Regulation of Cytokine Expression by HIV:Potential point

HIV对细胞因子表达的调节：潜在点

• 批准号: 6679835
• 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/6679835
• 关键词: AIDS /HIV neuropathy; AIDS therapy; HIV infections; antiAIDS agent; astrocytes; cell differentiation; cell population study; chemical kinetics; colony stimulating factor; cytokine; gene induction /repression; host organism interaction; human immunodeficiency virus 1; human tissue; immunogenetics; immunoregulation; macrophage; molecular pathology; monocyte; nitric oxide; nitric oxide synthase; patient oriented research; protein structure function; simian immunodeficiency virus; virus infection mechanism; virus receptors

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.

总结：巨噬细胞在HIV感染的发病机制中起着关键作用，既作为病毒复制的靶点，又作为多功能细胞因子的来源。我们的早期研究表明，用HIV-1包膜蛋白gp 120刺激的正常人单核细胞产生HIV调节细胞因子TNF-α、IL-1b、IL-6和GM-CSF（JI 1991）和有效的血管活性肽ET-1（JI 1993）。随后对单核细胞衍生的巨噬细胞（MDM）的研究表明，HIV-1感染在体外不能诱导这些细胞因子，但可持续诱导M-CSF产生（JI 1995），M-CSF促进单核细胞分化，并通过增强HIV受体、CD 4和CCR 5的表达增加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））测定MDM中M-CSF产生的病毒特异性。只有HIV-1（JI，2000年）和HIV-2（in prep，2002年）的单嗜性毒株导致M-CSF的产生增加。趋化因子MIP-1a/B和MCP-1可被HIV-1诱导，但HIV-2的产生量极低，表明需要趋化因子和M-CSF来建立病毒库，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HIV感染的MDM中，病毒复制和M-CSF的产生密不可分，因此抑制一种药物会导致同时抑制另一种药物（ARHR 2002）。由于HIV源于SIV的跨物种传播，并从良性发展为高致病性疾病，初始感染针对MDM，我们研究了SIV感染人类MDM的能力。我们发现16株SIV分离株中有12株属于5个不同的灵长类慢病毒家族，能够感染MDM，其中11株也能够在人PBMC中复制。在MDM中复制的分离株也诱导M-CSF的产生，但在诱导的趋化因子模式方面有所不同（在制备中，2002）。正在进行的研究将深入了解这些慢病毒的决定因素，这些慢病毒对人类人群具有致病性，希望能够确定治疗干预的新靶点。 由于星形胶质细胞包围着大脑中产生HIV的细胞，并有可能影响病毒的复制，我们研究了它们对人类MDM中HIV表达的影响。HIV感染的MDM与原代人星形胶质细胞的共培养导致HIV复制减少，这部分由未鉴定的星形胶质细胞分泌因子介导（AIDS 1999），此外还导致诱导型一氧化氮合酶（iNOS）表达和星形胶质细胞产生NO（Blood 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，在确定神经系统HIV疾病的过程中起着关键作用。这也使我们推测，在HIV疾病中观察到的神经系统损伤可能是由于星形胶质细胞长时间高水平产生NO，这可能反映了宿主试图抑制病毒复制。