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

As its name suggests, the host receptor herpesvirus entry mediator (HVEM) facilitates herpes simplex virus (HSV) entry through interactions with a viral envelope glycoprotein. HVEM also bridges several signaling networks, binding ligands from both tumor necrosis factor (TNF) and immunoglobulin (Ig) superfamilies with diverse, and often opposing, outcomes. While HVEM was first identified as a viral entry receptor for HSV, it is only recently that HVEM has emerged as an important host factor in immunopathogenesis of ocular HSV type 1 (HSV-1) infection. Surprisingly, HVEM exacerbates disease development in the eye independently of entry. HVEM signaling has been shown to play a variety of roles in modulating immune responses to HSV and other pathogens, and there is increasing evidence that these effects are responsible for HVEM-mediated pathogenesis in the eye. Here, we review the dual branches of HVEM function during HSV infection: entry and immunomodulation. HVEM is broadly expressed; intersects two important immunologic signaling networks; and impacts autoimmunity, infection, and inflammation. We hope that by understanding the complex range of effects mediated by this receptor, we can offer insights applicable to a wide variety of disease states.KEYWORDS HVEM, herpes simplex virus, herpes stromal keratitis H erpes simplex virus 1 (HSV-1) infects the majority of the world's population by adulthood and is responsible for the vast majority of ocular herpesvirus infections (1-3). In humans and mice, HSV-1 establishes lifelong latency in the trigeminal ganglia (TG) (4,5). Reactivations of HSV-1 in the TG can lead to anterograde movement of the virus along the ophthalmic branch of the trigeminal nerve, resulting in recurrent infection of virtually all the superficial tissues of the eye, including the cornea, conjunctiva, and eyelid (6-8). Ocular herpesvirus infections can lead to epithelial ulceration of the cornea, uveitis, and retinitis but most commonly cause herpes stromal keratitis, or HSK (9). HSK is characterized by chronic inflammation of the corneal stroma, leading to corneal thickening, opacification, scarring, and, potentially, blindness (10, 11). While reactivation accounts for the majority of human disease, most murine studies of HSK model primary infection as mice do not efficiently or reliably reactivate from latency (6).In the primary murine model of HSK, actively replicating HSV-1 in the cornea is detectable by plaque assay for up to 5 to 6 days postinfection (dpi) (9,12). Viral replication initiates HSK, as UV-inactivated or replication-deficient mutant HSV fail to induce HSK in BALB/c mice (13). However, HSK is an inflammatory disease, brought about by host infiltrates, particularly CD4 ϩ T cells and polymorphonuclear cells (PMN), that invade the murine cornea several days after replicating virus has been cleared and that persist chronically (14)(15)(16)(17)(18). A dizzying array of cytokines, chemokines, and immune cell types have been implicated in the pathogenesis of HSK, the temporal and...

Section: Discussionmentioning

confidence: 99%

Section: Hvem Alters Host Immune Responses To Hsvmentioning

confidence: 99%

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confidence: 99%

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Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye

Edwards

Longnecker

2017

“…The threshold cycle (C T ) values, which represent the PCR cycle at which there is a noticeable increase in the reporter fluorescence above baseline, were determined using SDS 2.2 software. Copy numbers of LAT RNA were calculated using a standard curve generated using pGEM5317-LAT, as described previously (86,106,110).…”

Section: Methodsmentioning

confidence: 99%

Roles of M1 and M2 Macrophages in Herpes Simplex Virus 1 Infectivity

Lee

Ghiasi

2017

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Macrophages are the predominant infiltrate in the corneas of mice that have been ocularly infected with herpes simplex virus 1 (HSV-1). However, very little is known about the relative roles of M1 (classically activated or polarized) and M2 (alternatively activated or polarized) macrophages in ocular HSV-1 infection. To better understand these relationships, we assessed the impact of directed M1 or M2 activation of RAW264.7 macrophages and peritoneal macrophages (PM) on subsequent HSV-1 infection. In both the RAW264.7 macrophage and PM in vitro models, HSV-1 replication in M1 macrophages was markedly lower than in M2 macrophages and unstimulated controls. The M1 macrophages expressed significantly higher levels of 28 of the 32 tested cytokines and chemokines than M2 macrophages, with HSV-1 infection significantly increasing the levels of proinflammatory cytokines and chemokines in the M1 versus the M2 macrophages. To examine the effects of shifting the immune response toward either M1 or M2 macrophages in vivo, wild-type mice were injected with gamma interferon (IFN-␥) DNA or colony-stimulating factor 1 (CSF-1) DNA prior to ocular infection with HSV-1. Virus replication in the eye, latency in trigeminal ganglia (TG), and markers of T cell exhaustion in the TG were determined. We found that injection of mice with IFN-␥ DNA, which enhances the development of M1 macrophages, increased virus replication in the eye; increased latency; and also increased CD4, CD8, IFN-␥, and PD-1 transcripts in the TG of latently infected mice. Conversely, injection of mice with CSF-1 DNA, which enhances the development of M2 macrophages, was associated with reduced virus replication in the eye and reduced latency and reduced the levels of CD4, CD8, IFN-␥,and PD-1 transcripts in the TG. Collectively, these results suggest that M2 macrophages directly reduce the levels of HSV-1 latency and, thus, T-cell exhaustion in the TG of ocularly infected mice.IMPORTANCE Our findings demonstrate a novel approach to further reducing HSV-1 replication in the eye and latency in the TG by modulating immune components, specifically, by altering the phenotype of macrophages. We suggest that inclusion of CSF-1 as part of any vaccination regimen against HSV infection to coax responses of macrophages toward an M2, rather than an M1, response may further improve vaccine efficacy against ocular HSV-1 replication and latency.KEYWORDS macrophages, infectivity, latency, exhaustion, HSV-1, CSF-1, IFN-␥, polarized, primary infection, reactivation M acrophage infiltrates play key roles in the immune defense system and are a central component of the innate immune system (1-4). Macrophages exhibit a wide variety of critically important functions, including phagocytosis, cytokine/chemokine secretion, and tumor cytotoxicity (5, 6). Resident macrophages are not detectable in the corneas of naive mice (7, 8), and we have confirmed the lack of resident macrophages in the corneas of uninfected mice by immunostaining using anti-F4/80, as well as anti-CD11b, antib...

“…Following ocular infection, latent HSV genomes express LAT in a portion of those neurons maintaining them, and virus can be recovered by cocultivation of ex-planted ganglia (22)(23)(24). In contrast to spontaneous reactivation in rabbits and humans, spontaneous reactivation in the murine model of ocular HSV-1 is rare (25).…”

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confidence: 99%

Interrelationship of Primary Virus Replication, Level of Latency, and Time to Reactivation in the Trigeminal Ganglia of Latently Infected Mice

Matundan

Mott

Allen

et al. 2016

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F ollowing ocular infection with herpes simplex virus type 1 (HSV-1), the virus travels in a retrograde direction toward neuronal cell bodies and establishes latency in trigeminal ganglia (TG) of infected mice (1-3). After establishment of latency in neurons, the latency-associated transcript (LAT) is the only viral product consistently detected in abundance in infected mouse, rabbit, and human TG (4-9). LAT is important for the high, wildtype (WT) rate of in vivo spontaneous (10) and induced (4) reactivation from latency. At various times throughout the life of the latently infected individual, the latent virus spontaneously reactivates and returns to the eye in an anterograde direction (1-3). The eye disease that is broadly referred to as herpes stromal keratitis (HSK) or corneal scarring (CS) occurs mainly as the result of virus reactivation rather than primary ocular infection in humans (11-15).Neurovirulence of HSV-1 strains can influence the eye disease in ocularly infected mice (16,17). Based on neurovirulence in animal studies, HSV-1 strains can be classified into two main categories: (i) avirulent HSV-1 strains, such as strains KOS and RE, which do not kill BALB/c mice or New Zealand White (NZW) rabbits following ocular infection and do not replicate efficiently in the eye without corneal scarification, and (ii) virulent HSV-1 strains, such as McKrae and its LAT (Ϫ) -derived virus, dLAT2903, that kill ϳ80% and ϳ50% of BALB/c mice and NZW rabbits, respectively, following ocular infection (18-21) and do not require corneal scarification for efficient ocular infection. Thus, in addition to the presence of LAT, the degree of HSV-1 virulence can also influence the level of recurrence.Following ocular infection, latent HSV genomes express LAT in a portion of those neurons maintaining them, and virus can be recovered by cocultivation of ex-planted ganglia (22-24). In contrast to spontaneous reactivation in rabbits and humans, spontaneous reactivation in the murine model of ocular HSV-1 is rare (25). Previously, it was suggested that the HSV-1 genome is maintained in a quiescent state in sensory neurons during latency in mice due to the absence of detectable viral protein synthesis. However, studies from mice indicate that lytic transcripts and proteins