Modulation of HIV-1 Replication by Cytokines

细胞因子对 HIV-1 复制的调节

• 批准号: 6545874
• 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/6545874
• 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: Macrophages (MO) are the first cells infected with HIV-1 in vivo and act as a virus reservoir. Cytokines are potent modulators of HIV, which enhance and inhibit virus replication. We have conducted studies to identify cytokines or antagonists (anti-cytokine antibodies or soluble cytokine receptors) capable of inhibiting HIV replication in human 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 prove beneficial as therapies for inhibiting HIV replication in vivo in MO by blocking production of virus, 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 therapeutic restoration of CD4+ T cells in AIDS patients, has been 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 not only in restoring T cell function in AIDS patients, but also in preventing MO infection with HIV (AIDS 1998). Interferon-alpha (IFN-a) has potent anti-HIV activity in vitro but clinical utility only in AIDS patients with high levels of CD4+ T cells. IFN-a species vary in their ability to inhibit HIV replication in vitro, which may correlate with the varying effects in vivo. We have found that IFN-a components and molecular hybrid molecules are effective at inhibiting HIV-1 replication in MO, but show considerable variation in human T cells. This appears to correlate with observed differences in the ability of some hybrids to inhibit monocyte vs. T cell tropic strains of HIV-1. Ongoing studies will determine whether: 1) IFN-a recombinant hybrid species modulate CD4, CCR5 or CXCR4 expression in MO and T cells; 2) anti-viral activity correlates with anti-proliferative activity in primary T cells; and 3) whether an IFN-a species with low anti-proliferative and high anti-viral activity on both MO and T cells can be identified which may cause fewer toxic side effects when used clinically. NK cells are the first line of defense against virus-infected cells and produce cytokines that are biologically active on MO. We studied the ability of NK cells to produce cytokines capable of preventing HIV replication in 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. The small size and basic pI are characteristic of a chemokine, but the ability of this factor to inhibit replication of HIV, and not virus entry, indicate that it is not a chemokine blocking via binding to CCR5. Consistent with this, we find that antibodies to beta chemokines are unable to reverse the inhibition when the NK cell-derived factor is added to MO after HIV adsorption. However, these antibodies can reverse inhibitory activity that occurs when this factor is added during virus adsorption. Our data suggest that this NK cell factor is distinct from beta chemokines that inhibit HIV entry and that NK cells may play a significant role in the regulation of HIV-1 expression in human MO.

总结： 巨噬细胞（MO）是体内感染HIV-1的第一批细胞，并充当病毒库。细胞因子是HIV的有效调节剂，其增强和抑制病毒复制。我们已经进行了研究以鉴定能够抑制HIV在人MO或T细胞中复制的细胞因子或拮抗剂（抗细胞因子抗体或可溶性细胞因子受体）。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拮抗剂可通过阻断病毒的产生、减少HIV易感细胞的趋化因子募集和防止体内HIV感染的MO储库的建立/维持，证明作为抑制MO体内HIV复制的疗法是有益的（JI 2000）。用于治疗性恢复AIDS患者中的CD 4 + T细胞的淋巴因子IL-2已被报道增加人单核细胞中的M-CSF，并在给药后引起血浆中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的产生没有增加，这表明IL-2可能不仅有益于恢复AIDS患者的T细胞功能，而且有益于预防MO感染HIV（AIDS 1998）。 干扰素-α（IFN-α）在体外具有有效的抗HIV活性，但仅在具有高水平CD 4 + T细胞的AIDS患者中具有临床效用。IFN-α种类在体外抑制HIV复制的能力不同，这可能与体内不同的作用相关。我们已经发现IFN-α组分和分子杂交分子在MO中有效抑制HIV-1复制，但在人T细胞中显示出相当大的变化。这似乎与观察到的一些杂交体抑制HIV-1的单核细胞与T细胞嗜性株的能力差异相关。正在进行的研究将确定：1）IFN-α重组杂合物种是否调节MO和T细胞中的CD 4、CCR 5或CXCR 4表达; 2）抗病毒活性与原代T细胞中的抗增殖活性相关;和3）是否可以鉴定对MO和T细胞两者具有低抗增殖和高抗病毒活性的IFN-α物种，其在临床上使用时可以引起较少的毒副作用。 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。我们研究了自然杀伤细胞产生细胞因子的能力，这些细胞因子能够阻止MO中的HIV复制。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。小尺寸和碱性pI是趋化因子的特征，但该因子抑制HIV复制而不是病毒进入的能力表明它不是通过结合CCR 5阻断的趋化因子。与此一致，我们发现，抗体β趋化因子是无法逆转的抑制时，NK细胞衍生的因子被添加到MO后，HIV吸附。然而，这些抗体可以逆转在病毒吸附期间加入该因子时发生的抑制活性。我们的数据表明，这种NK细胞因子是不同的β趋化因子，抑制HIV进入和NK细胞可能发挥重要作用，在人类MO的HIV-1表达的调节。