Regulation of Cytokine Expression by HIV:Potential point

摘要：巨噬细胞在HIV感染的发病机制中起着关键作用，既是病毒复制的目标，也是多功能细胞因子的来源。我们早期的研究表明，正常人单核细胞在HIV-1包膜蛋白gp120的刺激下，产生HIV调节细胞因子TNF-a、IL-1b、IL-6和GM-CSF(JI 1991)和强大的血管活性多肽ET-1(JI 1993)。后来对单核细胞来源的巨噬细胞(MDM)的研究发现，HIV-1感染在体外不能诱导这些后者的细胞因子，但持续诱导M-CSF的产生(JI 1995)，促进单核细胞分化，并通过增强HIV受体CD4和CCR5的表达增加MDM对HIV感染的易感性。然后用一组单链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产生M-CSF的病毒特异性。只有单核细胞毒株HIV-1(JI 2000)和HIV-2(PREP，2002)能增加M-CSF的产生。HIV-1可诱导趋化因子MIP-1a/b和MCP-1的产生，但HIV-2诱导的趋化因子MIP-1a/b和MCP-1的产生极大地减少，提示趋化因子和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的产生有着千丝万缕的联系，因此抑制其中一个就会导致对另一个的全面抑制(ARHR 2002)。由于HIV源于SIV的跨物种传播，并从良性疾病发展到高致病性疾病，最初的感染针对MDM，因此我们研究了SIV感染人类MDM的能力。我们发现，属于5个不同的灵长类慢病毒科的16株SIV分离株中，有12株能够感染MDM，其中11株还能够在人的PBMC中复制。在MDM中复制的分离株也可以诱导M-CSF的产生，但在诱导趋化因子的模式方面有所不同(在PREP，2002)。正在进行的研究将提供对这些慢病毒的决定因素的洞察，这些决定因素对人类群体是致病的，希望确定新的治疗干预目标。 由于星形胶质细胞包围着大脑中产生HIV的细胞，并有可能影响病毒复制，我们研究了它们对人类MDM中HIV表达的影响。HIV感染的MDM与原代人类星形胶质细胞共培养后，除了表达诱导型一氧化氮合酶(INOS)和星形胶质细胞产生NO外，还导致HIV复制减少，部分是由一种未知的星形胶质细胞分泌因子(AIDS，1999)介导的(血液1999)。我们的数据表明，星形胶质细胞通过产生HIV调节细胞因子和iNOS/NO的表达，在决定神经系统HIV疾病的进程中发挥关键作用。这也让我们推测，在HIV疾病中观察到的神经损伤可能是星形胶质细胞长期、高水平产生NO所致，这可能反映了宿主试图抑制病毒复制。

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.