Role of HIV glycan shield in mucus penetration

HIV 聚糖盾在粘液渗透中的作用

• 批准号: 10516749
• 负责人: Preethi Lourdes Chandran
• 金额: $ 7.73万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516749
• 关键词: Adhesions; Affect; Africa South of the Sahara; African; African American population; Age; Atomic Force Microscopy; Bacterial Vaginosis; Binding; Biological; Cells; Chronic Disease; Clinical; Collaborations; Crowding; Data; Deposition; Development; Diffuse; Disease; Epithelium; Estrogens; Ethnic Origin; Excision; Goals; HIV; HIV Infections; HIV Seronegativity; HIV risk; HIV-1; Image; Infection; Investigation; Irrigation; Lead; Link; Mediating; Menstrual cycle; Methods; Microscopy; Minority Groups; Mission; Mucins; Mucous Membrane; Mucous body substance; Nature; Participant; Particle Size; Patients; Pattern; Penetration; Pilot Projects; Polysaccharides; Predisposition; Premenopause; Protein Glycosylation; Proteins; Race; Reporting; Role; Route; Sampling; Site; Source; Surface; Technology; Testing; Tissues; United States National Institutes of Health; Vagina; Variant; Vesicular stomatitis Indiana virus; Virus; Woman; Women' s Interagency HIV Study; biobank; biophysical analysis; cervicovaginal; comorbidity; disparity reduction; embryo tissue; glycosylation; high reward; high risk; internal control; light scattering; new therapeutic target; novel; patient population; prevent; reproductive; screening; sugar; transmission process; vaginal transmission; viral transmission

Project Summary HIV-1 infection is a devastating disorder which disproportionally affects Africans in Sub-Saharan Africa and African- Americans in US. Vaginal transmission remains the most common route of HIV infection among women who represent over half of HIV infections globally. In this route, the first barrier to virus penetration is the mucus layer. The mucus is a crowded network of heavily-glycosylated proteins called mucins. While the vaginal mucus is generally effective in containing HIV penetration, it is not consistent and fundamental questions about when and why it fails to trap virus remain unanswered. Like mucin molecules, the HIV virus is also heavily glycosylated. When HIV-1 enters mucus, the sugars between the virus and mucus will be the first to make contact. This study proposes a novel hypothesis that the adhesions that form between the virus and mucin sugars play a role in determining if mucin traps virus. The premise for the hypothesis comes from biophysical studies which found that each of the sugars on virus and mucin adhere only to specific sugar partners. The hypothesis will be tested with mucins from stored cervicovaginal lavage samples (CVL) obtained from participants in the Women's Interagency HIV Study (WIHS). The samples are exhaustively catalogued against relevant participant details (e.g., age, ethnicity, menstrual cycle, etc.). The study will select paired samples collected prior and during an episode of Bacterial Vaginosis (BV) from a subset of participants who are premenopausal and also HIV negative. The mucus sugar composition is known to shift in BV infection, and BV also creates a biologic state that is associated with increased susceptibility to HIV acquisition. We will determine how virus adhesion to mucins varies in CVL between matched BV+ and BV- states to test the hypothesis that sugar composition and sugar-sugar adhesions change and play a role in virus entrapment by mucus. The study is significant because while sugars on virus are relatively conserved, those on mucins vary with age, race, comorbidities, and reproductive cycle. If the hypothesis is true, the virus entrapment by sugar-sugar adhesion and therefore its penetration into mucus is expected to change with mucus sugar composition. This implies that patient mucus sugar composition can be screened for vulnerability to HIV infection. Moreover, systematic changes in the vulnerability (with age, race, reproductive cycle, co-morbidities, etc.) can be assessed with the ultimate goal of identifying possible methods to alter women's susceptibility to HIV infection.

项目摘要 HIV-1感染是一种毁灭性疾病，对撒哈拉以南非洲和非洲 - 非洲非洲人的影响不成比例 美国人。阴道传播仍然是代表的女性中最常见的艾滋病毒感染途径 全球艾滋病毒感染的一半以上。在这种途径中，病毒穿透的第一个障碍是粘液层。粘液是 拥挤的重糖基化蛋白质网络称为粘蛋白。而阴道粘液通常在 包含艾滋病毒的渗透，它不一致，并且关于何时以及为什么无法捕获病毒的根本问题 保持没有答复。像粘蛋白分子一样，HIV病毒也被大量糖基化。当HIV-1进入粘液时 病毒和粘液之间的糖将是第一个接触的糖。这项研究提出了一个新的假设 病毒和粘蛋白糖之间形成的粘附在确定粘蛋白捕获病毒中是否起作用。前提 该假设来自生物物理研究，该研究发现病毒和粘蛋白上的每种糖仅粘附于 特定的糖伴侣。该假设将用储存的宫颈阴道灌洗样品（CVL）的粘蛋白进行测试 从妇女间艾滋病毒研究（WIHS）的参与者获得。样品详尽地分类 相对于相关的参与者细节（例如，年龄，种族，月经周期等）。该研究将选择配对样品 从一部分的参与者中收集了先前和期间细菌性阴道病（BV）的发作 以及HIV阴性。已知粘液糖成分会在BV感染中转移，并且BV也会产生生物学 与增加对艾滋病毒获取的易感性有关的状态。我们将确定病毒对粘蛋白的粘附方式 匹配的BV+和BV状态之间的CVL各种，以检验糖成分和糖糖的假设 粘附在粘液中改变并在病毒捕获中发挥作用。这项研究很重要，因为虽然病毒上的糖 相对保守，粘蛋白上的患者随着年龄，种族，合并症和生殖周期而变化。如果假设是 的确，糖糖粘附的病毒捕获，因此预计其渗透到粘液中会随着 粘液糖成分。这意味着可以筛选患者粘液糖成分以发现艾滋病毒的脆弱性 感染。此外，脆弱性（随着年龄，种族，生殖周期，合并症等）的系统变化可以 评估以确定可能改变妇女对艾滋病毒感染的敏感性的可能方法的最终目标。