Cutting edge: human beta defensin 3--a novel antagonist of the HIV-1 coreceptor CXCR4.
Previously, we showed that human epithelial cell-derived beta-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.
Feng
Zhimin
Z
Department of Biological Sciences, Case School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Dubyak
George R
GR
Lederman
Michael M
MM
Weinberg
Aaron
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism*; D020013:Calcium Signaling / Q000276:immunology; D002217:Carbachol / Q000378:metabolism; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D023083:beta-Defensins / Q000378:metabolism / Q000502:physiology*
D019380:Anti-HIV Agents; D018946:Chemokine CCL5; C422950:DEFB103A protein, human; D019718:Receptors, CXCR4; D023083:beta-Defensins; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000255:Adenosine Triphosphate; D002217:Carbachol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3