Regulation of Cytokine Expression by HIV:Potential point

摘要：巨噬细胞作为病毒复制的靶点和多功能细胞因子的来源，在HIV感染的发病机制中起着关键作用。我们的早期研究表明，受HIV-1包膜蛋白gp120刺激的正常人单核细胞产生hiv调节细胞因子，TNF-a, IL-1b， IL-6和GM-CSF （JI 1991）和有效的血管活性肽ET-1 （JI 1993）。后来对单核细胞来源的巨噬细胞（MDM）的研究表明，HIV-1感染不能在体外诱导后一种细胞因子，但可以持续诱导M-CSF的产生（JI 1995），这促进了单核细胞分化，并通过增强HIV受体、CD4和CCR5的表达增加了MDM对HIV感染的易感性。然后使用一组单链RNA病毒（包括HIV-1、HIV-2、麻疹和呼吸道合胞病毒（MV和RSV））来确定MDM中M-CSF产生的病毒特异性。只有单核细胞株HIV-1 （JI 2000）和HIV-2 （in prep, 2002）能促进M-CSF的产生。趋化因子MIP-1a/b和MCP-1可被HIV-1诱导，但在HIV-2中产生的趋化因子显著减少，这表明趋化因子和M-CSF是建立病毒库所必需的，但趋化因子的产生可能与致病性更密切相关。其他使用抗逆转录病毒药物（AZT和利托那韦）的研究证实，在艾滋病毒感染的MDM中，病毒复制和M-CSF的产生有着不可分割的联系，因此，抑制其中一种会导致另一种同时受到抑制（ARHR 2002）。由于HIV起源于SIV的跨物种传播，并从良性发展为高致病性疾病，初始感染以MDM为目标，因此我们研究了SIV感染人类MDM的能力。我们发现16个SIV分离株中有12个属于5个不同的灵长类慢病毒家族，能够感染MDM，其中11个也能够在人类PBMC中复制。在MDM中复制的分离物也诱导M-CSF的产生，但在诱导趋化因子的模式方面有所不同（in prep, 2002）。正在进行的研究将深入了解这些慢病毒对人类致病性的决定因素，并希望确定治疗干预的新靶点。

Summary: Macrophages play a critical role in the pathogenesis of HIV infection, both as targets for virus replication and as sources of multifunctional cytokines. Our early studies showed that normal human monocytes stimulated with the HIV-1 envelope protein, gp120, produce the HIV-modulatory cytokines, TNF-a, IL-1b, IL-6 and GM-CSF (JI 1991) and the potent vasoactive peptide, ET-1 (JI 1993). Later studies with monocyte derived macrophages (MDM) revealed that HIV-1 infection fails to induce these latter cytokines in vitro, but consistently induces M-CSF production (JI 1995) which facilitates monocyte differentiation and increases the susceptibility of MDM to HIV infection by enhancing expression of the HIV receptors, CD4 and CCR5. Viral specificity of M-CSF production in MDM was then determined using a panel of single-stranded RNA viruses, including HIV-1, HIV-2, measles and respiratory syncytial viruses (MV and RSV). Only monocytropic strains of HIV-1 (JI 2000) and HIV-2 (in prep, 2002) caused enhanced production of M-CSF. Chemokines MIP-1a/b and MCP-1 were induced by HIV-1, but production was extremely diminished with HIV-2, suggesting that chemokines and M-CSF are needed to establish a viral reservoir, but chemokine production may correlate more closely with pathogenicity. Other studies using anti-retroviral agents (AZT and Ritonavir) confirmed that virus replication and M-CSF production are inextricably linked in HIV-infected MDM, such that inhibition of one leads to comcommitant inhibition of the other (ARHR 2002). Since HIV arose from cross-species transmission of SIV and progressed from a benign to highly pathogenic disease with initial infections targeting MDM, we investigated the ability of SIV to infect human MDM. We found that 12 of 16 SIV isolates belonging to 5 different primate lentivirus families were capable of infecting MDM and 11 of these were also able to replicate in human PBMC. Isolates that replicated in MDM also induced production of M-CSF, but varied with regard to pattern of chemokines induced (in prep, 2002). Ongoing studies will provide insight into determinants of these lentiviruses that are pathogenic for the human population with the hope of identifying novel targets for therapeutic intervention. Since astrocytes surround HIV-producing cells in the brain and would have the potential to influence virus replication, we studied their effect on HIV expression in human MDM. Co-culture of HIV-infected MDM with primary human astrocytes caused reduced HIV replication, mediated in part by an unidentified astrocyte secreted factor (AIDS 1999), in addition to expression of inducible nitric oxide synthase (iNOS) and production of NO by astrocytes (Blood 1999). Our data indicate that astrocytes play a pivotal role in determining the course of neurologic HIV disease via production of HIV modulating cytokines and expression of iNOS/NO. This also leads us to speculate that neurologic damage observed in HIV disease may ensue from prolonged, high level production of NO by astrocytes, which may reflect a host attempt to inhibit virus replication.