Investigating the crosstalk between lipid metabolism and HIV

 描述（由申请人提供）：世界卫生组织（WHO）估计，全球有3500万人感染艾滋病毒。改善病毒复制的治疗控制显著增加了患有慢性HIV感染的个体的数量。将HIV从更急性感染转变为慢性感染的意外后果是出现了许多使HIV阳性个体的临床管理复杂化的合并症。脂质代谢功能障碍（例如，高脂血症和脂肪代谢障碍）似乎是由HIV和抗逆转录病毒疗法（HAART）两者驱动的）。也许并不奇怪，冠状动脉疾病和动脉粥样硬化已成为那些接受HAART治疗的HIV患者的主要合并症。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。固醇调节元件结合蛋白（SREBP）是细胞和全身脂质稳态的关键转录调节因子，通过其反式激活参与脂质生物合成、脂蛋白输入、细胞内脂质转运和储存的40多个基因的能力，SREBP的遗传破坏导致细胞脂质稳态和炎症的严重扰动。研究表明，HIV感染上调SREBP途径，可能是为了支持病毒复制的脂质生物合成要求。相反，I型IFN信号下调免疫细胞中的SREBP活性，推测是为了控制病毒复制，表明SREBP转录轴在HIV免疫中的重要作用。与此一致，我们发现细胞激活SREBP的能力的遗传扰动使巨噬细胞对HIV感染具有抗性。在R21申请中提出的实验旨在扩展这些有趣的初步观察，并定义SREBP转录程序影响活性HIV感染的分子机制。此外，我们将确定通过SREBP轴重编程细胞脂质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HIV驱动的代谢编程之间的关系提供重要的机制见解，并且可以指出潜在的治疗机会，以减弱HIV感染，并纠正HIV感染。 脂质功能障碍

 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.