Role of HIV glycan shield in mucus penetration

HIV 聚糖盾在粘液渗透中的作用

• 批准号: 10403303
• 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 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403303
• 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; Crowding; Data; Deposition; Development; Diffuse; Disease; Epithelial; 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; Play; Polysaccharides; Predisposition; Premenopause; 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; exhaustion; 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.

项目概要 HIV-1 感染是一种毁灭性的疾病，对撒哈拉以南非洲地区的非洲人和非洲人影响尤为严重。 在美国的美国人。阴道传播仍然是女性中最常见的艾滋病毒感染途径 全球一半以上的艾滋病毒感染者。在这条路线中，病毒渗透的第一道屏障是粘液层。粘液是一种 被称为粘蛋白的高度糖基化蛋白质的拥挤网络。虽然阴道粘液通常有效 遏制艾滋病毒渗透，关于何时以及为何未能捕获病毒的问题并不一致 仍然没有得到答复。与粘蛋白分子一样，HIV 病毒也被高度糖基化。当 HIV-1 进入粘液时， 病毒和粘液之间的糖将首先发生接触。这项研究提出了一个新的假设，即 病毒和粘蛋白糖之间形成的粘附在确定粘蛋白是否捕获病毒方面发挥着重要作用。前提为 该假设来自生物物理学研究，该研究发现病毒和粘蛋白上的每种糖只粘附在 特定的糖合作伙伴。该假设将用来自储存的宫颈阴道灌洗样本 (CVL) 的粘蛋白进行检验 从妇女机构间艾滋病毒研究 (WIHS) 的参与者处获得。样本已详尽编目 根据相关的参与者详细信息（例如年龄、种族、月经周期等）。该研究将选择配对样本 在细菌性阴道病 (BV) 发作前和发作期间从绝经前参与者子集收集 并且艾滋病毒呈阴性。众所周知，粘液糖成分会在 BV 感染中发生变化，并且 BV 还会产生一种生物制剂 状态与感染艾滋病毒的易感性增加有关。我们将确定病毒如何粘附到粘蛋白上 匹配的 BV+ 和 BV- 状态之间的 CVL 有所不同，以检验糖成分和糖-糖的假设 粘连发生变化并在粘液捕获病毒中发挥作用。这项研究意义重大，因为虽然糖对病毒 相对保守，粘蛋白上的那些随年龄、种族、合并症和生殖周期而变化。如果假设是 确实，病毒被糖-糖粘附所捕获，因此其对粘液的渗透预计会随着 粘液糖成分。这意味着可以通过患者粘液糖成分来筛查其对艾滋病毒的易感性 感染。此外，脆弱性的系统性变化（年龄、种族、生殖周期、合并症等）可以 进行评估的最终目标是确定改变妇女对艾滋病毒感染易感性的可能方法。