifferentiated; Viremia; Virus Replication; Work; cohort; cytokine; defined contribution; design; immune activation; improved; lymph nodes; nonhuman primate; pathogen; peripheral blood; rectal; research study; response

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.

描述（由申请人提供）：许多非洲非人灵长类动物，包括白眉猴，是SIV的天然宿主，并与各自的SIV共同进化了至少30，000年。对SIV感染自然宿主物种的研究从两个基本方面极大地影响了我们对艾滋病发病机制的认识。首先，预防疾病进展不需要抑制病毒复制，因为天然SIV宿主尽管存在高水平的病毒血症，但仍无临床体征。其次，艾滋病的缺乏与慢性感染期间系统免疫激活水平低有关。Sodora实验室已经建立了一组SIV感染的白眉猴，这些白眉猴意外地出现了严重的CD 4 + T细胞耗竭（CD 4血液水平<80个细胞/ul），但仍然没有进展为AIDS。这些“CD 4-低”动物挑战了目前的范式，即非常低的CD 4 + T细胞计数与长期存活不相容。SIV感染的CD 4-低水平白眉猴队列引发的关键未解问题是：这些不稳定的白眉猴如何在如此少的CD 4 + T细胞的情况下维持表面上正常的T辅助细胞功能？在该提案中，我们将检验以下假设：CD 3 + CD 4-CD 8-双阴性（DN）T细胞在CD 4-低SIV感染的恒河猴中提供基本的T辅助细胞功能，允许维持正常的免疫系统，而DN T细胞功能在人/猕猴中病原性HIV/SIV感染后的CD 4 + T细胞耗竭期间是次优的。由于缺乏CD 4受体，DN T细胞固有地抵抗SIV感染。除了研究这些细胞在白眉猴中的功能外，我们还将研究DN T细胞在人类和猕猴的致病性HIV和SIV感染期间作为辅助细胞的潜力。在以前的研究中，我们已经证明，在CD 4-低SIV感染的白眉猴中，DN T细胞：（i）在外周血中以相对高的水平存在，无论是在感染之前还是之后， SIV感染;（ii）可以是SIV特异性的并响应于SIV肽刺激产生细胞因子;（iii）主要表现出中枢记忆T细胞表型;和（iv）产生Th 1、Th 2 和Th 17细胞因子。这些初步数据表明，DN T细胞提供辅助性T细胞样功能，可以帮助免疫应答对SIV和条件致病菌的CD 4-低白眉猴。该提案的具体目标将评估DN T细胞在SIV感染的白眉猴以及两种病原性感染（SIV感染的猕猴和HIV感染的人）中的表型和功能（目标1），以及DN T细胞在免疫白眉猴中进行抗原特异性应答的能力（目标2）。最终，这项工作将提供必要的基本评估，以确定未来的免疫治疗干预是否可能在致病性HIV/SIV感染期间增加DN T细胞的功能。我们设想，改善DN T细胞功能的免疫治疗方法可能会提供一种“功能性治愈”，其中HIV感染者将达到一种非致病性状态， 我们在SIV感染的自然宿主中记录到的。