In Vivo Role of Nectin-1 in Entry of Herpes Simplex Virus Type 1 (HSV-1) and HSV-2 through the Vaginal Mucosa

Abstract

Herpes simplex virus type 2 (HSV-2) is transmitted through the genital mucosa during sexual encounters. In recent years, HSV-1 has also become commonly associated with primary genital herpes. The mechanism of viral entry of HSV-1 and HSV-2 in the female genital tract is unknown. In order to understand the molecular interactions required for HSV entry into the vaginal epithelium, we examined the expression of herpesvirus entry mediator nectin-1 in the vagina of human and mouse at different stages of their hormonal cycle. Nectin-1 was highly expressed in the epithelium of human vagina throughout the menstrual cycle, whereas the mouse vaginal epithelium expressed nectin-1 only during the stages of the estrous cycle in which mice are susceptible to vaginal HSV infection. Furthermore, the ability of nectin-1 to mediate viral entry following intravaginal inoculation was examined in a mouse model of genital herpes. Vaginal infection with either HSV-1 or HSV-2 was blocked by preincubation of the virus with soluble recombinant nectin-1. Viral entry through the vaginal mucosa was also inhibited by preincubation of HSV-2 with antibody against gD. Together, these results suggest the importance of nectin-1 in mediating viral entry for both HSV-1 and HSV-2 in the genital mucosa in female hosts.Understanding the entry events of herpes simplex virus type 2 (HSV-2) at the genital mucosa is important in the development of preventative measures, such as topical microbicides, to stop its spread through sexual transmission. Although HSV-1 is classically associated with oral infection, an alarming increase in HSV-1 has been observed in association with primary genital herpes in recent years (14). The in vivo mechanism of viral entry in the female genital tract of HSV-1 and HSV-2 is unknown.The molecular mechanisms of virus attachment and entry have been a focus of intense investigations, especially for HSV-1 but also for HSV-2 (reviewed in reference 30). Currently, the model for HSV entry begins with the attachment of the virus to a target cell through binding of HSV glycoprotein C (gC) and/or gB to the cell surface heparan sulfate proteoglycans (reviewed in reference 28). Subsequently, the attached virus can begin its entry through interaction between gD and a variety of unrelated cell surface receptors, including the herpesvirus entry mediator A (HveA) (21), a member of the tumor necrosis factor receptor family, HveB (nectin-2) (33) and HveC (nectin-1) (4), both members of the immunoglobulin superfamily, and 3-O-sulfated heparan sulfate (27).Owing to its limited expression in lymphocytes and monocytes (13), HveA has been shown to mediate HSV entry into human activated T lymphocytes (21). Whether HveA participates in viral entry through genital epithelial cells is unknown. Human HveB mediates the entry of HSV-2 and certain mutant strains of HSV-1 but fails to mediate entry of wild-type HSV-1 (33). Furthermore, evidence indicates that the mouse homologue of HveB fails to mediate entry of either HSV-1 or HSV-2 (16). In contrast, necti...

Multiple Receptor Interactions Trigger Release of Membrane and Intracellular Calcium Stores Critical for Herpes Simplex Virus Entry

“…18, August 2007 3123 step in viral entry is binding of gD to a coreceptor. Several studies suggest that nectin-1 is the major coreceptor on human epithelial cells (Linehan et al, 2004;Galen et al, 2006). Transfection of cells with nectin-1 sequence-specific, but not HVEM-specific, siRNA reduced its expression by at least 90% (based on scanning of confocal microscopy images and Western blots) ( Figure 3A).…”

“…The cascade is initiated by binding of HSV to heparan sulfate proteoglycans at the cell surface; glycoprotein C plays the major role in mediating binding for HSV-1, whereas gB plays the dominant role in mediating binding for HSV-2 (Herold et al, 1991;Cheshenko and Herold, 2002). After engagement of this attachment receptor, gD interacts with one of several coreceptors, of which nectin-1 may play the predominant role on human epithelial cells (Linehan et al, 2004). Independently of its role in attachment, gB is also required for fusion as are heterodimers of gH-gL (Spear, 2004).…”

Contribution of Direct and Cross-Presentation to CTL Immunity against Herpes Simplex Virus 1

“…Host plasma membrane proteins such as nectin-1 and herpesvirus entry mediator (HVEM) provide entry receptors for HSV1 infections (14,40,41). First, we assessed the surface expression of these molecules on spleen-derived conventional DC using polyclonal Abs.…”

Early Resolution of Herpes Simplex Virus Type 2 Infection of the Murine Genital Tract Involves Stimulation of Genital Parenchymal Cells by Gamma Interferon

“…To test if non-T-cell sources of IFN-␥ were sufficient for HSV-2 clearance, Rag1-deficient mice (Rag1 Ϫ/Ϫ ) genetically deficient in adaptive immune cells but possessing an intact innate immune system, including macrophages, dendritic cells, and NK cells (19), were utilized as recipients of activated wild-type OT-I or IFN-␥-deficient OT-I (OT-I IFN Ϫ/Ϫ ) T cells. Mice were treated with medroxyprogesterone in all experiments to induce susceptibility to genital HSV-2 inoculation (15), most likely reflecting hormonal induction of the HSV entry receptor, nectin-1, on vaginal epithelial cells (14). Rag1 Ϫ/Ϫ mice were injected intravenously (i.v.)…”