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）：许多非洲非人类灵长类动物，包括烟灰芒果，是SIV的天然寄主，并且已经与各自的SIV共同发展了至少30，000年。自然寄主物种中SIV感染的研究极大地影响了我们以两种基本方式对艾滋病发病机理的看法。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，但天然SIV宿主仍然没有临床体征。其次，缺乏艾滋病与慢性感染期间的全身免疫激活水平低有关。 Sodora实验室已经建立了一系列SIV感染的芒果，这些芒果意外形成了严重的CD4+ T细胞耗竭（CD4血液水平<80细胞/UL），但仍未发展为艾滋病。这些“ CD4-low”动物挑战了当前的范式，即非常低的CD4+ T细胞计数与长期存活不兼容。关键的未解决的问题是，感染了SIV的CD4-LOW MANGABEY队列引用的是：这些烟熏芒果如何在表面上保持正常的T辅助细胞功能，而CD4+ T细胞很少？ 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.由于缺乏CD4受体，DN T细胞对SIV感染具有固有的抗性。除了研究这些细胞在烟熏芒果中的功能外，我们还将研究DN T细胞在病原HIV和人类和猕猴的病原HIV和SIV感染期间充当辅助细胞的潜力。在先前的研究中，我们已经证明，在CD4-low SIV感染的烟灰芒果中，DN T细胞：（i）在外周血中都存在相对较高的水平。 SIV感染； （ii）可以是特异性的，并响应SIV肽刺激而产生细胞因子； （iii）主要表现出中央记忆T细胞表型； （iv）产生Th1，Th2 和Th17细胞因子。这些初步数据表明，DN T细胞提供了类似的辅助T细胞功能，可以帮助CD4-LOW MANGABEYS中的SIV和机会性病原体的免疫反应。该提案的具体目的将评估DN T细胞在SIV感染的芒果中的表型和功能，以及两种致病性感染，SIV感染的猕猴和HIV感染的人（AIM 1）以及DN T细胞在免疫植物中具有抗原特异性反应的能力（AIM 1）。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措施是否可以在病原HIV/SIV感染过程中提高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“功能治愈”，其中HIV感染的个体将获得与类似于什么的非致病状态 我们已经记录了SIV感染的天然寄主。