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）：巨噬细胞是艾滋病毒可以在潜在状态下施加有效复制和持续的主要细胞类型之一，在HIV发病机理中起着至关重要的作用。与CD4+ T细胞相反，巨噬细胞对艾滋病毒诱导的杀戮具有抗性，并且具有很长的寿命。实际上，巨噬细胞似乎是重要的储层，并且在艾滋病患者中CD4+ T细胞耗尽后以及高度致病性的感染恒河猕猴之后，巨噬细胞承受了高病毒载荷。重要的是，巨噬细胞是机会性感染期间HIV的主要来源，在艾滋病的高级阶段，巨噬细胞发生的频率更高。由于长期寿命的HIV储藏构成了消除HIV的主要障碍，因此了解HIV-Mocrophage相互作用的细胞和分子机制对于发展针对HIV和AIDS流行的新型有效的治疗策略至关重要。 原发性巨噬细胞对HIV的敏感性取决于细胞的解剖位置和激活状态。对HIV-1与巨噬细胞之间相互作用的实验研究受到了分离大量人类原代巨噬细胞的困难。我们最近证明，腹膜肝硬化患者的腹液中腹膜巨噬细胞高度丰富，并且容易受到HIV-1感染的影响。这些细胞在体外长期存在，可以冷冻保存。新鲜分离的PM易受HIV R5，X4，X4R5主要分离株的影响，但不能对X4-T细胞系改编（TCLA）菌株。有趣的是，经过7天的培养，PMS对X4-TCLA菌株的敏感性比新鲜分离的PMS产生了更多的原代X4和X4R5 HIV。同时，在7天的培养过程中，CXCR4 mRNA的水平和CC化学因子的产生显着增加，这表明HIV受感受器和CC化学因子的水平增加可能有助于X4-TCLA的易感性，并分别增强X4培养分离株的毒性产生。 当巨噬细胞是HIV的主要来源时，HIV coecector从R5转换为X4与AIDS的快速CD4+ T细胞损失和进展有关。尽管HIV共受体开关的基础归因于病毒种群与免疫系统各种细胞种群的复杂相互作用，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充当重要的储层，以及它们是否在疾病进展的后期在HIV受体转换中起作用。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发病机理中的作用提供重要的见解。 该提案的目的是剖析PMS中动态HIV共受体使用的潜在机制，并从腹膜巨噬细胞中放大和表征来自HIV感染的个体的HIV信封。这项研究的结果将增强我们对巨噬细胞在HIV发病机理中的作用的理解，并可能促进新的治疗方法的发现。 公共卫生相关性：该提案的目的是剖析PMS中动态HIV共受体使用的潜在机制，并在PMS中表征来自HIV感染患者的PMS的HIV ENV。