Targeting HIV infectivity by stimulating cholesterol efflux

描述（由申请人提供）：尽管抗HIV治疗最近取得了进展，但在HIV感染患者的长期治疗期间，药物毒性和耐药分离株的出现使得有必要寻找可用于开发新型抗病毒药物的新靶点。一个这样的目标是病毒胆固醇。许多报告表明，HIV的感染性主要取决于在组装过程中掺入病毒颗粒的胆固醇的量。我们发表的研究表明，HIV-1对胆固醇逆向转运（RCT）有负面影响，表明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：刺激胆固醇流出，RCT的细胞成分，有效地抑制HIV-1复制。在本申请中，我们拟研究TO- 901317的抗HIV活性机制，TO- 901317是一种合成的肝X受体（LXR）激动剂，是RCT的有效诱导剂。具体目标如下：具体目标1。确定LXR激动剂TO-901317的抗HIV活性机制。具体目标2。为了测试TO-901317在HIV感染的体内模型中的抗HIV活性，人源化Rag-/-3c-/-小鼠。拟议研究的基本原理是，如果了解LXR激动剂的抗HIV活性机制，并在HIV感染的体内模型中证明这些化合物的治疗潜力，则可以启动开发这些化合物作为抗HIV药物用于临床的计划。这些化合物可能对HIV感染患者非常有益。事实上，它们不仅可以通过一种新的机制靶向HIV复制，而且由于它们对RCT的刺激作用，还有助于预防HIV感染患者动脉粥样硬化的发展。此外，由于这些化合物靶向细胞机制而不是病毒酶，因此可以延迟或预防对这些药物的耐药性的发展。这一探索性建议完全符合本PA的目标，因为它涉及艾滋病毒研究中的一个创新概念，对基础研究和转化研究都有影响。完成后，这些研究预计将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：通过刺激胆固醇流出靶向HIV感染性拟议的研究与公共卫生高度相关，因为它将研究一类新的抗HIV药物。这些药物通过与其他抗HIV药物不同的机制靶向HIV感染性，因此将是用于高效抗逆转录病毒疗法的药物组合的有用补充。

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.