FAST TRACK Human epithelial â-defensins 2 and 3 inhibit HIV-1 replication Miguel E. Quin ˜ ones-Mateu a,b , Michael M. Lederman b , Zhimin Feng c , Bikram Chakraborty a , Jan Weber a , Hector R. Rangel a , Michael L. Marotta a , Muneer Mirza a , Bin Jiang c , Patti Kiser a , Kathy Medvik b , Scott F. Sieg b and Aaron Weinberg b,c Objective: Mechanisms underlying mucosal transmission of HIV-1 are incompletely understood. We describe the anti-HIV-1 activity of human â-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 down- modulation 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 â-defensin expres- sion in human oral epithelial cells and that â-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. & 2003 Lippincott Williams & Wilkins AIDS 2003, 17:F39–F48 Keywords: human beta-defensins, HIV-1, oral epithelial cells, viral transmission, receptors Introduction The mechanisms of resistance to HIV-1 infection in the oral cavity are incompletely understood. Epidemiological evidence indicates that per-oral infection with HIV-1 is uncommon when compared to the risks for infection through vaginal or rectal mucosa [1]. In addition, while persons chronically infected with HIV-1 may be infected Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. From the a Department of Virology, Lerner Research Institute, Cleveland Clinic Foundation, the b Center for AIDS Research, and the c School of Dentistry, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA. Correspondence to A. Weinberg, School of Dentistry, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA. Received: 24 July 2003; revised: 8 September 2003; accepted: 16 September 2003. DOI: 10.1097/01.aids.0000096878.73209.4f ISSN 0269-9370 & 2003 Lippincott Williams & Wilkins F39