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

参与影响的细胞和分子途径 促炎和免疫调节细胞因子和趋化因子 调节艾滋病毒复制，以及艾滋病毒对 研究了CD 4 + T细胞对某些细胞因子的应答。 CD 4+外周血单个核细胞体外HIV复制水平 来自HIV感染者的外周血单个核细胞（PBMC）被发现反映了 内源性HIV抑制性β趋化因子的调节作用 （MIP-1 α，MIP-1 β，RANTES）和内源性HIV诱导 促炎细胞因子（肿瘤坏死因子-α [TNF-α]， 白细胞介素[IL]-1 β）。 此外，还发现， 体外刺激或细胞因子条件导致选择性 嗜巨噬细胞或嗜T细胞内源性病毒复制 从某些HIV感染个体获得的CD 4 + PBMC中的菌株。 各种PBMC亚群产生β-半乳糖苷酶的能力分析 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的应答， IL-15，并且NK衍生的β-趋化因子强烈抑制 嗜巨噬细胞的HIV体外进入和复制。 一 已知阻断TNF-α分泌的金属蛋白酶抑制剂 在慢性感染者中， HIV感染细胞系、体外急性HIV感染PBMC和PBMC中 来自HIV感染受试者;对细胞活化无有害影响 或增殖。 这些发现导致了 在英国开始临床试验。 这些研究证明 细胞因子、趋化因子和HIV之间复杂的相互作用 复制的 此外，我们还证明了几种新的 干扰细胞过程或重要因素的试剂， HIV的高效复制可以有效抑制HIV。

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.