TNF-alpha inhibits HIV-1 replication in peripheral blood monocytes and alveolar macrophages by inducing the production of RANTES and decreasing C-C chemokine receptor 5 (CCR5) expression.
TNF-alpha inhibits HIV-1 replication in peripheral blood monocytes and alveolar macrophages by inducing the production of RANTES and decreasing C-C chemokine receptor 5 (CCR5) expression.
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DOI：
10.4049/jimmunol.163.7.3653
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发表时间：
1999-10
影响因子：
4.4
通讯作者：
Brian R. Lane;D. Markovitz;N. Woodford;Rosemary Rochford;R. Strieter;Michael J. Coffey
中科院分区：
文献类型：
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作者：
Brian R. Lane;D. Markovitz;N. Woodford;Rosemary Rochford;R. Strieter;Michael J. Coffey
HIV-1感染的发病机制受到宿主免疫调节反应的影响。淋巴组织中存在的巨噬细胞很容易受到 HIV-1 的感染，但对其细胞病变作用具有相对抵抗力，并在疾病过程中充当病毒的储存库。先前的研究人员已经证明，TNF-α血清水平升高会导致艾滋病的临床症状，并且TNF-α通过增加HIV-1基因表达来刺激慢性感染的淋巴细胞和单核细胞系中HIV-1的产生。尽管之前的研究表明TNF-α可能会增加原代人类单核细胞的HIV-1感染，但最近的一些研究表明TNF-α可以抑制巨噬细胞的HIV-1感染。我们现在证明，TNF-α 以剂量依赖性方式抑制新感染的外周血单核细胞 (PBM) 和肺泡巨噬细胞 (AM) 中的 HIV-1 复制。由于 TNF-α 已被证明在某些情况下会增加 C-C 趋化因子受体 (CCR5) 结合趋化因子的产生，因此我们假设 TNF-α 通过增加这些 HIV 抑制因子的表达来抑制 HIV-1 复制。我们现在表明，PBM 和 AM 的 TNF-α 处理可增加 C-C 趋化因子 RANTES 的产生。单独使用 RANTES 或与巨噬细胞炎症蛋白-1α 和 -1β 联合免疫耗竭，可阻断 TNF-α 抑制 PBM 和 AM 中病毒复制的能力。此外，我们发现 TNF-α 治疗可降低 PBM 和 AM 上的 CCR5 表达。这些发现表明，TNF-α 通过两种不同但互补的机制，在抑制 HIV-1 单核细胞株中发挥着重要作用。
The pathogenesis of HIV-1 infection is influenced by the immunoregulatory responses of the host. Macrophages present in the lymphoid tissue are susceptible to infection with HIV-1, but are relatively resistant to its cytopathic effects and serve as a reservoir for the virus during the course of disease. Previous investigators have demonstrated that increased serum levels of TNF-alpha contribute to the clinical symptoms of AIDS and that TNF-alpha stimulates the production of HIV-1 in chronically infected lymphocytic and monocytic cell lines by increasing HIV-1 gene expression. Although previous studies have suggested that TNF-alpha may increase HIV-1 infection of primary human mononuclear cells, some recent studies have indicated that TNF-alpha suppresses HIV-1 infection of macrophages. We now demonstrate that TNF-alpha suppresses HIV-1 replication in freshly infected peripheral blood monocytes (PBM) and alveolar macrophages (AM) in a dose-dependent manner. As TNF-alpha has been shown to increase the production of C-C chemokine receptor (CCR5)-binding chemokines under certain circumstances, we hypothesized that TNF-alpha inhibits HIV-1 replication by increasing the expression of these HIV-suppressive factors. We now show that TNF-alpha treatment of PBM and AM increases the production of the C-C chemokine, RANTES. Immunodepletion of RANTES alone or in combination with macrophage inflammatory protein-1alpha and -1beta block the ability of TNF-alpha to suppress viral replication in PBM and AM. In addition, we found that TNF-alpha treatment reduces CCR5 expression on PBM and AM. These findings suggest that TNF-alpha plays a significant role in inhibiting monocytotropic strains of HIV-1 by two distinct, but complementary, mechanisms.