ROLE OF CYTOKINES IN THE REGULATION OF HIV EXPRESSION

参与调控作用的细胞和分子途径 促炎症和免疫调节细胞因子和趋化因子对人体的影响 免疫缺陷病毒(HIV)复制以及HIV对 CD4+T细胞对某些细胞因子的反应能力是 调查过了。外周血中HIV病毒的体外复制水平 HIV感染者的单个核细胞(PBMC)被发现反映了 内源性HIV抑制β趋化因子的净调节作用 (MIP-1α、MIP-1β、RANTES)与内源性HIV诱导 促炎症细胞因子(肿瘤坏死因子-α、白介素1-β)。对能力的分析 不同的PBMC亚群产生β趋化因子并抑制HIV 目前正在进行体外复制。一种金属蛋白酶抑制剂 已知可阻断肿瘤坏死因子-α的分泌 迅速抑制HIV慢性感染细胞系中的HIV复制 HIV感染者的PBMC和HIV感染者的PBMC；这种治疗 对细胞的激活或增殖没有不利影响。 同样，一种新的氨基甾醇被发现能显著抑制HIV 在这些相同的3个细胞群体中以及在尖锐的猿猴中复制 免疫缺陷病毒(SIV)感染猕猴的PBMC。一种功效 对感染SIV的猕猴体内的这种氨基类固醇的研究正在进行中。最后， 初步研究表明HIV gp160介导的抑制作用 CD4交联剂对T细胞激活DNA结合能力的影响 STATS(信号转导和转录激活子) 白介素2受体占有率。这些研究表明， 细胞因子和趋化因子与HIV的复杂相互作用 复制。此外，几种新型的干扰因子 对高效复制很重要的细胞过程或因素 HIV在体外表现出了有效的HIV抑制活性。

The cellular and molecular pathways involved in the regulatory effects of proinflammatory and immunoregulatory cytokines and chemokines on human immunodeficiency virus (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 (PBMC) 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 proinflammatory cytokines (TNF-alpha, IL-1beta). Analysis of the ability of various PBMC subsets to produce beta chemokines and to suppress HIV replication in vitro is being conducted. A metalloproteinase inhibitor known to block the secretion of TNF-alpha was found to dramatically suppress HIV replication in chronically HIV-infected cell lines, acutely HIV-infected PBMC and in PBMC from HIV-infected subjects; this treatment had no detrimental effect on cellular activation or proliferation. Similarly, a novel aminosterol was found to dramatically inhibit HIV replication in these same 3 cell populations as well as in acutely simian immunodeficiency virus (SIV)-infected PBMC from macaques. An efficacy study of this aminosterol in SIV-infected macaques is ongoing. Finally, preliminary studies suggest an inhibitory effect of HIV gp160-mediated CD4 crosslinking on the ability of T cells to activate DNA binding of STATs (signal transducers and activators of transcription) upon interleukin (IL)-2 receptor occupancy. These studies demonstrate the complex interactions between cytokines and chemokines and HIV replication. In addition, several novel agents which interfere with cellular processes or factors important for the efficient replication of HIV have demonstrated effective HIV-inhibitory activity in vitro.