Role of HIV glycan shield in mucus penetration

项目总结

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.