Defensins in STI-Mediated Enhanced HIV Infectivity

防御素在性传播感染介导的艾滋病毒感染性增强中的作用

• 批准号: 7927752
• 负责人: Theresa L Chang
• 金额: $ 20.79万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2010-07-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7927752
• 关键词: AIDS prevention; Accounting; Acute; Antibodies; Bacterial Vaginosis; CD4 Positive T Lymphocytes; Charge; Clinical; Clinical Research; Complex; Conditioned Culture Media; Defensins; Development; Endocervix; Epidemiology; Epithelial Cells; Female; Gene Expression Regulation; Genital system; Glycoproteins; Goals; HDAC5 gene; HDAC6 gene; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Heparin; Human; In Vitro; Individual; Infection; Inflammatory Response; Intestines; Lead; Ligands; Liquid substance; Longitudinal Studies; Mediating; Molecular; Mucosal Immunity; Mucous Membrane; Neisseria gonorrhoeae; Paneth Cells; Predisposition; Prevention strategy; Principal Investigator; Probability; Proteins; Publications; Regulation; Reporting; Research; Role; Route; Sexual Transmission; Sexually Transmitted Diseases; Site; Specimen; Structure; T-Cell Depletion; Vaccines; Vagina; Virus; Woman; analog; antimicrobial peptide; clinically significant; cytokine; domain mapping; insight; microbicide; mutant; novel; programs; public health relevance; response; transcytosis; transmission process

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.

描述（由申请人提供）：性传播是艾滋病毒感染的最常见途径，妇女占全球感染者的近一半。需要采取不同的预防策略来降低传播的可能性。流行病学和临床研究强烈表明，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的增加可能是多方面的（38，84），但了解性传播感染如何增加艾滋病毒感染对制定预防艾滋病毒的新战略至关重要。防御素是一种对先天性粘膜免疫有重要作用的抗菌肽。事实上，生殖器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具有潜在作用。人防御素5和6（HD5和HD6）是肠道中最丰富的抗微生物肽，肠道是急性HIV感染期间CD4+ T细胞耗竭的主要部位。HD5和HD6在潘氏细胞中组成型表达，但也在女性生殖器粘膜中发现。据报道，在患有C的个体的生殖液中诱导HD5。沙眼衣原体（CT）和N.淋病（GC）感染和细菌性阴道病（BV）。我们最近发表的文章表明，HD5和HD6显著增强HIV感染性，这些防御素的诱导有助于增强来自N.淋病暴露的阴道上皮细胞。与X4病毒相比，HD5和HD6对R5病毒的HIV增强作用更明显，这表明其临床意义，因为R5病毒几乎仅在性传播时检测到。重要的是，我们获得并分析了有或没有CT感染的妇女的宫颈标本，发现CT感染妇女的临床标本中HD5蛋白升高。此外，性病妇女宫颈标本中HD5水平升高与体外HIV感染性增强有关。我们推测，性传播感染可能有助于增加艾滋病毒的传播，通过上调先天效应，如防御素，反过来促进艾滋病毒的感染性和诱导生殖器粘膜的炎症反应。性传播感染后防御素水平升高的结果不仅可能导致对HIV感染的易感性增加，而且还对杀微生物剂和抗体诱导疫苗的效力产生负面影响。本研究的目的是建立防御素在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。这项研究将提供一个更好的理解的复杂功能的防御素在粘膜传播的艾滋病毒，并提供深入了解新的预防策略的发展，特别是在设置性传播感染。 公共卫生关系：本项目的目的是了解防御素在性传播感染（STI）介导的HIV感染性增强中的作用。