HIV-Human Peritonal Macrophage Interactions

HIV-人腹膜巨噬细胞相互作用

• 批准号: 8232027
• 负责人: Theresa L Chang
• 金额: $ 19.77万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232027
• 关键词: Acquired Immunodeficiency Syndrome; Blood; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Line; Cells; Cirrhosis; Co-Receptor Switch; Complex; Disease Progression; Epidemic; Foundations; Goals; HIV; HIV Infections; HIV-1; Human; Immune system; In Vitro; Individual; Infection; Investigation; Life; Location; Longevity; Macaca mulatta; Messenger RNA; Molecular; Opportunistic Infections; Outcome Study; Pathogenesis; Patients; Peritoneal Fluid; Peritoneal Macrophages; Play; Population; Predisposition; Production; Resistance; Role; Source; Staging; T-Lymphocyte; Therapeutic; Viral; Viral Load result; Viral load measurement; Virus; base; beta-Chemokines; cell type; insight; killings; macrophage; novel; public health relevance; receptor; simian human immunodeficiency virus; treatment strategy

DESCRIPTION (provided by applicant): Macrophages, one of the major cell types in which HIV can both productively replicate and persist in a latent state, play a crucial role in HIV pathogenesis. In contrast to CD4+ T cells, macrophages are resistant to HIV-induced killing and have long lifespan. Indeed, macrophages appear to be an important reservoir and sustain high virus loads after depletion of CD4+ T cells in AIDS patients and in highly pathogenic SHIV- infected rhesus macaques. Importantly, macrophages are the major source of HIV during opportunistic infections, which occur more frequently during the advanced stages of AIDS. Because the long-lived HIV reservoirs constitute a major obstacle to HIV eradication, understanding the cellular and molecular mechanisms underlying HIV-macrophage interactions is vital for developing novel and efficacious therapeutic strategies against HIV and the AIDS epidemic. Susceptibility of primary macrophages to HIV depends on the anatomical location and activation state of the cells. Experimental investigation of the interactions between HIV-1 and macrophages has been impeded by the difficulty of isolating a large amount of human primary macrophages. We recently demonstrate that peritoneal macrophages (PMs) are highly abundant in ascitic fluid of patients with cirrhosis and are susceptible to HIV-1 infection. These cells are long-lived in vitro and can be cryopreserved. Freshly isolated PMs are susceptible to HIV R5, X4, X4R5 primary isolates by not but not to X4-T cell line adapted (TCLA) strains. Interestingly, after 7 days in culture, PMs acquired susceptibility to X4-TCLA strains and produced greater amounts of primary X4 and X4R5 HIV than freshly-isolated PMs. Concurrently, the level of CXCR4 mRNA and production of CC-chemokines increased significantly during 7 days in culture, suggesting that an increase in levels of HIV-coreceptors and CC-chemokines may contribute to the susceptibility to X4-TCLA and enhanced viral production of X4-ultizing isolates, respectively. HIV coreceptor switch from R5 to X4 has been associated with rapid CD4+ T cell loss and progression of AIDS when macrophages are the major source of HIV. Although the basis for HIV co-receptor switch is attributed to the complex interaction of the viral population with various cell populations of the immune system, the contribution by macrophages to HIV co-receptor switch is not known. Our long-term goal is to determine whether macrophages serve as an important reservoir and whether they play a role in HIV-coreceptor switch at the late stage of disease progression. Thus, further characterization of HIV-peritoneal macrophage interactions will offer an important insight into the role of macrophages in HIV pathogenesis. The goal of this proposal is to dissect the underlying mechanisms of dynamic HIV co-receptor usages in PMs and to amplify and characterize HIV envelopes from peritoneal macrophages from HIV-infected individuals. The outcome of this study will enhance our understanding of the role of macrophages in HIV pathogenesis and may facilitate discoveries of new ways for treatment. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to dissect the underlying mechanisms of dynamic HIV co-receptor usages in PMs and to characterize HIV Env in PMs from HIV-infected patients.

描述（由申请人提供）：巨噬细胞是 HIV 能够高效复制并持续处于潜伏状态的主要细胞类型之一，在 HIV 发病机制中发挥着至关重要的作用。与 CD4+ T 细胞相比，巨噬细胞能够抵抗 HIV 诱导的杀伤，并且寿命较长。事实上，巨噬细胞似乎是一个重要的储存库，在艾滋病患者和感染高致病性 SHIV 的恒河猴体内 CD4+ T 细胞耗尽后，巨噬细胞仍能维持高病毒载量。重要的是，巨噬细胞是机会性感染期间艾滋病毒的主要来源，这种情况在艾滋病晚期更常见。由于长寿命的艾滋病毒储存库构成了根除艾滋病毒的主要障碍，因此了解艾滋病毒-巨噬细胞相互作用的细胞和分子机制对于开发针对艾滋病毒和艾滋病流行的新颖有效的治疗策略至关重要。 原代巨噬细胞对 HIV 的易感性取决于细胞的解剖位置和激活状态。由于难以分离大量人类原代巨噬细胞，HIV-1 和巨噬细胞之间相互作用的实验研究受到阻碍。我们最近证明，肝硬化患者腹水中的腹膜巨噬细胞（PM）非常丰富，并且容易受到 HIV-1 感染。这些细胞在体外寿命很长，并且可以冷冻保存。新鲜分离的 PM 对 HIV R5、X4、X4R5 原代分离株敏感，但对 X4-T 细胞系适应 (TCLA) 菌株不敏感。有趣的是，培养 7 天后，PM 获得了对 X4-TCLA 菌株的敏感性，并比新鲜分离的 PM 产生更多量的原代 X4 和 X4R5 HIV。同时，CXCR4 mRNA 的水平和 CC 趋化因子的产量在培养 7 天期间显着增加，表明 HIV 辅助受体和 CC 趋化因子水平的增加可能分别有助于 X4-TCLA 的易感性和 X4-ultizing 分离株的病毒产量的增加。 当巨噬细胞是 HIV 的主要来源时，HIV 辅助受体从 R5 到 X4 的转换与 CD4+ T 细胞的快速损失和 AIDS 的进展相关。尽管HIV共受体转换的基础归因于病毒群体与免疫系统的各种细胞群的复杂相互作用，但巨噬细胞对HIV共受体转换的贡献尚不清楚。我们的长期目标是确定巨噬细胞是否作为重要的储存库，以及它们是否在疾病进展后期的 HIV 辅助受体转换中发挥作用。因此，HIV-腹膜巨噬细胞相互作用的进一步表征将为巨噬细胞在 HIV 发病机制中的作用提供重要的见解。 该提案的目标是剖析 PM 中动态 HIV 共受体使用的基本机制，并放大和表征 HIV 感染者腹膜巨噬细胞的 HIV 包膜。这项研究的结果将增强我们对巨噬细胞在艾滋病毒发病机制中的作用的理解，并可能有助于发现新的治疗方法。 公共健康相关性：本提案的目标是剖析 PM 中动态 HIV 共受体使用的基本机制，并描述 HIV 感染者 PM 中 HIV 包膜的特征。