Role of HIV glycan shield in mucus penetration

项目摘要 HIV-1感染是一种毁灭性的疾病，它不成比例地影响撒哈拉以南非洲的非洲人和非洲人-- 美国人在美国。阴道传播仍然是女性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。在这一途径中，病毒渗透的第一个障碍是粘液层。粘液是一种 由大量糖基化的蛋白质组成的拥挤的网络，称为粘蛋白。而阴道粘液通常对 遏制艾滋病毒的渗透，对于它何时以及为什么未能捕获病毒，并不是始终如一的基本问题 仍未得到答复。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分将首先接触到。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连在确定粘蛋白是否捕获病毒方面发挥了作用。的前提是 这一假说来自生物物理研究，研究发现病毒和粘蛋白上的每一种糖都只附着在 特定的糖伙伴。这一假说将用储存的宫颈阴道灌洗液样本(CVL)中的粘蛋白进行检验。 从妇女机构间艾滋病毒研究(WIHS)的参与者那里获得。这些样品被详尽地编目。 对照相关参与者的详细信息(例如，年龄、种族、月经周期等)。这项研究将选择配对样本 在细菌性阴道病(BV)发病前和发病期间从绝经前参与者中收集 而且艾滋病毒也是阴性的。已知在BV感染中粘液糖组成发生变化，并且BV还创建了一种生物 与艾滋病毒感染易感性增加相关的州。我们将确定病毒如何黏附在粘蛋白上 在匹配的BV+和BV-状态之间改变CVL，以检验糖组成和糖-糖之间的假设 黏附改变并在粘液捕获病毒的过程中起作用。这项研究意义重大，因为虽然病毒上的糖类 相对保守，粘蛋白上的那些随年龄、种族、共病和生殖周期而不同。如果假设是 诚然，病毒通过糖-糖的黏附而被捕获，因此它对粘液的渗透预计会随着 粘液糖组成。这意味着可以对患者的粘液糖组成进行筛查，以确定其对艾滋病毒的易感性。 感染。此外，脆弱性的系统性变化(与年龄、种族、生殖周期、共病等有关)。能 评估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。

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.