REGULATION OF HIV REPLICATION BY HOST FACTORS--ENDOGENOUS CYTOKINES & CHEMOKINES

细胞和分子途径参与的影响 促炎症和免疫调节细胞因子和趋化因子 调控艾滋病毒复制，以及艾滋病毒对能力的影响 研究了CD_4~+T细胞对某些细胞因子的反应。 外周血单个核细胞中HIV病毒复制水平的研究 来自HIV感染者的细胞(PBMC)被发现反映了网络 内源性HIV抑制β趋化因子的调节作用 (MIP-1α、MIP-1β、RANTES)与内源性HIV诱导 促炎细胞因子(肿瘤坏死因子-α[肿瘤坏死因子-α]， 白介素1β)。此外，还发现不同的在 体外刺激或细胞因子条件导致选择性 巨噬细胞或嗜T细胞内源性病毒的复制 从某些HIV感染者身上获得的CD4+PBMCs中的菌株。 不同外周血单核细胞亚群产生β细胞的能力分析 趋化因子显示自然杀伤(NK)细胞能够产生 高水平的β-趋化因子，特别是对IL-2和 IL-15和NK衍生β趋化因子强烈抑制 巨噬细胞嗜性艾滋病毒体外进入和复制。一个 已知的金属蛋白酶抑制剂可阻断肿瘤坏死因子-α的分泌 被发现能显著抑制慢性艾滋病病毒的复制 HIV感染细胞系，体外急性HIV感染PBMC和PBMC 来自HIV感染者；对细胞激活没有有害影响 或可见细胞增殖。这些发现导致了 在英国启动一项临床试验。这些研究表明 细胞因子、趋化因子与HIV的复杂相互作用 复制。此外，我们还展示了几部小说 干扰细胞过程或重要因素的药物 艾滋病病毒的有效复制可以有效地抑制艾滋病病毒。

The cellular and molecular pathways involved in the effects of pro-inflammatory and immunoregulatory cytokines and chemokines on regulating HIV replication, as well as the effect of HIV on the ability of CD4+ T cells to respond to certain cytokines were investigated. Levels of in vitro HIV replication in CD4+ peripheral blood mononuclear cells (PBMCs) from HIV-infected subjects was found to reflect the net regulatory effects of endogenous HIV-suppressing beta chemokines (MIP-1alpha, MIP-1beta, RANTES) and endogenous HIV-inducing pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta). In addition, it was found that different in vitro stimulatory or cytokine conditions result in the selective replication of either macrophage or T cell-tropic endogenous viral strains in CD4+ PBMCs obtained from certain HIV-infected individuals. Analyses of the ability of various PBMC subsets to produce beta chemokines revealed that natural killer (NK) cells are able to produce high levels of beta-chemokines, particularly in response to IL-2 and IL-15, and that NK-derived beta-chemokines strongly inhibit macrophage-tropic HIV entry and replication in vitro. A metalloproteinase inhibitor known to block the secretion of TNF-alpha was found to dramatically suppress HIV replication in chronically HIV-infected cell lines, in vitro acutely HIV-infected PBMC and in PBMC from HIV-infected subjects; no detrimental effect on cellular activation or proliferation was observed. These findings have led to the initiation of a clinical trial in the U.K.. These studies demonstrate the complex interactions between cytokines, chemokines and HIV replication. In addition, we have demonstrated that several novel agents which interfere with cellular processes or factors important for the efficient replication of HIV can effectively inhibit HIV.