The mechanisms of resistance to HIV-1 infection in the human oral cavity are incompletely understood. While salivary components have been implicated in protection, there is growing evidence that human defensins may be playing an important role in prevention of HIV infection. New antiviral, chemotaxis and immunosurveillance properties are being attributed to beta-defensins; small cationic antimicrobial innate response molecules expressed in mucosal epithelium. Inducible beta-defensins are always expressed in normal oral epithelium, a property not shared by other mucosal barriers. Certain oral commensal bacteria may contribute to this induction. We have shown that normal human oral epithelial cells (NHOECS) express the known beta-defensins and that Fusobacterium nucleatum, a ubiquitous bacterium of the oral cavity, upregulates human beta-defensin 2 (hBD2), resulting in protection from invasive bacteria. We now demonstrate that HIV-1 X4 and R5 viral phenotypes induce hBD2 mRNA in NHOECs and that hBD2 and -3 inhibit HIV-1 infection by both viral strains, with greater activity against X4 viruses. This proposal intends to test hypotheses emanating from the postulate that oral epithelial cells can be stimulated to produce beta-defensins that protect the host from HIV-1 at the oral mucosal barrier. The objectives of this proposal are (1) to study mechanisms of induction of hBD2 by HIV-1 in NHOECs, (2) to analyze the mechanisms by which hBD2 and -3 inhibit HIV-1 infectivity, and (3) to test the F. nucleatum hBD2 induction model for protection against HIV-1. Relative resistance to infection by the X4 phenotype, at mucosal sites, may in part be attributed to beta-defensins. Recent developments in defensin biology, coupled with our new observations, will facilitate rapid exploration of this newly discovered antiviral defense mechanism and may lead to future studies of HIV microbicidal strategies and mucosal barrier protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015510-02
Application #
6773830
Study Section
Special Emphasis Panel (ZDE1-YL (39))
Program Officer
Mcinnes, Pamela M
Project Start
2003-07-15
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
2
Fiscal Year
2004
Total Cost
$382,500
Indirect Cost
Name
Case Western Reserve University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
McCormick, Thomas S; Weinberg, Aaron (2010) Epithelial cell-derived antimicrobial peptides are multifunctional agents that bridge innate and adaptive immunity. Periodontol 2000 54:195-206
Diamond, Gill; Beckloff, Nicholas; Weinberg, Aaron et al. (2009) The roles of antimicrobial peptides in innate host defense. Curr Pharm Des 15:2377-92
Funderburg, Nicholas; Lederman, Michael M; Feng, Zhimin et al. (2007) Human -defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2. Proc Natl Acad Sci U S A 104:18631-5
Ghosh, Santosh K; Gerken, Thomas A; Schneider, Keith M et al. (2007) Quantification of human beta-defensin-2 and -3 in body fluids: application for studies of innate immunity. Clin Chem 53:757-65
Herzberg, M C; Weinberg, A; Wahl, S M (2006) (C3) The oral epithelial cell and first encounters with HIV-1. Adv Dent Res 19:158-66
Weber, Jan; Weberova, Jitka; Carobene, Mauricio et al. (2006) Use of a novel assay based on intact recombinant viruses expressing green (EGFP) or red (DsRed2) fluorescent proteins to examine the contribution of pol and env genes to overall HIV-1 replicative fitness. J Virol Methods 136:102-17
Xu, Weiling; Zheng, Shuo; Goggans, Tannishia M et al. (2006) Cystic fibrosis and normal human airway epithelial cell response to influenza a viral infection. J Interferon Cytokine Res 26:609-27
Feng, Zhimin; Dubyak, George R; Lederman, Michael M et al. (2006) Cutting edge: human beta defensin 3--a novel antagonist of the HIV-1 coreceptor CXCR4. J Immunol 177:782-6
Quinones-Mateu, M E; Arts, E J (2006) Virus fitness: concept, quantification, and application to HIV population dynamics. Curr Top Microbiol Immunol 299:83-140
Weinberg, A; Quinones-Mateu, M E; Lederman, M M (2006) Role of human beta-defensins in HIV infection. Adv Dent Res 19:42-8

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