Investigating the crosstalk between lipid metabolism and HIV

 描述(申请人提供)：世界卫生组织(WHO)估计，全球有3500万人感染艾滋病毒。改进了对病毒复制的治疗控制，显着增加了慢性艾滋病毒感染者的人数。艾滋病毒从更严重的感染转变为慢性感染的意外后果是出现了一些共病，使艾滋病毒阳性个人的临床管理复杂化。艾滋病毒阳性个体的脂代谢功能障碍(如高脂血症和脂营养不良)似乎是由艾滋病毒和抗逆转录病毒疗法(HAART)共同推动的。也许并不令人惊讶的是，冠状动脉疾病和动脉粥样硬化已经成为那些接受HAART治疗的HIV患者的主要共病。HIV感染、血脂异常和慢性炎症之间相互作用的分子机制仍然知之甚少。甾醇调节元件结合蛋白(SREBPs)是细胞和全身脂类平衡的关键转录调节因子，通过反式激活参与脂生物合成、脂蛋白输入、细胞内脂运输和储存的40+基因。SREBPs的遗传干扰导致细胞脂平衡和炎症的严重扰乱。研究表明，HIV感染上调了SREBP途径，推测是为了支持病毒复制的脂质生物合成要求。相反，I型干扰素信号下调免疫细胞中SREBP的活性，可能是为了控制病毒复制，表明SREBP转录轴在HIV免疫中发挥重要作用。与此一致，我们发现，细胞激活SREBPs能力的遗传扰动使巨噬细胞对艾滋病毒感染具有抵抗力。本R21申请中提出的实验旨在扩展这些有趣的初步观察，并确定SREBP转录程序影响活跃的HIV感染的分子机制。此外，我们将确定通过SREBP轴重新编程细胞脂代谢是否可以作为重新激活潜伏感染的新方法。这些研究的结果可以为艾滋病毒驱动的代谢编程之间的关系提供重要的机械性见解，并可能指出潜在的治疗机会，既可以减轻艾滋病毒感染，又可以纠正 血脂紊乱。

 DESCRIPTION (provided by applicant): The World Health Organization (WHO) estimates that 35 million people worldwide are living with HIV infections. Improved therapeutic control of viral replication has significantly increased the number of individuals living with chronic HIV infection An unintended consequence of shifting HIV from a more acute to chronic infection is the emergence of a number of co-morbidities that complicate clinical management of HIV-positive individuals. Lipid metabolic dysfunction (e.g., hyperlipidemia and lipodystrophy) in HIV-positive individuals appears to be driven by both HIV and anti-retroviral therapies (HAART)). Perhaps not surprisingly, coronary artery disease and atherosclerosis have become a major comorbidity for those individuals being treated for HIV with HAART. The molecular mechanisms underlying the crosstalk between HIV infection, dyslipidemia and chronic inflammation remain poorly understood. The Sterol Regulatory Element Binding Proteins (SREBPs) are key transcriptional regulators of cellular and whole body lipid homeostasis through their ability to transactivate 40+ genes involved in lipid biosynthesis, lipoprotein import, intracellular lipid transport and storage Genetic disruption of SREBPs results in severe perturbations in cellular lipid homeostasis and inflammation. Studies indicate that HIV infections upregulate the SREBP pathway, presumably to support the lipid biosynthetic requirements of viral replication. Conversely, type I IFN signaling downregulates SREBP activity in immune cells, presumably to control viral replication, suggest an important role for SREBP transcriptional axis in HIV immunity. Consistent with this, we find that genetic perturbations in the ability of a cell to activate SREBPs render macrophages resistant to HIV infection. The experiments proposed in this R21 application are designed to extend on these intriguing preliminary observations and define the molecular mechanisms by which the SREBP transcriptional program influences active HIV infection. Additionally, we will determine if reprogramming cellular lipid metabolism through the SREBP axis could serve as novel approach for re-activation of latent infection. The results of these studies could provide important mechanistic insights into the relationship between HIV driven metabolic programming and could point to potential therapeutic opportunities to both attenuate HIV infection, and correct lipid dysfunction.