Cocaine downregulates anti-HIV microRNAs in CD4+ T cells

可卡因下调 CD4 T 细胞中的抗 HIV microRNA

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：可卡因是艾滋病毒感染和艾滋病进展易感性的辅助因子。可卡因还能增加外周血单核细胞中 HIV-1 的复制，并增强动物模型中的病毒载量。此外，HIV 阳性可卡因使用者的 CD4+ T 细胞计数较低，并且 CD4+ T 细胞的下降速度显着加快。由于 CD4+ T 细胞是 HIV-1 感染和体内复制的主要靶标，因此有必要了解可卡因对 CD4+ T 细胞生物学的影响。该申请提出了一种潜在的新机制，可卡因可通过该机制增加 HIV-1 复制。有人提出，可卡因通过调节病毒进入来增强 HIV-1 的复制。我们的初步数据表明可卡因对 HIV-1 进入后的步骤进行调节。我们的数据还表明，可卡因下调原代 CD4+ T 细胞中的两种抗 HIV 细胞 microRNA (miRNA)：miR-125b 和 miR-328。由于这些 miRNA 靶向 HIV-1 mRNA 的 3'UTR，因此我们相信可卡因可能靶向 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细胞抗 HIV miRNA 的下调介导的。由于感染艾滋病毒的可卡因使用者的病毒载量较高，发展为艾滋病的风险也增加，因此我们的研究结果将对吸毒和艾滋病毒生物学产生深远的影响。我们将通过关注两个目标来检验我们的假设。目标 1：确定可卡因诱导的抗 HIV 细胞 miRNA 下调对 HIV-1 复制的影响。目标 2：检查可卡因诱导的抗 HIV 细胞 miRNA 下调是否激活潜伏感染的 HIV-1。公共卫生相关性：吸毒仍然是第二大常见的艾滋病毒暴露方式，非法药物是艾滋病毒感染和疾病进展易感性的辅助因素。尽管可卡因已被证明可以增强艾滋病毒的感染和复制，但其潜在机制仍不清楚。因此，该提案的重点是描述可卡因导致艾滋病毒/艾滋病的机制。