Cocaine downregulates anti-HIV microRNAs in CD4+ T cells

可卡因下调 CD4 T 细胞中的抗 HIV microRNA

• 批准号: 8329914
• 负责人: Chandravanu Dash
• 金额: $ 14.2万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329914
• 关键词: 3' Untranslated Regions; AIDS/HIV problem; Acceleration; Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Area; Award; Biology; CD4 Positive T Lymphocytes; Cell Count; Cell Line; Cell physiology; Cells; Cellular biology; Cessation of life; Cocaine; Cocaine Users; Data; Disease Progression; Down-Regulation; Drug abuse; Drug usage; Event; Exposure to; Genetic Transcription; Goals; HIV; HIV Infections; HIV Seropositivity; HIV-1; Illicit Drugs; Infection; Life Cycle Stages; Measurement; Measures; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Morphine; National Institute of Drug Abuse; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Play; Predisposition; Research; Research Personnel; Rest; Retrovirology; Risk; Role; Testing; Transcript; Translations; Viral; Viral Load result; base; career; cofactor; drug of abuse; in vivo; innovation; novel; programs; psychosocial

DESCRIPTION (provided by applicant): Cocaine serves as a cofactor for susceptibility to HIV infection and AIDS progression. Cocaine also increases HIV-1 replication in peripheral blood mononuclear cells and enhances viral load in animal models. Furthermore, HIV positive cocaine users have lower CD4+ T cell counts and have a significant acceleration of decline of CD4+ T cells. Since CD4+ T cells are primary targets for HIV-1 infection and replication in vivo, it is imperative to understand the effects of cocaine on CD4+ T cell biology. This application proposes a potentially novel mechanism by which cocaine may increase HIV-1 replication. It has been proposed that cocaine enhances HIV-1 replication by regulating viral entry. Our preliminary data suggest modulation of HIV-1 post entry steps by cocaine. Our data also reveal that cocaine down regulates two anti-HIV cellular microRNAs (miRNAs), miR-125b and miR-328 in primary CD4+ T cells. Since these miRNAs target the 3'UTR of HIV-1 mRNA, we believe cocaine may target post-transcription steps of HIV-1 replication. Therefore, we hypothesize that enhanced HIV-1 replication and increased viral load by cocaine is mediated by down regulation of cellular anti-HIV miRNAs. Since HIV infected cocaine users have higher viral loads and increased risk of progression to AIDS, our findings will have far reaching implications in drug use and HIV biology. We will test our hypothesis by focusing on two aims. Aim 1: Determine effects of cocaine-induced down-regulation of anti-HIV cellular miRNAs on HIV-1 replication. Aim 2: Examine whether cocaine-induced down-regulation of anti-HIV cellular miRNAs activate latently infected HIV-1. PUBLIC HEALTH RELEVANCE: Drug use remains the second most common mode of exposure to HIV and illicit drugs serve as cofactors for susceptibility to HIV infection and disease progression. Although cocaine has been shown to enhance HIV infection and replication, the underlying mechanism remains unclear. Therefore, the focus of this proposal is to delineate the mechanism by which cocaine contributes to HIV/AIDS.

描述（由申请人提供）：辅因子是HIV感染易感性和AIDS进展的辅助因子。在动物模型中，辅酶A还可增加外周血单核细胞中的HIV-1复制，并提高病毒载量。此外，HIV阳性可卡因使用者的CD 4 + T细胞计数较低，并且CD 4 + T细胞的下降速度显著加快。由于CD 4 + T细胞是HIV-1感染和体内复制的主要靶细胞，因此必须了解可卡因对CD 4 + T细胞生物学的影响。这项申请提出了一种潜在的新机制，可卡因可能会增加HIV-1的复制。已经提出可卡因通过调节病毒进入来增强HIV-1复制。我们的初步数据表明可卡因对HIV-1进入后步骤的调节。我们的数据还显示，可卡因下调两种抗HIV细胞microRNAs（miRNAs），miR-125 b和miR-328在原代CD 4 + T细胞。由于这些miRNA靶向HIV-1 mRNA的3 'UTR，我们认为可卡因可能靶向HIV-1复制的转录后步骤。因此，我们假设可卡因增强HIV-1复制和增加病毒载量是通过下调细胞抗HIV miRNA介导的。由于感染艾滋病毒的可卡因使用者有更高的病毒载量和更高的发展为艾滋病的风险，我们的研究结果将在药物使用和艾滋病毒生物学方面产生深远的影响。我们将通过关注两个目标来检验我们的假设。目的1：确定可卡因诱导的抗HIV细胞miRNAs下调对HIV-1复制的影响。目的2：检测可卡因诱导的抗HIV细胞miRNA下调是否激活潜伏感染的HIV-1。 公共卫生相关性：吸毒仍然是感染艾滋病毒的第二种最常见的方式，非法药物是易受艾滋病毒感染和疾病进展的辅助因素。虽然可卡因已被证明会增强艾滋病毒的感染和复制，但其潜在机制仍不清楚。因此，本建议的重点是阐明可卡因助长艾滋病毒/艾滋病的机制。