Caveolin-1 and negative modulation of HIV-1 replication

描述（由申请方提供）：Caveolin-1是一种高度定位于脂筏的完整膜蛋白，已显示可导致HIV-1蛋白表达显著降低。小窝是由小窝蛋白寡聚化形成的质膜内陷，参与细胞内胆固醇水平的调节。胆固醇和HIV-1生物学之间的联系已经通过我们实验室和其他人的研究得到了很好的建立。本提案中描述的工作将集中在通过阐明小窝蛋白-1和HIV-1生物发生之间的关系来进一步定义这种联系。我们假设小窝蛋白-1通过胆固醇依赖性机制在转录水平上对HIV-1复制产生负面影响。为了解决这一假设，本研究的目的1将寻求确定小窝蛋白介导的HIV-1抑制所涉及的途径。目的2研究caveolin-1在T细胞和巨噬细胞中的差异表达对HIV-1生物合成的影响。本研究的长期目标是确定能够限制HIV-1复制的新宿主因子。迄今为止，艾滋病毒/艾滋病已困扰地球仪近30年，在此期间，死亡人数不断增加，但几乎没有取得突破。抗逆转录病毒药物一直是一种有效的治疗方法，但获得和使用它们以及随后的副作用远非最佳解决方案。公共卫生相关性：迄今为止，预防方法收效甚微。确定可以抑制HIV表达的宿主因子，如caveolin-1，可以为新的治疗或预防策略提供见解。

DESCRIPTION (provided by applicant): Caveolin-1, an integral membrane protein highly localized to lipid rafts, has been shown to cause marked decrease in HIV-1 protein expression. Caveolae, the plasmalemmal invaginations formed by caveolin oligomerization, are involved in regulation of intracellular cholesterol levels. The connections between cholesterol and HIV-1 biology have been well established through studies performed by our lab and others. The work described in this proposal will focus on further defining that link by elucidating the relationship between caveolin-1 and HIV-1 biogenesis. We hypothesize that caveolin-1 negatively affects HIV-1 replication via a cholesterol dependent mechanisms at the transcriptional level. To address this hypothesis, Aim 1 of this study will seek to identify the pathways involved in caveolin-mediated HIV-1 inhibition. Aim 2 will examine the effects of differential expression of caveolin-1 on HIV-1 biogenesis in T cells and macrophages. The long-term goal of this study is to identify novel host factors capable of restricting HIV-1 replication. Thus far, HIV/AIDS has plagued the globe for nearly 30 years and in that time, few breakthroughs have accompanied the ever-increasing death toll. Anti-retrovirals have been an effective treatment, however access and use of them, and the subsequent side effects, is far from an optimal solution. PUBLIC HEALTH RELEVANCE: Prevention methods have had little success to date. Identifying host factors that can suppress HIV expression, like caveolin-1, could provide insight to novel therapeutic or preventive strategies.