Modulation of HIV Replication by Cytokines, Cytokine Ant

细胞因子、细胞因子 Ant 对 HIV 复制的调节

• 批准号: 6682424
• 负责人: K. A CLOUSE-STREBEL
• 金额: --
• 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/6682424
• 关键词: HIV infections; antiAIDS agent; antibody; cell population study; chemical structure function; chemokine; clinical research; colony stimulating factor; cytokine; cytokine receptors; gene expression; helper T lymphocyte; host organism interaction; human immunodeficiency virus 1; human tissue; immunogenetics; immunoregulation; inhibitor /antagonist; interferon alpha; interleukin 2; macrophage; monocyte; natural killer cells; pathologic process; tissue /cell culture; virus replication

Summary: We have conducted studies to identify cytokines or their antagonists (anti-cytokine antibodies or soluble cytokine receptors) capable of inhibiting HIV replication in human macrophages (MO) or T cells. Subsequent to showing that HIV-infected MO produce high levels of M-CSF and MIP-1a, which enable an HIV/MO reservoir to be established, we found that antagonists to M-CSF inhibit HIV replication and reduce production of MIP-1a when added to infected MO in vitro. These M-CSF antagonists may have clinical benefit as therapies for HIV by blocking production of virus by MO, reducing chemokine recruitment of HIV susceptible cells, and preventing establishment/maintenance of HIV-infected MO reservoirs in vivo (JI 2000). The lymphokine IL-2, used for restoration of CD4+ T cells in AIDS patients, was reported to increase M-CSF in human monocytes and cause a transient burst of HIV mRNA in plasma after administration. We asked if MO were the source of released HIV and found that exposure of MO to IL-2 prior to HIV infection in vitro leads to a dramatic decrease in virus replication, which correlates with an IL-2-induced decrease of CD4 and CCR5 expression. Production of M-CSF was not enhanced, suggesting that IL-2 may be beneficial in preventing MO infection, as well as restoring T cell function (AIDS 1998). Interferon-alpha (IFN-a) species differ in their ability to inhibit HIV replication in vitro, which may correlate with the varying therapeutic effects. We found that IFN-a species are effective at inhibiting HIV-1 replication in human MO, but show considerable variation in T cells that parallels cellular tropism (monocyte vs. T cell tropic). No correlation existed between antiviral and antiproliferative activity; modulation of CD4/CCR5/CXCR4 expression on MO and T cells was also not observed. Future studies will determine whether the inhibitory capacity of various species of IFN-a depends on the chemokine co-receptor, rather than the cell type infected with HIV, and whether this contributes to the toxicities associated with IFN-a therapy in HIV disease. NK cells are the first line of defense against virus-infected cells and produce cytokines that are biologically active on MO. We found that NK cells produce a novel factor which prevents HIV-1 replication following virus entry in MO, but not T cells. Partial purification indicates that the inhibitory factor(s) is approximately 10 kD with a pI of 8-10, similar to chemokines. The ability of this factor to inhibit replication of HIV, and not virus entry, and the failure of antibodies to beta chemokines to reverse the inhibition suggest that this NK cell factor is unique and may play a role in the regulation of HIV-1 expression in human MO. More recent studies focus on the identification of molecules distinct from CD4, CCR5 and CXCR4, that are involved in HIV entry. Our intent is to identify agents that target these structures and prevent fusion of the HIV envelope with the cell membrane and/or delivery of the viral capsid into the cytoplasm. We will also determine whether such inhibitors can cause deterimental effects due to modulation of cell signalling and/or cytokine production.

总结：我们已经进行了研究，以确定细胞因子或其拮抗剂（抗细胞因子抗体或可溶性细胞因子受体）能够抑制人类巨噬细胞（MO）或T细胞中的HIV复制。在证明感染HIV的MO产生高水平的M-CSF和MIP-1a，从而能够建立HIV/MO储存库之后，我们发现M-CSF的拮抗剂在体外添加到感染的MO中时可以抑制HIV复制并减少MIP-1a的产生。这些M-CSF拮抗剂可通过阻断MO产生病毒、减少HIV易感细胞的趋化因子募集和防止体内HIV感染MO储库的建立/维持，作为HIV治疗药物具有临床获益（JI 2000）。据报道，用于恢复AIDS患者中的CD 4 + T细胞的淋巴因子IL-2在给药后可增加人单核细胞中的M-CSF，并引起血浆中HIV mRNA的短暂爆发。我们询问MO是否是释放的HIV的来源，并发现在体外HIV感染之前MO暴露于IL-2导致病毒复制急剧减少，这与IL-2诱导的CD 4和CCR 5表达减少相关。M-CSF的产生并未增强，这表明IL-2可能有助于预防MO感染以及恢复T细胞功能（艾滋病1998）。 干扰素-α（IFN-α）种类在体外抑制HIV复制的能力上不同，这可能与不同的治疗效果相关。我们发现IFN-α类在抑制人类MO中的HIV-1复制方面是有效的，但在T细胞中显示出相当大的变化，其与细胞嗜性（单核细胞对T细胞嗜性）平行。抗病毒和抗增殖活性之间不存在相关性; MO和T细胞上的CD 4/CCR 5/CXCR 4表达的调节也未观察到。未来的研究将确定各种IFN-α的抑制能力是否取决于趋化因子共受体，而不是感染HIV的细胞类型，以及这是否有助于与IFN-α治疗HIV疾病相关的毒性。 NK细胞是抵御病毒感染细胞的第一道防线，并产生对MO具有生物活性的细胞因子。我们发现NK细胞产生一种新的因子，该因子在病毒进入MO而不是T细胞后阻止HIV-1复制。部分纯化表明抑制因子约为10 kD，pI为8-10，与趋化因子相似。该因子抑制HIV复制而非病毒进入的能力，以及β趋化因子抗体逆转抑制的失败表明该NK细胞因子是独特的，并且可能在人类MO中HIV-1表达的调节中发挥作用。 最近的研究集中在识别与CD 4，CCR 5和CXCR 4不同的分子，这些分子参与HIV进入。我们的目的是鉴定靶向这些结构并防止HIV包膜与细胞膜融合和/或将病毒衣壳递送到细胞质中的试剂。 我们还将确定这种抑制剂是否会由于细胞信号传导和/或细胞因子产生的调节而引起免疫效应。