Targeting HIV infectivity by stimulating cholesterol efflux

描述(申请人提供)：尽管最近在抗艾滋病毒治疗方面取得了进展，但在艾滋病毒感染者的长期治疗中，药物毒性和耐药分离株的出现要求寻找新的靶点，以用于开发新的抗病毒药物。其中一个目标就是病毒胆固醇。许多报告表明，HIV的传染性严重依赖于组装过程中病毒颗粒中胆固醇的含量。我们发表的研究表明，HIV-1对胆固醇反向运输(RCT)产生负面影响，这表明该病毒积极调节细胞胆固醇代谢。我们的初步实验揭示了一个意想不到的现象：刺激胆固醇外流，RCT的细胞成分，有效地抑制了HIV-1的复制。在这一应用中，我们建议研究TO-901317的抗HIV活性的机制，TO-510是一种合成的肝X受体激动剂，它是一种有效的随机对照试验的诱导剂。具体目标如下：具体目标1.确定LXR激动剂TO-901317的抗HIV作用机制。具体目的2.以人源化RAG-/-3c-/-小鼠为模型，检测TO-901317的抗HIV活性。这项研究的基本原理是，如果了解了LXR激动剂的抗HIV活性的机制，并在HIV感染的体内模型中证明了这些化合物的治疗潜力，就可以启动一个开发这些化合物作为抗HIV药物的计划。这些化合物可能对艾滋病毒感染患者非常有益。事实上，它们不仅以HIV复制为靶点，可能通过一种新的机制，而且由于它们对RCT的刺激作用，还将有助于防止HIV感染患者的动脉粥样硬化的发展。此外，由于这些化合物针对的是细胞机制，而不是病毒酶，因此可能会延缓或防止对这些药物的耐药性的发展。这一探索性建议完全符合该方案的目标，因为它涉及艾滋病毒研究中的一个创新概念，这一概念对基础研究和翻译研究都有影响。完成后，这些研究有望确定有效的抗艾滋病毒化合物通过一种不同于任何其他目前使用的药物的新机制发挥作用。公共卫生相关性：通过刺激胆固醇外流来瞄准艾滋病毒的传染性这项拟议的研究与公共卫生高度相关，因为它将调查一类新的抗艾滋病毒药物。这些药物以不同于其他抗艾滋病毒药物的机制靶向艾滋病毒感染性，因此将是用于高效抗逆转录病毒治疗的药物组合的有用添加剂。

DESCRIPTION (provided by applicant): Despite recent progress in anti-HIV therapy, drug toxicity and emergence of drug-resistant isolates during long- term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel anti-viral agents. One such target is the viral cholesterol. A number of reports demonstrated that HIV infectivity critically depends on the amount of cholesterol incorporated into the viral particle during assembly. Our published studies showed that HIV-1 negatively affects reverse cholesterol transport (RCT), suggesting that the virus actively regulates cellular cholesterol metabolism. Our preliminary experiments revealed an unexpected phenomenon: stimulation of cholesterol efflux, the cellular component of RCT, potently inhibited HIV-1 replication. In this application, we propose to investigate the mechanism of anti-HIV activity of TO- 901317, a synthetic agonist of liver X receptor (LXR), which is a potent inducer of RCT. The following Specific Aims will be addressed: Specific Aim 1. To determine the mechanism of anti-HIV activity of the LXR agonist TO-901317. Specific Aim 2. To test the anti-HIV activity of TO-901317 in an in vivo model of HIV infection, humanized Rag-/-3c-/- mice. The rationale for the proposed research is that if the mechanism of anti-HIV activity of LXR agonists is understood and therapeutic potential of these compounds is demonstrated in an in vivo model of HIV infection, a program to develop these compounds for clinical use as anti-HIV agents can be initiated. Such compounds may be highly beneficial for HIV-infected patients. Indeed, they will not only target HIV replication, presumably by a novel mechanism, but, due to their stimulatory effect on RCT, will also help prevent development of atherosclerosis in HIV-infected patients. In addition, since these compounds target a cellular mechanism and not a viral enzyme, development of resistance to these drugs may be delayed or prevented. This exploratory proposal is fully consistent with the goals of this PA as it addresses an innovative concept in HIV research which has implications both for basic and translational studies. Upon completion, these studies are expected to define potent anti-HIV compounds working through a novel mechanism different from that of any other currently used drug. PUBLIC HEALTH RELEVANCE: Targeting HIV infectivity by stimulating cholesterol efflux The proposed research is highly relevant to public health, as it will investigate a new class of anti-HIV agents. These agents target HIV infectivity by a mechanism different from that of other anti-HIV drugs, and thus would be a useful addition to a drug combination used for highly active anti-retroviral therapy.