Inhibition of HIV-1 infection by human α-defensin-5, a natural antimicrobial peptide expressed in the genital and intestinal mucosae

PLoS One. 2012;7(9):e45208. doi: 10.1371/journal.pone.0045208. Epub 2012 Sep 27.

Abstract

Background: α-defensin-5 (HD5) is a key effector of the innate immune system with broad anti-bacterial and anti-viral activities. Specialized epithelial cells secrete HD5 in the genital and gastrointestinal mucosae, two anatomical sites that are critically involved in HIV-1 transmission and pathogenesis. We previously found that human neutrophil defensins (HNP)-1 and -2 inhibit HIV-1 entry by specific bilateral interaction both with the viral envelope and with its primary cellular receptor, CD4. Despite low amino acid identity, human defensin-5 (HD5) shares with HNPs a high degree of structural homology.

Methodology/principal findings: Here, we demonstrate that HD5 inhibits HIV-1 infection of primary CD4(+) T lymphocytes at low micromolar concentration under serum-free and low-ionic-strength conditions similar to those occurring in mucosal fluids. Blockade of HIV-1 infection was observed with both primary and laboratory-adapted strains and was independent of the viral coreceptor-usage phenotype. Similar to HNPs, HD5 inhibits HIV-1 entry into the target cell by interfering with the reciprocal interaction between the external envelope glycoprotein, gp120, and CD4. At high concentrations, HD5 was also found to downmodulate expression of the CXCR4 coreceptor, but not of CCR5. Consistent with its broad spectrum of activity, antibody competition studies showed that HD5 binds to a region overlapping with the CD4- and coreceptor-binding sites of gp120, but not to the V3 loop region, which contains the major determinants of coreceptor-usage specificity.

Conclusion/significance: These findings provide new insights into the first line of immune defense against HIV-1 at the mucosal level and open new perspectives for the development of preventive and therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCR5 Receptor Antagonists
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Female
  • Gene Expression
  • Genitalia / immunology
  • Genitalia / virology
  • HIV Envelope Protein gp120 / antagonists & inhibitors*
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / metabolism
  • HIV Infections / immunology
  • HIV Infections / prevention & control*
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / growth & development
  • HIV-1 / metabolism
  • Humans
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / virology
  • Male
  • Mucous Membrane / immunology*
  • Mucous Membrane / virology
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / pharmacology
  • Virus Internalization / drug effects
  • alpha-Defensins / genetics
  • alpha-Defensins / immunology*
  • alpha-Defensins / pharmacology

Substances

  • CCR5 Receptor Antagonists
  • DEFA5 protein, human
  • HIV Envelope Protein gp120
  • Receptors, CCR5
  • Receptors, CXCR4
  • Recombinant Proteins
  • alpha-Defensins
  • human neutrophil peptide 1
  • human neutrophil peptide 2

Grants and funding

This work was supported in part by the Istituto Superiore di Sanità (ISS)-AIDS Project, Rome; the European Microbicides Project (EMPRO); and Combined Highly Active Anti-Retroviral Microbicides (CHAARM), EU, Brussels. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.