Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding

Johnston, Christine; Corey, Lawrence

doi:10.1128/cmr.00043-15

Cited by 146 publications

(98 citation statements)

References 153 publications

(159 reference statements)

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“…HSV-2 causes a persistent, lifelong infection that increases risk for STI acquisition, including human immunodeficiency virus [2]. Despite the availability of therapeutic interventions to limit HSV-2 disease, the virus can be transmitted through asymptomatic shedding and even during chronic suppressive therapy [3–5]. …”

Section: Introductionmentioning

confidence: 99%

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Gardner

Herbst-Kralovetz

2018

Cytokine

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Herpes simplex virus 2 (HSV-2) causes a persistent, lifelong infection that increases risk for sexually transmitted infection acquisition. Both the lack of a vaccine and the need for chronic suppressive therapies to control infection presents the need to further understand immune mechanisms in response to acute HSV-2 infection. The IL-36 cytokines are recently identified members of the IL-1 family and function as inflammatory mediators at epithelial sites. Here, we first used a well-characterized three-dimensional (3-D) human vaginal epithelial cell (VEC) model to understand the role of IL-36γ in the context of HSV-2 infection. In 3-D VEC, IL-36γ is induced by HSV-2 infection, and pretreatment with exogenous IL-36γ significantly reduced HSV-2 replication. To assess the impact of IL-36γ treatment on HSV-2 disease pathogenesis, we employed a lethal genital infection model. We showed that IL-36γ treatment in mice prior to lethal intravaginal challenge significantly limited vaginal viral replication, delayed disease onset, decreased disease severity, and significantly increased survival. We demonstrated that IL-36γ treatment transiently induced pro-inflammatory cytokines, chemokines, and antimicrobial peptides in murine lower female reproductive tract (FRT) tissue and vaginal lavages. Induction of the chemokines CCL20 and KC in IL-36γ treated mice also corresponded with increased polymorphonuclear (PMN) leukocyte infiltration observed in vaginal smears. Altogether, these studies demonstrate that IL-36γ drives the transient production of immune mediators and promotes PMN recruitment in the vaginal microenvironment that increases resistance to HSV-2 infection and disease. Our data indicate that IL-36γ may participate as a key player in host defense mechanisms against invading pathogens in the FRT.

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Section: Introductionmentioning

confidence: 99%

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Gardner

Herbst-Kralovetz

2018

Cytokine

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“…Ocular HSV infections remain the leading virus-mediated cause of stromal keratitis and corneal scarring, while neonatal infections can result in death, developmental delays, or persisting neurological issues (1,2). In addition to these pathologies, HSV-2 infection is linked to enhanced acquisition and transmission of HIV (3)(4)(5).…”

mentioning

confidence: 99%

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

Arbuckle

Gardina

Gordon

et al. 2017

mBio

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Epigenetic regulation is based on a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets used to treat a range of diseases, including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach used to control infection, persistence, and the resulting recurrent disease. The histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1) are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3-enriched chromatin domains. However, while EZH2/1 are implicated in the repression of herpesviral gene expression, inhibitors of these enzymes suppressed primary herpes simplex virus (HSV) infection in vitro and in vivo. Furthermore, these compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia. Suppression correlated with the induction of multiple inflammatory, stress, and antipathogen pathways, as well as enhanced recruitment of immune cells to in vivo infection sites. Importantly, EZH2/1 inhibitors induced a cellular antiviral state that also suppressed infection with DNA (human cytomegalovirus, adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through the activation of cellular antiviral and immune responses.IMPORTANCE A significant proportion of the world's population is infected with herpes simplex virus. Primary infection and subsequent recurrent reactivation can result in diseases ranging from mild lesions to severe ocular or neurological damage. Herpesviruses are subject to epigenetic regulation that modulates viral gene expression, lytic replication, and latency-reactivation cycles. Thus, epigenetic pharmaceuticals have the potential to alter the course of infection and disease. Here, while the histone methyltransferases EZH2/1 are implicated in the suppression of herpesviruses, inhibitors of these repressors unexpectedly suppress viral infection in vitro and in vivo by induction of key components of cellular innate defense pathways. These inhibitors suppress infection by multiple viral pathogens, indicating their potential as broad-spectrum antivirals.KEYWORDS antiviral, chromatin, epigenetics, herpesvirus, immune mechanisms, innate immunity, Zika virus F ollowing primary infection with herpes simplex virus (HSV), the virus establishes lifelong latency in sensory neurons. However, multiple biological or stress stimuli can induce reactivation of latent genomes and recurrent disease. Ocular HSV infections remain the leading virus-mediated cause of stromal keratitis and corneal scarring, while

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“…And the tissue distribution of these T cells may be equally important for stable latency. Similarly, herpes simplex 2 (HSV2) shedding can be detected continuously and chronically in subclinical latent infections, suggesting that latency is multifocal and subject to chronic reactivation (Johnston and Corey, 2016). Epstein-Barr virus (EBV), which establishes an asymptomatic long-term latent infection in 90% of healthy adults, is detected chronically in saliva and blood at variable levels.…”

Section: Latency Reservoirs and Reactivation Rates In Natural Infectionmentioning

confidence: 99%

Epigenetics and Genetics of Viral Latency

Lieberman

2016

Cell Host & Microbe

133

118

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Viral latency can be considered a metastable, nonproductive infection state that is capable of subsequent reactivation to repeat the infection cycle. Viral latent infections have numerous associated pathologies, including cancer, birth defects, neuropathy, cardiovascular disease, chronic inflammation, and immunological dysfunctions. The mechanisms controlling the establishment, maintenance, and reactivation from latency are complex and diversified among virus families, species, and strains. Yet, as examined in this review, common properties of latent viral infections can be defined. Eradicating latent virus has become an important but elusive challenge and will require a more complete understanding of the mechanisms controlling these processes.

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Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding

Cited by 146 publications

References 153 publications

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

Epigenetics and Genetics of Viral Latency

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