Cocaine downregulates anti-HIV microRNAs in CD4+ T cells

描述(由申请人提供)：可卡因是艾滋病毒感染和艾滋病进展的易感性的辅助因素。可卡因还会增加外周血单核细胞中HIV-1的复制，并在动物模型中提高病毒载量。此外，HIV阳性可卡因吸毒者的CD4T细胞计数较低，且CD4T细胞下降的速度明显加快。由于CD4T细胞是HIV-1在体内感染和复制的主要靶点，了解可卡因对CD4T细胞生物学的影响是非常必要的。这项申请提出了一种潜在的新机制，通过这种机制，可卡因可能会增加HIV-1的复制。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进入后的步骤进行了调节。我们的数据还显示，可卡因下调了原代CD4T细胞中两个抗HIV细胞microRNAs(MiRNAs)，miR-125b和miR-328。由于这些miRNAs针对的是HIV-1mRNA的3‘非编码区，我们认为可卡因可能针对HIV-1复制的转录后步骤。因此，我们假设可卡因促进HIV-1复制和增加病毒载量是通过下调细胞内抗HIV miRNAs来实现的。由于感染艾滋病毒的可卡因使用者病毒载量更高，发展为艾滋病的风险更高，我们的发现将对药物使用和艾滋病毒生物学产生深远影响。我们将通过关注两个目标来检验我们的假设。目的1：研究可卡因诱导的抗HIV细胞miRNAs表达下调对HIV-1复制的影响。目的2：检测可卡因诱导的抗HIV细胞miRNAs下调是否激活潜伏感染的HIV-1。 与公共卫生有关：吸毒仍然是接触艾滋病毒的第二种最常见的方式，非法药物是艾滋病毒感染和疾病进展的易感性的辅助因素。尽管可卡因已被证明可促进艾滋病毒感染和复制，但其潜在机制仍不清楚。因此，这项提案的重点是描述可卡因导致艾滋病毒/艾滋病的机制。

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.