Inactivated Wild-Type Herpes Simplex Virus (HSV-2, G)

Herpes simplex virus 2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical with spontaneous viral reactivation. To study the host-HSV-2 interaction, a rhesus monkey (RM) animal model of HSV-2 infection was established here. Proteins related to wound healing, innate immunity, and inflammation were significantly increased in cervical secretions following HSV-2 vaccination. There is histological evidence of acute herpesvirus pathology, including acantholysis of squamous epithelium and ballooning degeneration and intranuclear inclusions of epithelial cells, with HSV antigen in mucosal epithelial cells and keratinocytes. In addition, an intense inflammatory infiltrate was found in the cervix and vulva. Spontaneous HSV-2 shedding following acute inoculation was detected in 80% of RMs, demonstrating evidence of latent infection and reactivation. Furthermore, HSV-2 DNA was detected in the ganglia of most necropsy animals. HSV-2-specific T cell responses were detected in all animals, although HSV-2 antibodies were detected in only 30% of animals. Thus, HSV-2 infection of RM recapitulates many of the cardinal features of subclinical HSV-2 infection in women but appears to be more limited, as viral shedding remains undetected more than 40 days after the last viral vaccination.

A total of 526 proteins were detected across all time points from live HSV-2-challenged RM (groups 2, 3, and 4) samples, while 726 proteins were detected from inactivated HSV-2-challenged RM (group 5) samples (Figure 1A). In cervicovaginal secretion (CVS) of RMs inoculated with live HSV-2 (groups 2, 3, and 4), proteomic changes were observed on days 1, 2, and 29 that were significant after correction for multiple hypothesis testing. However, by 7 days postinfection (days 7 and 35), the proteome was not significantly different from the day 0 proteome (Figure 1B). Crucially, no significant changes were observed after inactivated HSV-2-challenge (group 5) at any time point (Figure 1B). Functional enrichment analysis of differentially expressed proteins following in vivo HSV-2 challenge using the Gene Ontology database. The analysis showed that inflammation and wound healing processes were significantly associated with these proteins. Visualization by hierarchical clustering revealed that these inflammatory proteins were significantly increased at days 1 and 2 after in vivo HSV-2 exposure (Figure 1C). The top three unique features enriched at days 1, 2, and 29 are shown (Figure 1D).

Figure 1. Mucosal wound healing and inflammatory responses were observed in CVS after live HSV-2 inoculation. (Lo M, et al., 2019)