The elucidation of the early immune system in percutaneous infection of HSV and HIV and the development of novel methods to prevent their cutaneous infection

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HSV-2 shedding is associated with increased risk for sexually acquiring HIV. Because Langerhans cells (LCs) are suspected to be the initial target cells infected by HIV following sexual exposure, we studied whether HSV-2 affects HIV infection of LCs. HSV-2 enhanced HIV susceptibility in LCs within skin explants, even though relatively few HSV-2/HIV co-infected LCs were detected, suggesting that HSV-2 enhances HIV infection of LCs through indirect mechanisms. Indeed, HSV-2 stimulated production of antimicrobial peptides (AMPs) by epithelial cells, including human defensins and LL-37, and the latter strongly enhanced HIV susceptibility in LCs by up-regulating HIV receptors. Culture supernatants of epithelial cells infected with HSV-2 enhanced HIV susceptibility in LCs, and this effect was abrogated by blocking LL-37 production. These data suggest that HSV-2 enhances sexual transmission of HIV by increasing HIV susceptibility of LCs via epithelial cell production of LL-37.