REGULATION OF HIV REPLICATION BY HOST FACTORS: ROLE OF ENDOGENOUS CYTOKINES....

宿主因素对 HIV 复制的调节：内源细胞因子的作用......

• 批准号: 6288918
• 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/6288918
• 关键词: AIDS therapy; CD4 molecule; HIV infections; antiviral agents; cell line; chemokine; cytokine; drug design /synthesis /production; drug screening /evaluation; gene expression; host organism interaction; human immunodeficiency virus; human tissue; immunopathology; immunoregulation; interleukin 2; leukocyte activation /transformation; leukocyte count; lymphocyte; monocyte; natural killer cells; protease inhibitor; tissue /cell culture; tumor necrosis factor alpha; virus replication; AIDS therapy; CD4 molecule; HIV infections; antiviral agents; cell line; chemokine; cytokine; drug design /synthesis /production; drug screening /evaluation; gene expression; host organism interaction; human immunodeficiency virus; human tissue; immunopathology; immunoregulation; interleukin 2; leukocyte activation /transformation; leukocyte count; lymphocyte; monocyte; natural killer cells; protease inhibitor; tissue /cell culture; tumor necrosis factor alpha; virus replication

This project was designed to investigate the cellular and molecular pathways involved in the HIV regulatory effects of cytokines/chemokines, tissue-associated factors and HIV envelope proteins. We had previously demonstrated that endogenous C-C chemokine receptor (CCR)-5-binding chemokines produced by CD4+ cells from asymptomatic HIV-infected individuals were found to play an important role in controlling in vitro replication of HIV strains that use CCR5 as an entry co-receptor. In contrast, CCR5- and CCR2-binding chemokines were found to enhance the level of endogenous HIV replication in CD4+ T cells of individuals at late stage HIV disease harboring X4 strains of HIV. Inflammatory cytokines and beta-chemokines acted cooperatively to enhance endogenous CXCR4 strain HIV replication, whereas these factors acted antagonistically in determining the level of endogenous R5 HIV strain replication. Our study of potential effects of chemokines on HIV replication are being expanded to include analysis of most C-C and CXC chemokines for their post-entry effects on HIV replication. Preliminary results suggest that numerous chemokines, such as SDF and RANTES, may influence post-entry HIV life cycle events, such as proviral integration. Following our previous in vitro observation that IL-2 and IL-15, but not IL-12, are potent inducers of CC chemokine production in lymphocytes, we have analyzed peripheral blood mononuclear cells from HIV-infected individuals receiving IL-2 subcutaneously. We have demonstrated that IL-2 administration in vivo results in increased CCR5 mRNA and intracellular protein levels, as well as in increased expression of CCR3 and CCR5 in the T lymphocyte population. Of interest, alterations in the susceptibility of PBMC to HIV infection in vitro were associated with IL-2 administration; however, these changes did not correlate with altered HIV CCR co-receptor expression.The ability of host factors or HIV envelope protein (gp160) to modulate HIV expression from cellular reservoirs of HIV, such as resting latently HIV-infected CD4+ T cells and macrophages isolated from HIV-infected subjects, was investigated. HIV gp160 was found to induce HIV expression from both cellular reservoirs of HIV. Induction of HIV from resting CD4+ T cells was not associated with expression of cellular activation markers, progression through the cell cycle, or interferon- gamma production. The fate of latently HIV-infected resting T cells stimulated to produce virus in this manner is being further investigated. In contrast, certain constitutive tissue associated factors, such as secondary lymphoid-associated chemokine (SLC) and the extracellular matrix protein tenascin, were found to suppress HIV expression from resting CD4+ T cells. These findings demonstrate that numerous lymphoid tissue-associated factors are capable of modulating HIV expression from cellular HIV reservoirs. - HIV; immunopathogenesis; cytokine; chemokine; lymphocyte; macrophage; HIV cellular reservoirs; envelope protein; extracellular matrix

该项目旨在研究细胞因子/趋化因子，组织相关因子和HIV包膜蛋白的HIV调节作用的细胞和分子途径。我们先前已经证明，发现由无症状的HIV感染个体CD4+细胞产生的内源性C-C趋化因子受体（CCR）-5结合趋化因子，发现在控制使用CCR5作为入学共肽的HIV菌株的体外复制中起着重要作用。相比之下，发现CCR5和CCR2结合趋化因子可提高携带HIV X4菌株的晚期HIV疾病个体CD4+ T细胞中内源性HIV复制水平。炎性细胞因子和β化学因子合作起作用，以增强内源性CXCR4菌株HIV复制，而这些因素在确定内源性R5 HIV菌株复制水平方面起作用。我们对趋化因子对HIV复制的潜在影响的研究正在扩展，包括分析大多数C-C和CXC趋化因子对HIV复制的影响。初步结果表明，许多趋化因子（例如SDF和RANTES）可能会影响进入后的HIV生命周期事件，例如病毒整合。在以前的体外观察到IL-2和IL-15（而不是IL-12）是淋巴细胞中CC趋化因子产生的有效诱导剂后，我们已经分析了来自接受IL-2皮下注射的HIV感染的个体的外周血单核细胞。我们已经证明，IL-2在体内给药会导致CCR5 mRNA和细胞内蛋白水平增加，以及在T淋巴细胞种群中CCR3和CCR5的表达增加。有趣的是，PBMC对HIV感染的敏感性改变与IL-2给药有关。然而，这些变化与HIV CCR共受体表达的改变无关。宿主因素或HIV包膜蛋白（GP160）的能力调节HIV细胞储层的HIV表达，例如在HIV感染的受试者中分离出HIV感染的HIV感染的CD4+ T细胞和巨噬细胞。发现HIV GP160诱导HIV两种细胞储存库的HIV表达。从静息CD4+ T细胞中诱导HIV与细胞活化标记的表达，通过细胞周期的进展或干扰素γ的产生无关。正在进一步研究以这种方式刺激产生病毒的潜在艾滋病毒的命运正在进一步研究。相反，发现某些组成型组织相关的因子，例如二次淋巴样趋化因子（SLC）和细胞外基质蛋白替氏蛋白，可抑制静息CD4+ T细胞中的HIV表达。这些发现表明，许多淋巴组织相关因素能够调节来自细胞HIV储量的HIV表达。 - 艾滋病病毒;免疫病变；细胞因子；趋化因子；淋巴细胞；巨噬细胞； HIV细胞库；包膜蛋白；细胞外基质