Antigen-Presenting Cells and Peripheral Neurons in HIV Transmission

Background: Human immunodeficiency virus (HIV) is now a manageable chronic infection as the virus can be suppressed to undetectable levels upon administration of antiretroviral therapy (ART). The use of ART as pre-exposure prophylaxis (PrEP) further revolutionized the field of HIV prevention. However, serious barriers still exist that limit both ART and PrEP implementation, and no HIV vaccine is currently available. Further investment in still required, not only to broaden ART/PrEP access but also to develop alternative, sometimes unexpected, approaches for HIV prevention and treatment. These could be achieved via fundamental research, aimed at better understanding of how HIV is transmitted and how HIV infection is locally controlled at the mucosal level. Summary: We review two crucial aspects related to mucosal HIV transmission, which are key barriers to HIV therapeutic efficacy. First, we present the most recent and comprehensive data of the human antigen-presenting cell (APC) system and detail the discovery of novel APC subsets and their roles in binding and transmitting HIV. Second, we discuss the overlooked roles of sensory peripheral nociceptors, that is “pain-transmitting” neurons, in limiting APC interactions with HIV via secreted neuropeptides, as well as APC contributions to sensory neuropathies. We then discuss open questions that should be addressed, to obtain complete knowledge of the APC-HIV-nociceptor axis, which could guide development of HIV vaccines and neuroimmune anti-HIV measures. Key Messages: Multi-omics approaches revealed the existence of unrecognized APC subsets, such as epithelial dendritic cells (epi-DCs) in the epidermis/epithelium of genital tissues, which transmit HIV in addition to the classically recognized and better studied Langerhans cells (LCs). Other studies re-defined expression of HIV-binding receptors on APCs in the supporting dermis/stroma, for instance, showing that the HIV-binding lectins previously suggested to be expressed by monocyte-derived DCs are in fact only expressed by monocyte-derived macrophages. Further, the nociceptor-derived neuropeptide calcitonin gene-related peptide (CGRP) inhibits LC-mediated HIV transfer to T cells, which could overcome the detrimental effects of neurotoxic HIV proteins secreted by infected cells.