The oral mucosae is predisposed to complications emerging from chronic HIV infections;a problem observed disproportionately in vulnerable populations, such as the African American community. Epithelial cell derived human beta defensins (hBDs) function to protect the host against microbial pathogens at the mucosal barrier. This protection may be elicited by their local antimicrobial properties, and/or by hBDs acting like chemokines;"cross-talking" with the adaptive immune system and modulating homeostasis of the epithelium through regulated autocrine effects. We have recently shown that (1) HIV-1 challenge promotes expression of inducible hBDs in normal human oral epithelial cells (HOECs) significantly above baseline, (2) that hBDs inhibit HIV-1 infectivity of immunocompetent cells, and (3) that hBD-3 preferentially protects against the HIV-1 X4 phenotype by promoting internalization of the HIV-1 X4-tropic dependent co-receptor, CXCR4, resulting in cellular antagonism;i.e., no calcium flux, ERK 1/2 phosphorylation, or chemotaxis. Moreover, our findings indicate that calcium influx and ERK phosphorylation are not necessary to induce CXCR4 internalization, implicating other as yet undescribed mechanisms in trafficking of CXCR4. The ability of hBD-3 to desensitize/antagonize cells expressing CXCR4, and thereby limiting the target for HIV-1 X4 entry, is an example of an innate response element coordinating homeostasis in a mucosal environment. Interestingly, a distinct genetic mutation in CXCR4 that leads to disproportionate susceptibility to HPV warts is the result of the inability of cells to be desensitized/antagonized (WHIM syndrome), suggesting the importance of innate molecules such as hBD-3 in monitoring and promoting steady state conditions. Our preliminary proteomic studies indicate that chronic HIV infection and/or highly active antiretroviral therapy predispose the oral mucosae to both cellular and innate immune impairment, and reduced hBD levels in HIV+ oral tissues have been reported. Therefore, elucidating the mechanisms of interaction between hBD-3 and CXCR4 is important. We intend to (1) conduct structure-function studies of hBD-3 and CXCR4 to identify critical sites of interaction on each molecule, (2) determine the mechanism(s) underlying hBD-3 induced CXCR4 antagonism and (3) study intracellular trafficking of hBD-3 and CXCR4. HBD-3 induced antagonism has potentially wide ranging implications for not only HIV related biology, but for a host of CXCR4 dependent activities involved in, but not limited to, hematopoiesis, angiogenesis, and immune cell trafficking and surveillance. Therefore, a fundamental understanding of how hBD-3 interacts with CXCR4 could shed important light on the biology of the oral mucosae and its predisposition to complications emerging from chronic HIV infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Program Projects (P01)
Project #
5P01DE019759-05
Application #
8462468
Study Section
Special Emphasis Panel (ZDE1-JH)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$283,838
Indirect Cost
$103,070
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Feng, Zhimin; Jia, Xun; Adams, Mark D et al. (2014) Epithelial innate immune response to Acinetobacter baumannii challenge. Infect Immun 82:4458-65
Chung, Charlotte Y; Alden, Stephanie L; Funderburg, Nicholas T et al. (2014) Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals. PLoS Pathog 10:e1004198
Willie, B; Hall, N B; Stein, C M et al. (2014) Association of Toll-like receptor polymorphisms with HIV status in North Americans. Genes Immun 15:569-77
Cheruvu, Vinay K; Igo Jr, Robert P; Jurevic, Richard J et al. (2014) African ancestry influences CCR5 -2459G>A genotype-associated virologic success of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 66:102-7
Ghosh, Santosh K; McCormick, Thomas S; Eapen, Betty L et al. (2013) Comparison of epigenetic profiles of human oral epithelial cells from HIV-positive (on HAART) and HIV-negative subjects. Epigenetics 8:703-9
Feng, Zhimin; Dubyak, George R; Jia, Xun et al. (2013) Human ?-defensin-3 structure motifs that are important in CXCR4 antagonism. FEBS J 280:3365-75
Golden, Jackelyn B; McCormick, Thomas S; Ward, Nicole L (2013) IL-17 in psoriasis: implications for therapy and cardiovascular co-morbidities. Cytokine 62:195-201
Meisch, Jeffrey P; Nishimura, Michiko; Vogel, Ryan M et al. (2013) Human ýý-defensin 3 peptide is increased and redistributed in Crohn's ileitis. Inflamm Bowel Dis 19:942-53
Tebit, Denis M; Ndembi, Nicaise; Weinberg, Aaron et al. (2012) Mucosal transmission of human immunodeficiency virus. Curr HIV Res 10:3-8
Funderburg, Nicholas T; Jadlowsky, Julie K; Lederman, Michael M et al. (2011) The Toll-like receptor 1/2 agonists Pam(3) CSK(4) and human ?-defensin-3 differentially induce interleukin-10 and nuclear factor-?B signalling patterns in human monocytes. Immunology 134:151-60

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