Wild-Type Herpes Simplex Virus (HSV-2, MS)

Herpes simplex virus (HSV) is widely spread worldwide, with both HSV-1 and HSV-2 being the etiology of genital herpes. During sexual transmission, HSV attacks epithelial cells, peripheral pain neurons that secrete the mucosal neuropeptide calcitonin gene-related peptide (CGRP), and mucosal immune cells including Langerhans cells (LCs). Here, researchers show that both HSV-1 and HSV-2 primary isolates can efficiently infect monocyte-derived Langerhans cells (MDLCs) and inner foreskin Langerhans cells. Furthermore, CGRP significantly inhibits infection with both HSV subtypes of MDLCs and langerin^high, but not langerin^low, inner foreskin LCs. For HSV-1, infection is mediated in a pH-dependent manner through its specific entry receptor 3-O-sulfated heparan sulfate (3-OS HS), and CGRP downregulates the surface expression of 3-OS HS and abolishes the pH dependence. For HSV-2, infection proceeds via Langerin-mediated pH-independent endocytosis, and CGRP upregulates surface expression of atypical Langerin double-trimer oligomers. These results suggest that CGRP inhibits mucosal HSV infection by differentially modulating subtype-specific entry receptors and mechanisms in human LCs. CGRP may contribute to the prevention of LC-mediated HSV infection as well as HSV/HIV-1 coinfection.

In addition to nectin-1, nectin-2, and HVEM, which mediate HSV-2 entry, HSV-2 also binds to and uses Langerin as an entry receptor on LCs21. Therefore, the researchers performed additional receptor blocking experiments using nAbs targeting the HSV-2 entry receptor and Langerin. These experiments showed that preincubation with nectin-1 and Langerin nAbs significantly inhibited HSV-2 infection in untreated MDLCs by approximately 15% and 50%, respectively, while the other nAbs had no significant effect (Figure 1a). Notably, heparinase pretreatment inhibited HSV-2 infection in untreated MDLCs by approximately 20% (Figure 1a), which is expected because HSV-2 uses HS, but not 3-OS HS, as an early attachment receptor. Importantly, preincubation with Langerin nAb also reduced HSV-2 infection by approximately 50% in CGRP-treated MDLCs (Figure 1b). Similarly, pre-incubation with Langerin nAb also significantly inhibited HSV-2 infection of untreated and CGRP-treated inner foreskin Langerin^high LCs (Figure 1c). These results show that HSV-2 uses langerin to enter untreated and CGRP-treated MDLCs and inner foreskin langerin^high LCs.

Figure 1. CGRP inhibits langerin-mediated HSV-2 infection of human LCs. (Cohen E, et al., 2022)