Characterization of Gallic Acid as a Novel HIV Microbicide Candidate

 描述(申请人提供)：艾滋病毒/艾滋病在人中的持续传播主要是由于性接触受艾滋病毒污染的精液/精浆(SP)所致。SP含有HIV感染性增强因子，包括至少两类主要的自然产生的淀粉样纤维，它们促进病毒粒子与细胞靶标的附着。SP还含有多种促炎因子，可通过促进细胞因子/趋化因子的产生间接促进艾滋病毒的传播，这些细胞因子/趋化因子可招募允许细胞，促进艾滋病毒跨生殖器上皮的移位，并激活艾滋病毒基因转录。SP的这些直接和间接增强艾滋病毒的作用可以帮助解释在开发高效艾滋病毒杀菌剂方面普遍缺乏成功的原因。为了确定SP增强HIV活性的抑制物，我们对HIV增强的SP淀粉样蛋白的解聚体进行了小分子筛选。我们确定了四种Hit，其中之一是没食子酸(GA)，这是一种存在于葡萄籽中的自然存在的化合物，此前有报道称，它可以通过与神经系统疾病相关的淀粉样多肽来抑制纤维的形成。我们证实GA抑制SP和SP淀粉样蛋白增强HIV感染的能力。有趣的是，此前已有报道称GA具有抗炎作用，包括抑制核因子-kB信号的能力。综上所述，这些观察表明，GA可能通过双重靶向淀粉样蛋白和SP的促炎特性来抑制SP介导的HIV感染的增强。在这个项目中，我们描述了GA和其他3种化合物HITS抑制SP淀粉样蛋白活性的条件及其发生的机制(目标1)，并确定GA是否抑制SP诱导的生殖器炎症，从而促进传播(目标2)。这些研究将揭示GA和其他化学解离剂是否会成为进一步开发为HIV微生物剂的一种有前途的化合物，并为SP增强HIV传播的多种机制提供见解。

 DESCRIPTION (provided by applicant): The continuing spread of HIV/AIDS in people is predominantly fueled by sexual exposure to HIV-contaminated semen/seminal plasma (SP). SP harbors HIV infectivity enhancing factors that include at least two major classes of naturally occurring amyloid fibrils that promote virion attachment to cellular targets. SP also harbors a variety of pro- inflammatory factors that can indirectly facilitate HIV transmission by promoting the production of cytokines/chemokines that recruit permissive cells, enhance the translocation of HIV across the genital epithelium, and activate HIV gene transcription. These direct and indirect HIV- enhancing effects of SP could help explain the general lack of success in developing a highly efficacious HIV microbicide. To identify inhibitors of SP's HIV-enhancing activity, we conducted a small molecule screen for disassemblers of HIV-enhancing SP amyloids. We identified four hits, one of which was gallic acid (GA), a naturally-occurring compound present in grape seeds that has previously been reported to inhibit fibril formation by amyloidogenic peptides associated with neurological diseases. We confirmed that GA inhibits the ability of both SP and SP amyloids to enhance HIV infection. Interestingly, GA has previously been reported to harbor anti-inflammatory properties, including the ability to inhibit NF-kB signaling. Together, these observations suggest that GA may inhibit SP-mediated enhancement of HIV infection by dually targeting the amyloids and the pro-inflammatory properties of SP. In this project, we characterize the conditions under which GA and the other 3 compound hits inhibit the activity of SP amyloids and the mechanisms by which this occurs (Aim 1), and determine whether GA inhibits SP-induced genital inflammation that can facilitate transmission (Aim 2). These studies will reveal whether GA and other chemical disassemblers would be a promising compound to develop further as a component of an HIV microbicide, and provide insights into the multiple mechanisms by which SP can enhance HIV transmission.