ROLE OF CYTOKINES IN THE REGULATION OF HIV EXPRESSION

细胞因子在 HIV 表达调节中的作用

• 批准号: 2566859
• 负责人: A 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/2566859
• 关键词: AIDS therapy; CD4 molecule; HIV envelope protein gp160; Macaca; antiviral agents; chemokine; cytokine; drug screening /evaluation; gene expression; human immunodeficiency virus; human tissue; immunopathology; immunoregulation; interleukin 2; leukocyte activation /transformation; leukocyte count; lymphocyte; monocyte; nonhuman therapy evaluation; simian immunodeficiency virus; tissue /cell culture; tissue inhibitor of metalloproteinases; tumor necrosis factor alpha; virus replication

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.

参与调节作用的细胞和分子途径 促炎和免疫调节细胞因子和趋化因子对人类 免疫缺陷病毒（HIV）复制以及HIV对 CD4 + T细胞对某些细胞因子应答能力 研究了HIV在CD4+外周血中的体外复制水平 来自HIV感染受试者的单核细胞（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-1 α，MIP-1 β，RANTES）和内源性HIV诱导 促炎细胞因子（TNF-α、IL-1 β）。 的能力的分析 产生β趋化因子和抑制HIV 正在进行体外复制。 金属蛋白酶抑制剂 已知阻断TNF-α分泌的药物， 在慢性HIV感染细胞系中抑制HIV复制，急性 HIV感染的PBMC和来自HIV感染的受试者的PBMC;这种治疗 对细胞活化或增殖没有不利影响。 同样，人们发现一种新型氨基固醇可以显着抑制艾滋病毒 在这3种细胞群中以及在急性猿猴中的复制 免疫缺陷病毒（SIV）感染的PBMC。 疗效 目前正在SIV感染猕猴中研究这种氨基甾醇。 最后， 初步研究表明，HIV gp160介导的 CD4交联对T细胞激活DNA结合的能力的影响 STATs（信号转导和转录激活因子） 白细胞介素（IL）-2受体占有率。 这些研究表明， 细胞因子和趋化因子与HIV之间的复杂相互作用 复制的此外，几种新的代理人，干扰 细胞过程或因素的有效复制重要的 HIV已经在体外证明了有效的HIV抑制活性。