Herpesvirus entry mediator is a serotype specific determinant of pathogenesis in ocular herpes

Abstract

Infection with herpes simplex virus type 1 (HSV-1) and HSV-2 is initiated by viral glycoprotein D (gD) binding to a receptor on the host cell. Two receptors, herpesvirus entry mediator (HVEM) and nectin-1, mediate entry in murine models of HSV-1 and HSV-2. HVEM is dispensable for HSV-2 infection of the vagina and brain, but is required for WT pathogenesis of HSV-1 infection of the cornea. By challenging WT and HVEM KO mice with multiple strains of HSV-1 and HSV-2, we demonstrate that without HVEM, all HSV-1 strains tested do not replicate well in the cornea and infection does not result in severe symptoms, as observed in WT mice. In contrast, all HSV-2 strains tested had no requirement for HVEM to replicate to WT levels in the cornea and still cause severe disease. These findings imply that HSV-2 does not require HVEM to cause disease regardless of route of entry, but HVEM must be present for HSV-1 to cause full pathogenesis in the eye. These findings uncover a unique role for HVEM in mediating HSV-1 infection in an area innervated by the trigeminal ganglion and may explain why the presence of HVEM can lead to severe inflammation in the cornea. Thus, the dependence on HVEM is a dividing point between HSV-1 and HSV-2 that evolved to infect areas innervated by different sensory ganglia.herpes stromal keratitis | viral pathogenesis | viral eye disease | eye infection H erpes simplex virus type 1 (HSV-1) and HSV-2 are common human pathogens with over 50% of United States adults seropositive for HSV-1 and over 15% seropositive for HSV-2 (1). Typically, HSV-1 is responsible for oral infections and HSV-2 is the cause of genital infections, but this division is becoming less distinct (2-4). Severe outcomes caused by both serotypes include encephalitis, stromal keratitis, and meningitis (4, 5). Importantly, HSV-1 remains a significant cause of ocular morbidity and blindness despite the availability of the antiviral drug, acyclovir (6, 7).Herpes infection begins when the viral envelope fuses with a host cell membrane. This process is dependent on envelope glycoprotein D (gD) binding to one of its receptors. The gDreceptor binding event triggers glycoproteins gB, gH, and gL to execute fusion by a yet unknown mechanism (8). The known gD receptors include: herpesvirus entry mediator (HVEM) (9), nectin-1 (10), nectin-2 (11), and 3-O-sulfated-heparan sulfate (3-O-S-HS) (12). Of these receptors, HVEM and nectin-1 have proven important in in vivo murine models of HSV infection (13-15). HVEM is a member of the TNF receptor superfamily and participates in a wide variety of cellular and physiological functions, including apoptosis (16) and immune cell signaling (17). Nectin-1 is a member of the Ig superfamily and functions in cell-cell adhesion (18).The importance of HVEM and nectin-1 in mediating HSV infection in vivo was demonstrated by the use of KO mice. HSV-2 vaginal infection was completely prevented in HVEM/nectin-1 double-KO mice. Interestingly, the absence of HVEM alone was not protective in the vaginal model of HSV-2 infe...

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

“…However, there was a trend toward decreased virus replication in Hvem Ϫ/Ϫ mice, suggesting that there may be some effect of HVEM on acute HSV-1 infection. This would be consistent with a recent study in which in a corneal scarification model of ocular HSV-1 infection, HVEM affected acute infection (48). The relative amount of latency on day 30 p.i.…”

Herpes virus entry mediator (HVEM) modulates proliferation and activation of regulatory T cells following HSV-1 infection

“…In our attempt to delineate the impact of defective Treg responses in HVEM−/− animals we observed a higher susceptibility of these animals to HSV-1 induced ocular immunopathology. This observation was unexpected as HVEM is an entry mediator for HSV and is in contrast to some other reports [35, 36]. It could be argued that the differences might be due to the strain and dose of virus used.…”

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

“…As its name suggests, HVEM was originally discovered as one of several entry receptors for herpes simplex virus (HSV). However, Nectin-1 appears to be the primary receptor required to generate neuronal infection in vivo through the skin, mucosal or ocular routes (Karaba et al, 2012; Spear et al, 2006; Taylor et al, 2007). Recently, the latency associated transcript (LAT) in HSV1 upregulates HVEM expression to maintain neuronal latency (Allen et al, 2014).…”