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能够有效复制并持续处于潜伏状态的主要细胞类型之一，在HIV的发病机制中起着至关重要的作用。与CD4+ T细胞相比，巨噬细胞能够抵抗hiv诱导的杀伤，并且具有较长的寿命。事实上，在艾滋病患者和高致病性SHIV感染的恒河猴体内，巨噬细胞似乎是一个重要的储存库，在CD4+ T细胞耗竭后维持高病毒载量。重要的是，巨噬细胞是机会性感染期间HIV的主要来源，机会性感染在艾滋病晚期更频繁发生。由于长期存在的HIV储存库是根除HIV的主要障碍，因此了解HIV-巨噬细胞相互作用的细胞和分子机制对于开发针对HIV和艾滋病流行的新型有效治疗策略至关重要。