Curcumin: A Multi-Mechanism HIV Microbicide

描述(由申请人提供)：随着艾滋病毒在世界范围内的流行升级，需要改进预防该疾病传播的战略。最有吸引力的方法之一是使用局部阴道/直肠内杀菌剂来阻止病毒的进入和传播。在为此目的而研究的化合物中，姜黄衍生的多酚姜黄素特别有希望，因为它通过几种机制抑制艾滋病毒复制。因此，它不会对病毒抗药性的发展做出重大贡献，应该继续积极应对人群中各种抗药性病毒。姜黄素结合并抑制HIV蛋白酶和HIV整合酶，这两种酶是病毒编码的三种酶中的两种。我们实验室最近的工作表明，姜黄素也可以通过其他机制阻止艾滋病毒的传播。具体地说，我们已经证明，艾滋病毒感染导致致炎细胞因子肿瘤坏死因子-a(TNF-a)的产生，并且肿瘤坏死因子-a上调宿主酶拓扑异构酶II的表达，而拓扑异构酶II是病毒复制的早期阶段所需的。由于姜黄素激活了配体依赖的抗炎核转录因子过氧化体增殖物激活受体？(PPAR-？)，我们预计姜黄素将在早期阶段阻止肿瘤坏死因子-α的产生并阻止病毒复制。我们还证明了PPAR-？抑制潜伏的艾滋病毒感染的激活。姜黄素有限的生物利用度阻碍了它在许多其他有吸引力的治疗应用中的使用，但我们最近开发了一种纳米颗粒配方，我们预计将优先将包裹的药物输送到艾滋病毒感染的细胞。基于这些实验结果，我们假设姜黄素将被证明是一种有效的艾滋病毒杀菌剂，通过在感染周期的不同时间点起作用的多种机制发挥作用。为了验证这一假设，我们提出了以下具体目标：1.在HIV感染的小鼠模型中，确定一种新的姜黄素制剂抑制通过阴道途径传播的能力；2.确定姜黄素是否通过激活PPAR-？来抑制HIV在人类细胞中的复制和激活。通过展示更多的姜黄素作用机制，我们期望在艾滋病毒耐药性日益增强的情况下支持其可能的长期有效性。验证我们的假设将为开发一种有效、廉价、无毒的局部杀微生物剂提供基础。

DESCRIPTION (provided by applicant): As the HIV epidemic escalates worldwide, improved strategies for preventing transmission of the disease are needed. One of the most attractive methods involves the use of topical intravaginal/intrarectal microbicides that block entry and spread of the virus. Among the compounds being investigated for this purpose, the turmeric- derived polyphenol curcumin is particularly promising because it inhibits HIV replication by several mechanisms. Accordingly, it will not contribute significantly to development of viral resistance and should remain active against the variety of resistant viruses in the population. Curcumin binds to and inhibits HIV protease and HIV integrase, two of the three enzymes encoded by the virus. Recent work in our laboratory suggests that curcumin may block the spread of HIV through other mechanisms as well. Specifically, we have shown that HIV infection leads to production of the proinflammatory cytokine tumor necrosis factor-a (TNF-a) and that TNF-a upregulates expression of the host enzyme topoisomerase II that is required for the earliest stages of viral replication. Since curcumin activates the ligand-dependent anti-inflammatory nuclear transcription factor peroxisome proliferator-activated receptor-? (PPAR-? ), we expect curcumin to block TNF-a production and halt virus replication at its earliest stages. We have also shown that activation of PPAR-? suppresses activation of latent HIV infection. Curcumin's limited bioavailability has constituted an impediment to its use for many otherwise attractive therapeutic applications, but we have recently developed a nanoparticle formulation that we anticipate will preferentially deliver the encapsulated drug to HIV-infected cells. Based on these experimental findings, we hypothesize that curcumin will prove an effective HIV microbicide, acting through multiple mechanisms that operate at different time points in the infection cycle. To test this hypothesis, we propose the following Specific Aims: 1. to determine the ability of a novel curcumin formulation to inhibit transmission via the intravaginal route in a mouse model of HIV infection; 2. to determine whether curcumin inhibits HIV replication and activation in human cells through mechanisms involving activation of PPAR-?. By demonstrating additional mechanisms of curcumin action we expect to support its likely long-term effectiveness in the presence of growing HIV resistance. Validation of our hypothesis would provide the foundation toward development of an effective, inexpensive, non-toxic topical microbicide.