Evasion of the Mucosal Innate Immune System by Herpes Simplex Virus Type 2

Abstract

Understanding the mechanisms by which herpes simplex virus (HSV) evades host immune defenses is critical to defining new approaches for therapy and prevention. We performed transcriptional analyses and immunocytochemistry on sequential biopsy specimens of lesional tissue from the acute through the posthealing phases of recurrent mucocutaneous HSV-2 infection. Histological analysis of these biopsy specimens during the acute stage revealed a massive infiltration of T cells, as well as monocytes/macrophages, a large amount of myeloid, and a small number of plasmacytoid dendritic cells, in the dermis of these lesional biopsy specimens. The pathogenesis of reactivating herpes simplex virus type 2 (HSV-2) infection at mucosal sites in humans is not well understood. Recent studies have shown frequent and rapid reactivation and clearance of HSV-2 in genital tissue (27,41,47), suggesting that local host responses in the periphery are imperfect determinants of viral clearance. Most recently, HSV-2-specific T cells have been shown to persist in skin for weeks after the healing of a reactivation episode (15,47). The mechanism by which HSV-2 evades such local host defense even for short time periods is unclear.Nearly 3 decades ago, antiviral activities in vesicle fluid during recurrent acute HSV infection in 18 of 19 patients were demonstrated using a plaque reduction assay (32). Type I interferon (IFN) was shown using type I IFN neutralizing antibodies to be the source of this antiviral effect in Ͻ50% of such persons. Significant amounts of T lymphocytes and monocytes/ macrophages were seen to infiltrate near the infected epidermis during HSV reactivation (4), and a recent study found plasmacytoid dendritic cells (pDCs) near the infected epidermis during HSV reactivation (5), suggesting that host innate immune cells play a role in host mucosal defense to recurrent HSV infection. However, the interaction of host mucosal innate immune systems with reactivating HSV-2 during acute infection is poorly understood.IFNs are a family of related cytokines that are classified according to receptor specificity and sequence homology. Type I IFN consists of multiple IFN-␣ subtypes, IFN-␤, and several less-understood species, including IFN-, IFN-ε, IFN-, IFN-, and IFN-␦. IFN-␥ is the only type II IFN. The more recently described type III IFN includes three IFN

Loss of the Type I Interferon Pathway Increases Vulnerability of Mice to Genital Herpes Simplex Virus 2 Infection

“…The importance of this observation is further supported by transcriptional array analysis of biopsy samples taken from patients that present with acute-stage HSV-2 reactivation. The results included the detection of extremely low levels of IFN-␣ and IFN-␤, suggesting reactivated virus is capable of disarming a pivotal antiviral system long enough to allow for local replication and thus facilitate acquisition of newly synthesized virions by unsuspecting recipients (49).…”

An Effector Phenotype of CD8+T Cells at the Junction Epithelium during Clinical Quiescence of Herpes Simplex Virus 2 Infection

“…HSV-2 serostatus was determined by Western blotting as previously described (20); all participants were HIV seronegative. Biopsy procedures were conducted as described previously (22,29). All samples were immediately placed on dry ice and stored at Ϫ80°C until processing.…”

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

“…HSV-2 has been shown to evade mucosal innate immunity, but the underlying mechanisms remain to be elucidated (48). Considering the important role played by IFN-b in innate immunity (56) and that HSV-2 can inhibit type I IFN induced signaling (57), we examined the effect of HSV-2 infection on IFN-b production.…”

“…After initial infection, HSV-2 dsDNA, dsRNA, and proteins such as gB, gH/L, as pathogen-associated molecular patterns are most likely recognized by cellular sensors (1,(41)(42)(43)(44)(45)(46)(47), which causes the induction of host antiviral immune responses. Early investigation indicates that whole HSV-2 lesional tissues contain a large quantity of IFN-g but surprisingly low levels of type I IFNs (48). Given that current understanding of HSV-2 immune evasion is limited, we investigated whether HSV-2 infection could modulate type I IFN production and investigated the underlying mechanisms.…”