Cocaine downregulates anti-HIV microRNAs in CD4+ T cells

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。

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.