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CUTTING EDGE |
Defensin 3—A Novel Antagonist of the HIV-1 Coreceptor CXCR41
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* Department of Biological Sciences, Case School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106;
Department of Physiology and Biophysics, Case School of Medicine, Case Western Reserve University, Cleveland, OH; and
Department of Medicine, and
Center for AIDS Research, Case Western Reserve University/University Hospitals, Cleveland, OH 44106
Previously, we showed that human epithelial cell-derived 
-defensins (hBD)-2 and -3 block HIV-1 replication via a direct interaction with virions and through modulation of the CXCR4 coreceptor on immunocompetent cells. In the present study, we show that hBD-3 promotes directly the internalization of CXCR4 yet does not induce calcium flux, ERK (ERK-1/2) phosphorylation, or chemotaxis. hBD-3 competes with stromal-derived factor 1 (SDF-1), the natural ligand for CXCR4, for cellular binding and blocks SDF-1-induced calcium flux, ERK-1/2 phosphorylation, and chemotaxis, without effects on other G protein-coupled receptors. The novel activity of this endogenous CXCR4 antagonist may provide a new strategy for HIV therapies or immunomodulation. Moreover, since the SDF-1/CXCR4 axis plays an important role in hemopoiesis, neurogenesis, cardiogenesis, and angiogenesis, endogenous agents such as hBD-3 or its derivatives offer a new paradigm in immunoregulatory therapeutics and provide the opportunity to enhance future drug design.
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