Epithelial cell derived human beta defensins (hBDs) function to protect the host against microbialpathogenesis 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 modulatinghomeostasis of the epithelium through regulated autocrine effects. Our recent findings demonstrate (1) thatHIV-1 promotes expression of inducible hBDs in normal human oral epithelial cells (HOECs) significantlyabove baseline, (2) that hBDs inhibit HIV-1 infectivity of immunocompetent cells, and (3) that hBD-3preferentially protects against the HIV-1 X4 phenotype by promoting internalization of the HIV-1 X4 tropicdependent co-receptor, CXCR4. This results in cellular antagonism; i.e., no calcium flux, ERK 1/2phosphorylation, or chemotaxis. Moreover, our findings indicate that calcium influx and ERK phosphorylationare not necessary to induce CXCR4 internalization and thus implicate the importance of other as yetundescribed mechanisms in trafficking of CXCR4.The ability of hBD-3 to desensitize/antagonize cells expressing CXCR4 is an example of an innateresponse element coordinating homeostasis in a mucosal environment. Interestingly, a distinct geneticmutation in CXCR4 that leads to disproportionate susceptibility to HPV warts is the result of the inability ofcells to be desensitized/antagonized (WHIM syndrome), suggesting the importance of innate molecules suchas hBD-3 in monitoring and promoting steady state conditions. Our preliminary proteomic studies indicatethat chronic HIV infection and/or highly active antiretroviral therapy (HAART) predispose the oral mucosae toboth cellular and innate immune impairment, and reduced hBD levels in HIV+ oral tissues have beenreported. Therefore, elucidating the mechanisms of interaction between hBD-3 and CXCR4 is important. Weintend to (1) conduct structure-function studies of hBD-3 and CXCR4 to identify critical sites ofinteraction on each molecule, (2) determine the mechanism(s) underlying hBD-3 induced CXCR4antagonism and (3) study intracellular trafficking of hBD-3 and CXCR4.Since hBD-3 induced antagonism has potentially wide ranging implications for not only HIV relatedbiology, but for a host of CXCR4 dependent activities involved in, but not limited to, hemopoiesis,angiogenesis, and immune cell trafficking and surveillance, a fundamental understanding of how hBD-3interacts with CXCR4 could shed important light on the biology of the oral mucosae and its predisposition tocomplications emerging from chronic HIV infections.
| 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 |
| 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 |
| Jin, Ge; Kawsar, Hameem I; Hirsch, Stanley A et al. (2010) An antimicrobial peptide regulates tumor-associated macrophage trafficking via the chemokine receptor CCR2, a model for tumorigenesis. PLoS One 5:e10993 |
