Latent Herpes Simplex Virus Type Research Articles

Latent herpes simplex virus type 1 reactivation increases the susceptibility of neurodegenerative diseases: intervention with traditional Chinese medicine

Owing to environmental and lifestyle changes in modern society, physical and mental stress is on the rise among the population in attempting to compensate for the changes. Stress, defined as a series of non-specific responses to abnormal internal and external stimuli, has long been recognized to increase susceptibility to various diseases, including neurodegenerative diseases (NDs). Herpes simplex virus type 1 (HSV-1), a neurotropic herpes virus, establishes latent infections in the trigeminal ganglia for the lifetime of the host. Upon reactivation, the latent HSV-1 enters the lytic cycle, which not only causes a substantial production of reactive oxygen species (ROS) in the neurons, but also induces glial cells to produce inflammatory mediators, eventually resulting in neuronal damage and occurrence of NDs. Remarkably, both physical and psychological stress are common stimuli leading to latent HSV-1 reactivation. Acyclovir is a classic antiviral drug for the treatment of HSV-1 infection and recurrence, but acyclovir cannot reverse neuronal damage caused by HSV-1 reactivation. Recent studies have shown that traditional Chinese medicine (TCM) has advantages in the treatment of NDs. In addition, TCM is thought to prevent latent HSV-1 reactivation and NDs, which may involve regulation of the neuro-endocrine-immune network, treatment of emotional disorders, and modulation of oxidative stress. Understanding the mechanism underlying stress-induced reactivation of latent HSV-1 and the potential consequences of NDs is needed. TCM may be a promising alternative therapy for related diseases.

T-cells in human trigeminal ganglia express canonical tissue-resident memory T-cell markers

BackgroundTrigeminal ganglia (TG) neurons are the main site of lifelong latent herpes simplex virus type 1 (HSV-1) infection. T-cells in ganglia contribute to long-term control of latent HSV-1 infection, but it is unclear whether these cells are bona fide tissue-resident memory T-cells (TRM). We optimized the processing of human post-mortem nervous tissue to accurately phenotype T-cells in human TG ex vivo and in situ.MethodsPeripheral blood mononuclear cells (PBMC; 5 blood donors) were incubated with several commercial tissue digestion enzyme preparations to determine off-target effect on simultaneous detection of 15 specific T-cell subset markers by flow cytometry. Next, optimized enzymatic digestion was applied to ex vivo phenotype T-cells in paired PBMC, normal appearing white matter (NAWM) and TG of 8 deceased brain donors obtained < 9 h post-mortem by flow cytometry. Finally, the phenotypic and functional markers, and spatial orientation of T-cells in relation to neuronal somata, were determined in TG tissue sections of five HSV-1-latently infected individuals by multiparametric in situ analysis.ResultsCollagenase IV digestion of human nervous tissue was most optimal to obtain high numbers of viable T-cells without disrupting marker surface expression. Compared to blood, majority T-cells in paired NAWM and TG were effector memory T-cells expressing the canonical TRM markers CD69, CXCR6 and the immune checkpoint marker PD1, and about half co-expressed CD103. A trend of relatively higher TRM frequencies were detected in TG of latently HSV-1-infected compared to HSV-1 naïve individuals. Subsequent in situ analysis of latently HSV-1-infected TG showed the presence of cytotoxic T-cells (TIA-1+), which occasionally showed features of proliferation (KI-67+) and activation (CD137+), but without signs of degranulation (CD107a+) nor damage (TUNEL+) of TG cells. Whereas majority T-cells expressed PD-1, traits of T-cell senescence (p16INK4a+) were not detected.ConclusionsThe human TG represents an immunocompetent environment in which both CD4 and CD8 TRM are established and retained. Based on our study insights, we advocate for TRM-targeted vaccine strategies to bolster local HSV-1-specific T-cell immunity, not only at the site of recurrent infection but also at the site of HSV-1 latency.

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man.

Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen. HSV-1 genomes persist in trigeminal ganglia neuronal nuclei as chromatinized episomes, while epithelial cells are typically killed by lytic infection. Fluctuations in anti-viral responses, broadly defined, may underlay periodic reactivations. The ganglionic immune response to HSV-1 infection includes cell-intrinsic responses in neurons, innate sensing by several cell types, and the infiltration and persistence of antigen-specific T-cells. The mechanisms specifying the contrasting fates of HSV-1 in neurons and epithelial cells may include differential genome silencing and chromatinization, dictated by variation in access of immune modulating viral tegument proteins to the cell body, and protection of neurons by autophagy. Innate responses have the capacity of recruiting additional immune cells and paracrine activity on parenchymal cells, for example via chemokines and type I interferons. In both mice and humans, HSV-1-specific CD8 and CD4 T-cells are recruited to ganglia, with mechanistic studies suggesting active roles in immune surveillance and control of reactivation. In this review we focus mainly on HSV-1 and the TG, comparing and contrasting where possible observational, interventional, and in vitro studies between humans and animal hosts.

Herpes Simplex Virus Type 1 in the Brain, Apolipoprotein E Genotype and Alzheimer’s Disease

The ε4 allele of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease (AD), however, it is not required nor sufficient to cause the disease on its own. Herpes viruses cause acute and chronic diseases of the central nervous system and have been implicated in AD. Using a sensitive polymerase chain reaction method, latent herpes simplex virus type 1 (HSV-1) has been detected from five different brain regions (hippocampus, frontal cortex, occipital cortex, cerebellum and striatum) of neuropathologically confirmed AD and control tissue. HSV-1 positivity was then correlated with AD, presence of the virus in specific brain regions, and apoE genotype. The results confirm that the ε4 allele of apoE is a risk factor for AD, while HSV-1 alone is not. This held true for all five brain regions examined. Furthermore, no synergy between the two factors could be found when any one of the brain regions was examined individually or when the data were pooled. These findings emphasize that the ε4 allele of apoE is a risk factor for AD and that HSV-1, either alone or in combination with apoE, does not represent an increased risk for AD. Furthermore, no particular brain region seems to be more infected with HSV-1 than another, even in those regions most affected in AD.

Usefulness of Human Herpes Simplex Virus Type 1 Genotyping for Tracing the Geographical Origins of Unidentified Cadavers

Aim: We examined the possibility of tracing the origins of cadavers based on the geographic distribution of genotypes of the latent human herpes simplex virus type 1 (HSV-1). Materials &amp; methods: PCR of the V1 region (667 bp) was performed using DNA from human trigeminal ganglia of 107 Japanese cadavers. The phylogenetic analysis was performed using 16 cadavers in Chiba district and 84 reference sequences in the world. Results: The HSV-1 DNA detection rate was 54.2% and it increased with age. This phylogenetic tree showed four large clusters, types I–IV (African, European, Asian and the mixed-type), and two subclusters (Japanese–Korean type and Japanese–Chinese type) in type III. Conclusion: HSV-1 genotype is possible to trace the geographical origin of unidentified cadavers.

Stress Flips a Chromatin Switch to Wake Up Latent Virus.

Stress-induced reactivation of latent herpesviruses requires disabling of repression, but the mechanism for converting silenced chromatin into an active state is unknown. In this issue of Cell Host & Microbe, Cliffe et al. (2015) suggest a methyl/phospho switch on histone H3 overcomes repression to facilitate reactivation of latent herpes simplex virus type 1 (HSV-1).

A Cell Culture Model of Latent and Lytic Herpes Simplex Virus Type 1 Infection in Spiral Ganglion

Purpose of the Study: Reactivation of latent herpes simplex virus type 1 (HSV-1) in spiral ganglion neurons (SGNs) is supposed to be one of the causes of idiopathic sudden sensorineural hearing loss. This study aims to establish a cell culture model of latent and lytic HSV-1 infection in spiral ganglia. Procedures: In the presence of acyclovir, primary cultures of SGNs were latently infected with HSV-1 expressing green fluorescent protein. Four days later, these cells were treated with trichostatin A (TSA), a known chemical reactivator of HSV-1. TCID₅₀ was used to measure the titers of virus in cultures on Vero cells. RNA from cultures was detected for the presence of transcripts of ICP27 and latency-associated transcript (LAT) using reverse transcription polymerase chain reaction. Results: There is no detectable infectious HSV-1 in latently infected cultures, whereas they could be observed in both lytically infected and latently infected/TSA-treated cultures. LAT was the only detectable transcript during latent infection, whereas lytic ICP27 transcript was detected in lytically infected and latently infected/TSA-treated cultures. Conclusion: Cultured SGNs can be both latently and lytically infected with HSV-1. Furthermore, latently infected SGNs can be reactivated using TSA, yielding infectious virus.

Increased pathology in herpes stromal keratitis results from differences in local, and not systemic, immune responses (VIR5P.1028)

Abstract Harboring latent herpes simplex virus type 1 (HSV-1) in the trigeminal ganglion (TG) and periodic shedding of virus at the corneal surface can be asymptomatic or can trigger an immunopathological response called herpes stromal keratitis that leads to progressive scarring and visual impairment. Our goal is to understand the events that differentiate an asymptomatic from a pathological HSV-1 infection. To this end we infected mice with two different strains of HSV-1: RE that causes progressive corneal opacity, and KOS that induces no overt corneal pathology. The kinetics of viral clearance and the latent viral load in the TG at 30 days post-infection (dpi) were similar following corneal infection with the two HSV-1 strains. However, the pathogenic RE strain induced a stronger CD4 and CD8 T cell response in the draining lymph nodes and TG at 8 dpi that persisted in the TG through 30 dpi. Interestingly, bilateral infections with RE in one eye and KOS in the other resulted in pathology only in the RE infected eye, suggesting that the increased immunopathology caused by the RE strain reflects local differences in the cornea or ipsilateral TG, and not differences in the systemic immune response. We are currently testing the hypothesis that greater viral gene expression by the RE strain during latency results in a larger T cell infiltrate in both the cornea and the TG.

Increased risk of cancer after Bell’s palsy: a 5-year follow-up study

Reactivation of latent herpes simplex virus (HSV) type I or varicella-zoster virus (VZV) has been recognized as the most common pathomechanism underlying Bell's palsy. There is also increased reactivation of HSV or VZV in patients with immunosuppressed states and in cancer patients. The purpose of this study was to investigate the risk for cancer during a 5-year follow-up period after diagnosis of Bell's palsy by using a population-based dataset in Taiwan. We used data from the "Longitudinal Health Insurance Database". We identified 2,618 patients with Bell's palsy as the study cohort and randomly selected 13,090 patients to be used as a comparison cohort. Cox proportional hazards regression was performed to compare the 5-year risk of subsequent cancer between the study and comparison cohorts. We found that the incidence of cancer was 1.55 (95 % CI 1.35-1.78) per 100 person-years for patients with Bell's palsy and 1.09 (95 % CI 1.02-1.18) per 100 person-years for comparison patients. After censoring cases that died from non-cancer causes during the follow-up period and adjusting for urbanization, monthly income, geographic region, and diabetes, the hazard ratio (HR) for cancer during the 5-year follow-up period for patients with Bell's palsy was 1.43 times that for comparison patients (95 % CI 1.22-1.73). There was a particularly increased risk of oral cancer (HR = 2.49; 95 % CI 1.54-4.03) for patients with Bell's palsy compared with the other patients. We conclude that patients with Bell's palsy were at significant risk of cancer during a 5-year follow-up period after diagnosis.

The Influence of Stress Factors on the Reactivation of Latent Herpes Simplex Virus Type 1 in Infected Mice

This study shows that the influence of different stress factors impacts the reactivation of latent herpes simplex virus type 1 (HSV-1) specifically in the trigeminal ganglion of infected mice. Different stress factors including hyperthermia, hypothermia, fatigue, and immunosuppression were exerted on mice infected with HSV-1. These viral antigens were then detected in the trigeminal ganglion region of infected mice under the influence of each stress factor, with hyperthermia having the most influence on reactivation. Interestingly, an increase in IL-6 was also detected in mice subjected to hyperthermia. These studies therefore suggest that stress can induce the reactivation of latent HSV-1, possibly through the induction of IL-6, in the trigeminal ganglion region of infected mice. This reveals a new insight on the pathogenesis of relapse infection of HSV-1.

HSV1 in Alzheimer’s disease: Myth or reality?

AbstractAlzheimer’s disease (AD) is the most frequent cause of dementia in the elderly, characterized by the presence of cerebral amyloid plaques and neurofibrillary tangles. The causes of the disease are not well understood, especially considering that more than 95% of AD patients are non-familial. Due to the similarity of brain regions affected in herpes simplex encephalitis to those mainly affected in AD, and owing to the very high prevalence of latent herpes simplex virus type 1 (HSV1) infection, reactivation of HSV1 was proposed as one of the possible causes of AD. The trigeminal ganglion, located only a few millimeters from the entorhinal cortex, is the primary site of HSV1 latency, although other sites including the sensory neurons, the nodose ganglion of the vagus nerve and other regions of the brain may be involved, possibly in relation to very early neurofibrillary AD changes in the dorsal raphe, locus coeruleus and other brainstem nuclei. Novel data obtained upon infection of cultured neuronal cells and mouse brain with HSV1 further show that HSV1 infection causes intracellular amyloid-beta protein accumulation, as well as abnormal phosphorylation of tau protein, the major component of tangles. Another interesting fact is the existence of a significant degree of homology between HSV1 components and AD susceptibility genes. In this review we summarize findings that reveal connections between the two conditions, as well as different suggestions for the mechanisms of HSV1-induced AD. As most of the available results support a connection of AD and HSV1 infection, antiviral therapy should be taken into consideration for AD treatment following early diagnosis.

Vestibular Neuritis

The key signs and symptoms of vestibular neuritis are rotatory vertigo with an acute onset lasting several days, horizontal spontaneous nystagmus (with a rotational component) toward the unaffected ear, a pathologic head-impulse test toward the affected ear, a deviation of the subjective visual vertical toward the affected ear, postural imbalance with falls toward the affected ear, and nausea. The head-impulse test and caloric irrigation show an ipsilateral deficit of the vestibuloocular reflex. Vestibular neuritis is the third most common cause of peripheral vestibular vertigo. It has an annual incidence of 3.5 per 100,000 population and accounts for 7% of the patients at outpatient clinics specializing in the treatment of vertigo. The reactivation of a latent herpes simplex virus type 1 (HSV-1) infection is the most likely cause, as HSV-1 DNA and RNA have been detected in human vestibular ganglia. Vestibular neuritis is a diagnosis of exclusion. Relevant differential diagnoses are vestibular pseudoneuritis due to acute pontomedullary brainstem lesions or cerebellar nodular infarctions, vestibular migraine, and monosymptomatically beginning Ménière's disease. Recovery from vestibular neuritis is due to a combination of (a) peripheral restoration of labyrinthine function, usually incomplete but can be improved by early treatment with corticosteroids, which cause a recovery rate of 62% within 12 months; (b) mainly somatosensory and visual substitution; and (c) central compensation, which can be improved by vestibular exercise.

Commentary: Understanding the pathophysiology of poverty

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Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

Acute morphine administration is known to alter the course of herpes simplex virus infection. In this study, the effect of acute morphine administration on the reactivation of latent herpes was investigated in a mouse model. Because of the important role of cytolytic T lymphocyte (CTL) activity in the inhibition of herpes simplex virus type 1 (HSV-1) reactivation, the effect of acute morphine administration on CTL responses was also evaluated. Furthermore, lymphocyte proliferation and IFN-gamma production were evaluated for their roles in the induction of the CTL response. The findings showed that acute morphine administration significantly reduced CTL responses, lymphocyte proliferation, and IFN-gamma production. Furthermore, acute morphine administration has been shown to reactivate latent HSV-1. Previous studies have shown that cellular immune responses have important roles in the inhibition of HSV reactivation. These findings suggest that suppression of a portion of the cellular immune response after acute morphine administration may constitute one part of the mechanism that induces HSV reactivation.

Fewer Latent Herpes Simplex Virus Type 1 and Cytotoxic T Cells Occur in the Ophthalmic Division than in the Maxillary and Mandibular Divisions of the Human Trigeminal Ganglion and Nerve

Following primary infection of the mouth, herpes simplex virus type 1 (HSV-1) travels retrogradely along the maxillary (V2) or mandibular (V3) nerve to the trigeminal ganglion (TG), where it establishes lifelong latency. Symptomatic HSV-1 reactivations frequently manifest as herpes labialis, while ocular HSV-1 disease is rare. We investigated whether these clinical observations are mirrored by the distribution of latent HSV-1 as well as cytotoxic T-cell infiltration around the nerve cell bodies and in the nerve fibers. The three divisions of the TG were separated by using neurofilament staining and carbocyanine dye Di-I tracing and then screened by in situ hybridization for the presence of HSV-1 latency-associated transcript (LAT). The T-cell distribution and the pattern of cytolytic molecule expression were evaluated by immunohistochemistry. The Di-I-labeled neurons were largely confined to the nerve entry zone of the traced nerve branches. Very few Di-I-labeled neurons were found in adjacent divisions due to traversing fiber bundles. LAT was abundant in the V2 and V3 divisions of all TG but was scarce or totally absent in the ophthalmic (V1) division. CD8(+) T cells were found in all three divisions of the TG and in the respective nerves, clearly clustering in V2 and V3, which is indicative of a chronic inflammation. Only T cells surrounding neurons in the V2 and V3 ganglionic divisions expressed granzyme B. In conclusion, the large accumulation of LAT and cytotoxic T cells in the V2 and V3 but not in the V1 division of the TG reflects the sites supplied by the sensory fibers and the clinical reactivation patterns.

In Vivo Changes in the Patterns of Chromatin Structure Associated with the Latent Herpes Simplex Virus Type 1 Genome in Mouse Trigeminal Ganglia Can Be Detected at Early Times after Butyrate Treatment

During herpes simplex virus type 1 (HSV-1) latency in mouse dorsal root ganglia (DRG), chromatin associated with the latency-associated transcript (LAT) region of the viral genome is hyperacetylated at lysines 9 and 14 of histone 3 [H3(K9, K14)], while lytic genes are hypoacetylated. Explanted DRG exhibit a pattern of deacetylation of the LAT enhancer followed by acetylation of the ICP0 promoter at early times postexplant. Recently, we reported that sodium butyrate induced in vivo reactivation of HSV-1 in latent mice. In this study, we assessed the effect of sodium butyrate on the chromatin patterns of latent and butyrate-treated mouse trigeminal ganglia (TG) via chromatin immunoprecipitation (ChIP). We detected deacetylation of acetyl H3(K9, K14) of the LAT promoter and LAT enhancer regions as early as 0.5 h post-butyrate treatment, and this deacetylation corresponded to an increase in the acetylation of the lytic promoters ICP0 and ICP4 at 0.5 h and 1 h post-butyrate treatment, respectively. This is the first study to combine in vivo reactivation with the examination of the HSV-1 genome through ChIP assays at early times after the introduction of in vivo reactivation stimuli.

CD8 T cells and latent herpes simplex virus type 1: keeping the peace in sensory ganglia

Herpes simplex virus type 1 (HSV-1) infections represent a significant worldwide heath problem. The lack of an effective therapy to curtail reactivation of HSV-1 from a state of neuronal latency has lead to significant morbidity and mortality. Effective therapies to prevent reactivation must likely elicit a protective CD8 T-cell response that could act to prevent reactivation from sensory neurons prior to release of infectious virus at the periphery. This review focuses on the present understanding of how CD8 T cells maintain HSV-1 latency and how this knowledge could facilitate the generation of more effective therapeutic modalities.

Isoform-specific effects of ApoE on HSV immediate early gene expression and establishment of latency

Alzheimer's disease (AD) is a common and devastating neurodegenerative disease in which most cases are of unknown, sporadic origin. In addition to age, the most prevalent known risk factor for developing AD is carriage of the ɛ4 allele of Apolipoprotein E (ApoE). Carriage of the ɛ2 or ɛ3 allele of ApoE confers protection or no change in risk for AD, respectively. Latent herpes simplex virus type 1 (HSV-1) infection in the brain concurrent with ApoE4 carriage exacerbates risk for AD, suggesting that these two factors interact to promote neuronal dysfunction and degeneration in selective brain areas. Indeed, HSV-1 DNA has been found in regions primarily affected by AD, such as the temporal lobes, hippocampus, and neocortex. We hypothesize that HSV-1 infection in the background of ApoE4, but not ApoE2 or ApoE3, promotes an environment more conducive to neuronal degeneration. To investigate this idea, we have utilized transgenic mice that express human ApoE2, 3, or 4 alleles from astrocytes in a murine ApoE −/− background. We find that carriage of the different ApoE alleles dramatically affects HSV-1 immediate early gene expression as well as the establishment of latency. Both of these factors are poised to impact neuronal viability, inflammation, and viral spread. Our data support the concept that HSV-1 and ApoE4 interact to provide an environment conducive to the development and/or spread of AD.

Capsaicin-induced reactivation of latent herpes simplex virus type 1 in sensory neurons in culture.

Herpes simplex virus type 1 (HSV-1) produces a life-long latent infection in neurons of the peripheral nervous system, primarily in the trigeminal and dorsal root ganglia. Neurons of these ganglia express high levels of the capsaicin receptor, also known as the vanilloid receptor-1 (VR-1). VR-1 is a non-selective ion channel, found on sensory neurons, that primarily fluxes Ca(2+) ions in response to various stimuli, including physiologically acidic conditions, heat greater than 45 degrees C and noxious compounds such as capsaicin. Using an in vitro neuronal model to study HSV-1 latency and reactivation, we found that agonists of the VR-1 channel - capsaicin and heat - resulted in reactivation of latent HSV-1. Capsaicin-induced reactivation of HSV-1 latently infected neurons was dose-dependent. Additionally, activation of VR-1 at its optimal temperature of 46 degrees C caused a significant increase in virus titres, which could be attenuated with the VR-1 antagonist, capsazepine. VR-1 activation that resulted in HSV-1 reactivation was calcium-dependent, since the calcium chelator BAPTA significantly reduced reactivation following treatment with caspsaicin and forskolin. Taken together, these results suggest that activation of the VR-1 channel, often associated with increases in intracellular calcium, results in HSV-1 reactivation in sensory neurons.

Caspase-3-dependent reactivation of latent herpes simplex virus type 1 in sensory neuronal cultures.

Life-long latent herpes simplex virus type 1 (HSV-1) is harbored in sensory neurons where sporadic reactivation occurs. Reactivation stimuli may involve activation of apoptotic signaling in the neuron. Previous experiments have demonstrated that reactivation of latent HSV-1 in dorsal root ganglion (DRG) neuronal cultures occurred following nerve growth factor (NGF) deprivation. NGF deprivation stimulates apoptotic signaling by activating the proapoptotic proteolytic enzyme, caspase-3. When DRG neuronal cultures harboring latent HSV-1 were treated with a caspase-3-specific inhibitor, NGF deprivation-induced reactivation was significantly reduced. Interestingly, the caspase-3 inhibitor had no effect on productive HSV-1 infection. Furthermore, activation of caspase-3 with either C2-ceramide or a recombinant adenovirus expressing caspase-3 caused significant HSV-1 reactivation.