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


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.
Department of Virology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Miguel E
ME
Quiñones-Mateu
Michael M
MM
Lederman
Zhimin
Z
Feng
Bikram
B
Chakraborty
Jan
J
Weber
Hector R
HR
Rangel
Michael L
ML
Marotta
Muneer
M
Mirza
Bin
B
Jiang
Patti
P
Kiser
Kathy
K
Medvik
Scott F
SF
Sieg
Aaron
A
Weinberg
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000821:virology; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009061:Mouth Mucosa / Q000378:metabolism / Q000821:virology*; D012333:RNA, Messenger / Q000235:genetics; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*; D023083:beta-Defensins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*
C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D012333:RNA, Messenger; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D023083:beta-Defensins