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感染是一种毁灭性的疾病，严重影响撒哈拉以南非洲和非洲的非洲人， 美国人在美国。阴道传播仍然是妇女感染艾滋病毒的最常见途径， 全球超过一半的艾滋病毒感染者。在这条途径中，病毒渗透的第一道屏障是粘液层。粘液是一种 密集的糖基化蛋白质网络称为粘蛋白。虽然阴道粘液通常对 包含艾滋病毒的渗透，它是不一致的和根本的问题，何时以及为什么它不能捕获病毒 仍然没有答案。像粘蛋白分子一样，HIV病毒也是高度糖基化的。当HIV-1进入粘液时， 病毒和粘液之间的糖将首先接触。这项研究提出了一个新的假设， 在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中起作用。的前提 这一假说来自生物物理学研究，该研究发现病毒和粘蛋白上的每一种糖都只粘附在 特殊的糖伴侣将用储存的宫颈阴道灌洗液样本（CVL）中的粘蛋白检验该假设 来自妇女机构间艾滋病毒研究（WIHS）的参与者。这些样本被详尽地编目 对照相关参与者细节（例如，年龄、种族、月经周期等）。研究将选择配对样本 在细菌性阴道病（BV）发作之前和期间从绝经前受试者亚组中采集 也是HIV阴性众所周知，粘液糖成分会在BV感染中发生变化，并且BV还会产生生物学作用 这种状态与艾滋病易感性增加有关。我们将确定病毒如何粘附粘蛋白 CVL在匹配的BV+和BV-状态之间变化，以检验糖组成和糖-糖 粘附发生变化并在粘液截留病毒中起作用。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-糖粘附包裹，因此其对粘液的渗透预计会随着 粘液糖组成。这意味着可以筛查患者粘液糖组成对HIV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 评估这些措施的最终目标是确定改变妇女对艾滋病毒感染的易感性的可能方法。