The Role of Host Factors in HIV Immunopathogenesis

宿主因素在 HIV 免疫发病机制中的作用

• 批准号: 7194095
• 负责人: Audrey Lewis Kinter
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7194095
• 关键词: Macaca mulatta; cellular immunity; electron microscopy; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; host organism interaction; human immunodeficiency virus; human tissue; immune response; immunofluorescence technique; immunomagnetic separation; immunopathology; immunoprecipitation; in situ hybridization; microorganism immunology; phenotype; small interfering RNA; tissue /cell culture; transfection /expression vector; virus cytopathogenic effect; virus genetics; virus replication

A hallmark of HIV infection is the recruitment of host factors involved in immune activation that help promote viral replication in various cellular compartments. HIV replication in CD4+ T cells, for example, is most efficient in the activated, memory subset. HIV antigen, in turn, acts to activate HIV-specific cells and, indirectly, can activate non-specific T cells, thus creating a vicious cycle of immune activation and HIV replication. The chronic immune activation generated by persistent HIV antigen is thought to contribute to the immune dysfunction characteristic of HIV disease. This project is designed to further our understanding of the host factors and cellular subsets that influence HIV replication, either directly or by modulating HIV-specific and non-specific immune activation. We are currently investigating the potential role of an immunosuppressive CD4+ T cell subset, CD25+ regulatory T cells (Treg) in the context of HIV infection. We have demonstrated that CD25+ Treg cells inhibit HIV-specific CD4+ and CD8+ T cell immune responses in vitro, particularly in individuals in the early stages of disease. HIV-specific immune responses suppressed by CD25+ Treg cells include proliferation, cytokine and chemokine secretion and the ability of CD8+ T cells to kill HIV expressing target cells. This detrimental effect of CD25+ Treg cells may be counter-balanced by the ability of these cells to suppress generalized, hyper-immune activation (as is induced during HIV infection) thereby reducing the pool of activated CD4+ T cells within which HIV can replicate and also reducing some of the cellular dysfunction and death associated with chronic activation. We have shown that CD25+Treg-like cells can suppress HIV replication in normal CD4+ T cells and are presently assessing whether or not they reduce activation-associated cellular dysfunction. Finally, the activity of lymphoid tissue-associated CD25+ Treg cells in HIV-infected individuals is being determined; this will be particularly relevant as lymphoid tissue is one of the primary sites of HIV replication as well as of the priming of immune responses. A second project investigated the role of host factors in generating and maintaining cellular HIV reservoirs. We have demonstrated that the lymphoid tissue microenvironment supports productive HIV infection in resting CD4+ T cells. Using cultured tonsil tissue, we found that purified resting CD4+ T cells produced HIV mRNA, p24 protein and infectious virus while maintaining a resting, non-dividing T cell phenotype when cultured with autologous lymphoid tissue, but not when cultured alone. HIV production from this cellular population was driven, in part, by pro-inflammatory cytokines and additional signals generated by the tissue matrix. These data repudiate the paradigm that HIV production in T cells requires classical T cell activation and demonstrate that the lymphoid tissue is an ideal microenvironment for suboptimal cellular activation leading to HIV replication in phenotypically resting CD4+ T cells.

艾滋病毒感染的标志是募集参与免疫激活的宿主因素，这些因素有助于促进各种细胞室中的病毒复制。例如，在激活的记忆子集中，CD4+ T细胞中的HIV复制最有效。反过来，HIV抗原起作用激活HIV特异性细胞，并间接地激活非特异性T细胞，从而产生免疫激活和HIV复制的恶性循环。持续性HIV抗原产生的慢性免疫激活被认为有助于HIV疾病的免疫功能障碍。该项目旨在进一步理解直接或通过调节HIV特异性和非特异性免疫激活来影响HIV复制的宿主因素和细胞子集。我们目前正在研究HIV感染的背景下，免疫抑制CD4+ T细胞子群CD25+调节T细胞（Treg）的潜在作用。我们已经证明，CD25+ Treg细胞在体外抑制HIV特异性CD4+和CD8+ T细胞免疫反应，特别是在疾病早期的个体中。被CD25+ Treg细胞抑制的HIV特异性免疫反应包括增殖，细胞因子和趋化因子分泌以及CD8+ T细胞杀死HIV表达靶细胞的能力。 CD25+ Treg细胞的这种有害作用可能是通过这些细胞抑制广义的，过度免疫激活的能力（如在HIV感染期间诱导的）的能力，从而减少了HIV激活的CD4+ T细胞的池，其中HIV可以重现并降低了一些细胞功能障碍和死亡的某些与Chrincication Chricnics Actications相关的细胞功能障碍和死亡。我们已经表明，CD25+ Treg样细胞可以抑制正常CD4+ T细胞中的HIV复制，并且目前正在评估它们是否减少与激活相关的细胞功能障碍。最后，正在确定淋巴组织相关的CD25+ Treg细胞在HIV感染的个体中的活性。这将特别重要，因为淋巴组织是HIV复制的主要部位之一，也是免疫反应的启动。第二个项目调查了宿主因素在产生和维持细胞HIV库中的作用。我们已经证明，淋巴组织微环境支持静止的CD4+ T细胞中的生产性HIV感染。使用培养的扁桃体组织，我们发现纯化的静息CD4+ T细胞产生了HIV mRNA，p24蛋白和感染性病毒，同时在用自体淋巴结组织培养时保持静止的，非分裂的T细胞表型，但没有单独培养。该细胞种群的HIV产生部分是由促炎性细胞因子和组织基质产生的其他信号驱动的。这些数据否认了T细胞中HIV的产生需要经典的T细胞激活的范例，并证明淋巴组织是次级细胞活化的理想微环境，从而导致表型静止的CD4+ T细胞中的HIV复制。