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Viruses 2017, 9(9), 244; doi:10.3390/v9090244

Key Determinants of Human α-Defensin 5 and 6 for Enhancement of HIV Infectivity

1
Department of Microbiology and Molecular Genetics, Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA
2
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21250, USA
3
Public Health Research Institute, Rutgers University, New Jersey Medical School, 225 Warren Street, Newark, NJ 07103, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Eric O. Freed
Received: 3 July 2017 / Revised: 13 August 2017 / Accepted: 24 August 2017 / Published: 29 August 2017
(This article belongs to the Special Issue Defensins)
View Full-Text   |   Download PDF [2693 KB, uploaded 29 August 2017]   |  

Abstract

Defensins are antimicrobial peptides important for mucosal innate immunity. They exhibit a broad spectrum of activity against bacteria, viruses, and fungi. Levels of α-defensins are elevated at the genital mucosa of individuals with sexually transmitted infections (STIs). Somewhat paradoxically, human α-defensin 5 and 6 (HD5 and HD6) promote human immunodeficiency virus (HIV) infectivity, and contribute to STI-mediated enhancement of HIV infection in vitro. Specific amino acid residues of HD5 and HD6 that are crucial for antimicrobial activities have been characterized previously; however, the key determinants of defensins responsible for enhancement of HIV infectivity are not known. Here, we have identified residues of HD5 and HD6 that are required for enhancement of HIV attachment and infection. Most of these residues are involved in hydrophobicity and self-association of defensins. Specifically, we found that mutant defensins L16A-HD5, E21me-HD5, L26A-HD5, Y27A-HD5, F2A-HD6, H27W-HD6, and F29A-HD6 significantly lost their ability to promote HIV attachment and infection. L29A mutation also reduced HIV infection-enhancing activity of HD5. Additionally, a number of mutations in charged residues variably affected the profile of HIV attachment and infectivity. One HD5 charged mutation, R28A, notably resulted in a 34–48% loss of enhanced HIV infectivity and attachment. These results indicate that defensin determinants that maintain high-ordered amphipathic structure are crucial for HIV enhancing activity. In a comparative analysis of the mutant defensins, we found that for some defensin mutants enhancement of HIV infectivity was associated with the reverse transcription step, suggesting a novel, HIV attachment-independent, mechanism of defensin-mediated HIV enhancement. View Full-Text
Keywords: defensins; HIV infectivity; attachment defensins; HIV infectivity; attachment
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Valere, K.; Lu, W.; Chang, T.L. Key Determinants of Human α-Defensin 5 and 6 for Enhancement of HIV Infectivity. Viruses 2017, 9, 244.

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