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TRANSMISSION AND INFECTIVITY"
Interdisciplinary Biomedical Sciences Program
B.S. Rider University, 2010, Lawrenceville, NJ
Thesis Advisor: Theresa Chang, PhD
Department of Microbiology, Biochemistry and Molecular Genetics
Monday, April 24, 2017
10:00 A.M., ICPH Auditorium
The risk of HIV acquisition is significantly increased in individuals with sexually transmitted infections (STIs). Individuals with STIs have elevated levels of antimicrobial peptides, including human neutrophil peptides (HNPs) and human defensin 5 (HD5) in their genital secretions. Defensins are antimicrobial peptides important for mucosal innate immunity, but their roles in the early events of HIV transmission have not been fully elucidated. HD5 and HD6 promote HIV infectivity and contribute to enhanced HIV infection by Neisseria gonorrhoeae in vitro. HNPs display anti-HIV activity in vitro; however, increased levels of HNPs have been associated with an increased risk of HIV acquisition. The goal of this work is to define the underlying mechanisms by which alpha-defensins modulate HIV transmission and infectivity. We found that HNP1 increased epithelial permeability, altered tight junction patterns, and promoted HIV traversal of epithelial barriers. Determination of residues in HD5 and HD6 that modulated enhanced HIV infectivity, revealed that amino acids involved in charge, hydrophobicity, and self-association were critical for defensin activity. Interestingly, HD5 or HD6 analogs with impaired abilities to promote HIV infectivity were not able to block HIV enhancement by WT defensins. Analysis of viral determinants important for defensin-mediated HIV enhancement indicated the role of the HIV envelope glycoprotein and its glycosylation state in the defensin-HIV interaction. Specifically, HD5 and HD6 interacted with glycans and the V3 loop of the HIV envelope glycoprotein, as demonstrated by the ability of defensins to alter the neutralization profiles of antibodies against distinct epitopes on the HIV glycoprotein. Our study provided the molecular mechanisms of defensin-mediated enhancement of HIV infection, which offer new insights into developing a new strategy to prevent HIV transmission in the setting of STIs.