Human epidermis is thought to contain a single dendritic cell (DC) population called a Langerhans cell (LC). We have recently described a second DC population, found in human epidermis that are transcriptionally and phenotypically related to dermal cDC2s. They are more abundant in genital tissues including foreskin, labia, glans penis, vagina, and fossa navicularis. Herpes Simplex Virus (HSV) types 1 and 2, and HIV, are among the most common human viral pathogens and are capable of causing serious disease. There is no effective HIV or HSV vaccine currently available but there are many live-attenuated, inactivated, and replication defective HSV vaccine approaches currently in development. However, HSV entry into DCs is not well understood.
Currently, it is known that HSV utilizes at least three different entry pathways to infect different cell types, a pH-dependent endocytic pathway, a pH-independent endocytic pathway, and a pH independent fusion pathway at the plasma membrane. We wanted to investigate how LCs, the newly described cDC2s and the model monocyte-derived DCs are infected by HSV and HIV. We have found that the epidermal cDC2s are more infectable than LCs and express higher levels of the HIV and HSV entry receptors. Using inhibitors of endosomal acidification, and macropinocytosis by flow cytometry we have shown that HSV-1 predominantly utilises a pH-dependent pathway to infect LCs sand monocyte-derived DCs but epidermal cDC2s are mostly infected via a pH-independent endocytic pathway. Using inhibitors of macropinocytosis, we have shown differential infection pathways for LCs and epidermal cDC2s. Further understanding of the mechanisms underlying HIV and HSV infection of human skin DCs should lead to more informed vaccine design.