Defensins in STI-Mediated Enhanced HIV Infectivity

描述(申请人提供)：性传播是最常见的艾滋病毒感染途径，妇女占全球感染者的近一半。需要采取不同方法的预防战略，以减少传播的可能性。流行病学和临床研究有力地表明，性传播感染增加了艾滋病毒传播的可能性。虽然性传播感染对艾滋病毒传播增加的贡献可能是多方面的(38，84)，但了解性传播感染如何增强艾滋病毒感染对于制定预防艾滋病毒的新战略至关重要。防御素是一种对粘膜天然免疫至关重要的抗菌肽。事实上，生殖液中的防御素水平在性传播感染患者中经常升高，这表明在调节艾滋病毒传播方面可能起到了作用。人类防御素5和6(HD5和HD6)是肠道中含量最丰富的抗菌肽，是急性HIV感染时CD4+T细胞耗尽的主要部位。HD5和HD6在Paneth细胞中有结构性表达，在女性生殖器粘膜中也有表达。据报道，沙眼衣原体(CT)、淋球菌(GC)感染和细菌性阴道病(BV)患者的生殖液中有HD5的诱导。我们最近发表的文章表明，HD5和HD6显著增强了HIV的感染性，并且这些防御素的诱导有助于从淋球菌暴露的阴道上皮细胞的条件培养液中增强HIV感染。与X4病毒相比，HD5和HD6对HIV的增强作用在R5病毒中更为明显，这表明其临床意义，因为R5病毒几乎只在性传播时被检测到。重要的是，我们获得并分析了有或没有CT感染的妇女的宫颈内样本，发现CT感染妇女的临床样本中HD5蛋白升高。此外，性传播感染妇女宫颈内标本中HD5水平的升高与体外HIV感染性增强有关。我们假设，性传播感染可能通过上调防御素等先天效应物，从而促进艾滋病毒的感染性，并在生殖器粘膜中诱导炎症反应，从而促进艾滋病毒的传播。性传播感染后防御素水平升高的后果不仅可能导致艾滋病毒感染的易感性增加，而且还会对杀微生物剂和抗体诱导疫苗的效力产生负面影响。这项建议的目的是确定防御素在STI介导的增强HIV感染性中的作用，并剖析其潜在的分子机制。这项研究将更好地了解防御素在HIV粘膜传播中的复杂功能，并为开发新的预防策略，特别是在性传播感染的背景下提供洞察力。 公共卫生相关性：该项目的目标是了解防御素在性传播感染(STI)介导的艾滋病毒传染性增强中的作用。

DESCRIPTION (provided by applicant): Sexual transmission is the most common route of HIV infection and women account for nearly half of those infected worldwide. Prevention strategies employing different approaches are needed to reduce the probability of transmission. Epidemiologic and clinical studies strongly indicate that sexually transmitted infections (STIs) increase the likelihood of HIV transmission. Although the contribution of STIs to the increase in HIV transmission is likely to be multifaceted (38, 84), understanding how STIs enhance HIV infection is vital to the development of new strategies for the prevention of HIV. Defensins are antimicrobial peptides important to innate mucosal immunity. Indeed, the levels of defensins in genital fluid are frequently elevated in individuals with STIs, suggesting a potential role in modulating HIV transmission. Human defensins 5 and 6 (HD5 and HD6) are the most abundant antimicrobial peptides in the intestine, a major site of CD4+ T cell depletion during acute HIV infection. HD5 and HD6 are constitutively expressed in Paneth cells, but also found in the female genital mucosa. Induction of HD5 has been reported in genital fluid from individuals with C. trachomatis (CT) and N. gonorrhoeae (GC) infection, and bacterial vaginosis (BV). Our recent publication indicates that HD5 and HD6 significantly enhance HIV infectivity and that induction of these defensins contributes to enhanced HIV infection of conditioned media from N. gonorrhoeae-exposed vaginal epithelial cells. The HIV enhancing effect of HD5 and HD6 is more pronounced with R5 virus compared to X4 virus, suggesting its clinical significance as R5 viruses are almost exclusively detected upon sexual transmission. Importantly, we obtained and analyzed endocervical specimens from women with or without CT infection and found that HD5 proteins were elevated in clinical specimens from CT-infected women. Additionally, elevated levels of HD5 in endocervical specimens from women with STIs were associated with enhanced in vitro HIV infectivity. We hypothesize that STIs may contribute to increased HIV transmission by up-regulating innate effectors such as defensins that in turn promote HIV infectivity and induce inflammatory responses in the genital mucosa. The consequence of elevated levels of defensins in response to STIs may not only lead to increased susceptibility to HIV infection but also negatively impact the efficacy of microbicides and antibody-inducing vaccines. The goal of this proposal is to establish the role of defensins in STI-mediated enhanced HIV infectivity and dissect its underlying molecular mechanism. This study will provide a better understanding of the complex function of defensins in mucosal transmission of HIV, and offer insight into the development of novel prevention strategies, especially in the setting of STIs. PUBLIC HEALTH RELEVANCE: The goal of this project is aim to understand the role of defensins in sexual transmitted infection (STI)-mediated enhancement of HIV infectivity.