title: Inhibition of HIV-1 infection by human α-defensin-5, a natural antimicrobial peptide expressed in the genital and intestinal mucosae.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Unit of Human Virology, Department of Biological and Technological Research, San Raffaele Scientific Institute, Milan, Italy. lucinda.furci@hsr.it
authors.forename: Lucinda
authors.initials: L
authors.lastname: Furci
authors.forename: Monica
authors.initials: M
authors.lastname: Tolazzi
authors.forename: Francesca
authors.initials: F
authors.lastname: Sironi
authors.forename: Lia
authors.initials: L
authors.lastname: Vassena
authors.forename: Paolo
authors.initials: P
authors.lastname: Lusso
mesh_terms: D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D005835:Genitalia / Q000276:immunology / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology* / Q000821:virology; D008297:Male; D009092:Mucous Membrane / Q000276:immunology* / Q000821:virology; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects; D023084:alpha-Defensins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology
chemical_list: D065100:CCR5 Receptor Antagonists; C500225:DEFA5 protein, human; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C406416:human neutrophil peptide 2