Cargando…

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

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, hum...

Descripción completa

Detalles Bibliográficos
Autores principales: Valere, Kimyata, Lu, Wuyuan, Chang, Theresa L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618010/
https://www.ncbi.nlm.nih.gov/pubmed/28850095
http://dx.doi.org/10.3390/v9090244
_version_ 1783267091125633024
author Valere, Kimyata
Lu, Wuyuan
Chang, Theresa L.
author_facet Valere, Kimyata
Lu, Wuyuan
Chang, Theresa L.
author_sort Valere, Kimyata
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5618010
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-56180102017-09-29 Key Determinants of Human α-Defensin 5 and 6 for Enhancement of HIV Infectivity Valere, Kimyata Lu, Wuyuan Chang, Theresa L. Viruses Article 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. MDPI 2017-08-29 /pmc/articles/PMC5618010/ /pubmed/28850095 http://dx.doi.org/10.3390/v9090244 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Valere, Kimyata
Lu, Wuyuan
Chang, Theresa L.
Key Determinants of Human α-Defensin 5 and 6 for Enhancement of HIV Infectivity
title Key Determinants of Human α-Defensin 5 and 6 for Enhancement of HIV Infectivity
title_full Key Determinants of Human α-Defensin 5 and 6 for Enhancement of HIV Infectivity
title_fullStr Key Determinants of Human α-Defensin 5 and 6 for Enhancement of HIV Infectivity
title_full_unstemmed Key Determinants of Human α-Defensin 5 and 6 for Enhancement of HIV Infectivity
title_short Key Determinants of Human α-Defensin 5 and 6 for Enhancement of HIV Infectivity
title_sort key determinants of human α-defensin 5 and 6 for enhancement of hiv infectivity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618010/
https://www.ncbi.nlm.nih.gov/pubmed/28850095
http://dx.doi.org/10.3390/v9090244
work_keys_str_mv AT valerekimyata keydeterminantsofhumanadefensin5and6forenhancementofhivinfectivity
AT luwuyuan keydeterminantsofhumanadefensin5and6forenhancementofhivinfectivity
AT changtheresal keydeterminantsofhumanadefensin5and6forenhancementofhivinfectivity