Herpes simplex virus (HSV) is a highly prevalent sexually transmitted infection (STI), and both HSV-1 and HSV-2 induce genital herpes. HSV-2 is also the largest STI contributor to increased acquisition of human immunodeficiency virus type 1 (HIV-1), with a synergistic relationship between HSV-2 and HIV-1 during co-infection. During sexual transmission, HSV infects epithelial cells in a lytic life cycle, and subsequently establishes life long latency in sensory peripheral pain neurons termed nociceptors that innervate all mucosal epithelia. One common cell type that is infected with both HSV and HIV-1 includes Langerhans cells (LCs), the resident antigen presenting immune cells in stratified mucosal epithelia, such as the vagina and inner foreskin. Indeed, HSV productive infection of LCs leads to their apoptosis, followed by relay of viral antigens. Previous studies, including those by the team, also demonstrated infection of LCs with HIV-1, followed by transfer of intact infectious HIV-1 virions from LCs to CD4+ T-cells.
As LCs are common HSV/HIV-1 cellular targets, identifying novel anti-viral factors acting on LCs themselves, rather than on the distinct life cycles of each virus, could facilitate the development of alternative co-infection preventive strategies. In this context, the team previously raised the hypothesis that neuroimmune interactions at the mucosal level might be harnessed for such a purpose, as protection against invading mucosal pathogens is orchestrated by a local neuroimmune cross talk between nociceptor-derived neuropeptides and resident mucosal immune cells.
In pioneering studies, the team discovered that calcitonin gene-related peptide (CGRP), a 37 amino-acid nociceptor-secreted neuropeptide that is a potent vasodilator playing important physiological and pathophysiological roles, also has strong vasodilator-independent anti-viral function. Accordingly, CGRP modulates a multitude of cellular and molecular mechanisms in LCs, which cooperate to strongly inhibit HIV-1 transfer from LCs to CD4+ T-cells. In a recent study published in Frontiers in Immunology 1, the authors further detail some of these mechanisms, and show that such inhibition requires activation of the CGRP receptor by full-length CGRP or its stable peptide analogue SAX (but not by several CGRP peptide fragments), and involves up-regulation of the transcription factor STAT4 and the LC-specific pathogen recognition C-type lectin langerin. This study also provides proof-of-concept for the clinical utility of CGRP, which limits mucosal HIV-1 transmission in-vivo in humanized mice.
In the present study published in Mucosal Immunology 2, the authors report that CGRP also inhibits infection of LCs with HSV. Accordingly, CGRP inhibits infection with both HSV-1 and HSV-2 of monocyte-derived LCs (MDLCs) and langerinhigh, but not langerinlow, inner foreskin tissue LCs. For HSV-1, infection is mediated via the HSV-1-specific entry receptor 3-O sulfated heparan sulfate (3-OS HS) in a pH-depended manner, and CGRP down-regulates 3-OS HS surface expression and abrogates pH dependency. For HSV-2, infection involves langerin-mediated endocytosis in a pH-independent manner, and CGRP up-regulates surface expression of atypical (and potentially defective) langerin double-trimer oligomers.
Figure legend: Summary of HSV-1 and HSV-2 infection mechanisms in human LCs, and their inhibition by CGRP. (1) Human inner foreskin LCs and MDLCs express HSV-1/2 entry receptors and langerin; (2) HSV-1 uses 3-OS HS to enter MDLCs via a pH-dependent endocytic mechanism, as well as langerin in inner foreskin langerinhigh LCs (broken line); (3) CGRP might inhibit HSV-1 infection by down-regulating 3-OS HS surface expression and abrogating pH dependency; (4) HSV-2 uses langerin to enter LCs, leading to clathrin/caveolin-mediated internalization and fusion in a pH-independent manner; (5) CGRP might inhibit HSV-2 infection by inducing formation of atypical high molecular weight langerin double trimers.
Copyright ©: The Author(s), under exclusive license to Society for Mucosal Immunology 2022
Although existing pre-exposure prophylaxis (PrEP) is effective for prevention of HIV-1 transmission, this strategy still has important barriers limiting its efficacy and usage. In addition, while HSV infection can be treated with anti-viral agents (e.g. acyclovir), no preventive HSV microbicides are available. For HIV-1/HSV co-infection, dual-protection approaches are under development, principally combinations of anti-viral molecules (e.g. acyclovir + tenofovir) that target HSV and HIV-1 separately. Hence, developing new and efficient strategies to prevent infection with both HIV-1 and HSV simultaneously is still an unmet need. In this context, the studies of the team reinforce the anti-viral role and potential utility of CGRP, and argue that CGRP-based formulations might represent a novel neuroimmune preventive strategy, capable of targeting LCs and dual inhibition of HIV-1 and HSV.
1) Mariotton J, Sams A, Cohen E, Sennepin A, Siracusano G, Sanvito F, Edvinsson L, Barry Delongchamps N, Zerbib M, Lopalco L, Bomsel M, Ganor Y. Native CGRP neuropeptide and its stable analogue SAX, but not CGRP peptide fragments, inhibit mucosal HIV-1 transmission. Front Immunol. 2021. 12:785072.
2) Cohen E, Mariotton J, Rozenberg F, Sams A, van Kuppevelt TH, Barry Delongchamps N, Zerbib M, Bomsel M, Ganor Y. CGRP inhibits human Langerhans cells infection with HSV by differentially modulating specific HSV-1 and HSV-2 entry mechanisms. Mucosal immunol. 2022. doi: 10.1038/s41385-022-00521-y.