Human epithelial beta-defensins 2 and 3 inhibit HIV-1 replication

AIDS. 2003 Nov 7;17(16):F39-48. doi: 10.1097/00002030-200311070-00001.

Abstract

Objective: Mechanisms underlying mucosal transmission of HIV-1 are incompletely understood. We describe the anti-HIV-1 activity of human beta-defensins (hBD), small cationic molecules that provide protection at mucosal surfaces.

Methods and results: HIV-1 induced expression of hBD-2 and -3 mRNA (but not that of hBD-1) 4- to 78-fold, respectively, above baseline in normal human oral epithelial cells. HIV-1 failed to infect these cells, even after 5 days of exposure. Recombinant hBD-1 had no antiviral activity, while rhBD-2 and rhBD-3 showed concentration-dependent inhibition of HIV-1 replication without cellular toxicity. Inhibition was greater against CXCR4-tropic than against the CCR5-tropic HIV-1 isolates. hBD-2 and hBD-3 induced an irreversible effect on virion infectivity, with electron microscopy confirming binding of hBDs to viral particles. Finally, hBD-2 and -3 induced downmodulation of the HIV-1 coreceptor CXCR4 (but not CCR5) in peripheral blood mononuclear cells and T lymphocytic cells as shown by confocal microscopy and flow cytometry.

Conclusions: This study shows for the first time that HIV-1 induces beta-defensin expression in human oral epithelial cells and that beta-defensins block HIV-1 replication via a direct interaction with virions and through modulation of the CXCR4 coreceptor. These properties may be exploited as strategies for mucosal protection against HIV-1 transmission.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Epithelial Cells / virology
  • Gene Expression Regulation
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Mouth Mucosa / metabolism
  • Mouth Mucosa / virology*
  • RNA, Messenger / genetics
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR4 / metabolism
  • Recombinant Proteins / pharmacology
  • Virus Replication / drug effects*
  • beta-Defensins / biosynthesis
  • beta-Defensins / genetics
  • beta-Defensins / pharmacology*

Substances

  • DEFB103A protein, human
  • DEFB4A protein, human
  • RNA, Messenger
  • Receptors, CCR5
  • Receptors, CXCR4
  • Recombinant Proteins
  • beta-Defensins