Publications by authors named "Don Gilden"

141 Publications

Primary and Acquired Immunodeficiencies Associated with Severe Varicella-Zoster Infections.

Clin Infect Dis 2020 Aug 28. Epub 2020 Aug 28.

Laboratory of Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

Background: While most cases of varicella or zoster are self-limited, patients with certain immune deficiencies may develop severe or life-threatening disease.

Methods: We studied a patient with varicella-zoster virus (VZV) CNS vasculopathy and as part of the evaluation, tested his plasma for antibodies to cytokines. We reviewed the literature for cases of varicella or zoster associated with primary and acquired immunodeficiencies.

Results: We found that a patient with VZV CNS vasculopathy had antibody that neutralized interferon (IFN)-α, but not IFN-γ. The patient's plasma blocked phosphorylation in response to stimulation with IFN-α in healthy control peripheral blood mononuclear cells. In addition to acquired immunodeficiencies like HIV or autoantibodies to IFN, variants in specific genes have been associated with severe varicella and/or zoster. While these genes encode proteins with very different activities, many affect IFN signaling pathways, either those that sense double-stranded RNA or cytoplasmic DNA that trigger IFN production, or those involved in activation of IFN stimulated genes in response to binding of IFN with its receptor.

Conclusions: Immune deficiencies highlight the critical role of IFN in control of VZV infections and suggest new approaches for treatment of VZV infection in patients with certain immune deficiencies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1274DOI Listing
August 2020

Targeted Genome Sequencing Reveals Varicella-Zoster Virus Open Reading Frame 12 Deletion.

J Virol 2017 10 27;91(20). Epub 2017 Sep 27.

Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

The neurotropic herpesvirus varicella-zoster virus (VZV) establishes a lifelong latent infection in humans following primary infection. The low abundance of VZV nucleic acids in human neurons has hindered an understanding of the mechanisms that regulate viral gene transcription during latency. To overcome this critical barrier, we optimized a targeted capture protocol to enrich VZV DNA and cDNA prior to whole-genome/transcriptome sequence analysis. Since the VZV genome is remarkably stable, it was surprising to detect that VZV32, a VZV laboratory strain with no discernible growth defect in tissue culture, contained a 2,158-bp deletion in open reading frame (ORF) 12. Consequently, ORF 12 and 13 protein expression was abolished and Akt phosphorylation was inhibited. The discovery of the ORF 12 deletion, revealed through targeted genome sequencing analysis, points to the need to authenticate the VZV genome when the virus is propagated in tissue culture. Viruses isolated from clinical samples often undergo genetic modifications when cultured in the laboratory. Historically, VZV is among the most genetically stable herpesviruses, a notion supported by more than 60 complete genome sequences from multiple isolates and following multiple passages. However, application of enrichment protocols to targeted genome sequencing revealed the unexpected deletion of a significant portion of VZV ORF 12 following propagation in cultured human fibroblast cells. While the enrichment protocol did not introduce bias in either the virus genome or transcriptome, the findings indicate the need for authentication of VZV by sequencing when the virus is propagated in tissue culture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.01141-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625521PMC
October 2017

Induction of varicella zoster virus DNA replication in dissociated human trigeminal ganglia.

J Neurovirol 2017 02 28;23(1):152-157. Epub 2016 Sep 28.

Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Box B-182, Aurora, CO, 80045, USA.

Varicella zoster virus (VZV), a human neurotropic alphaherpesvirus, becomes latent after primary infection and reactivates to produce zoster. To study VZV latency and reactivation, human trigeminal ganglia removed within 24 h after death were mechanically dissociated, randomly distributed into six-well tissue culture plates and incubated with reagents to inactivate nerve growth factor (NGF) or phosphoinositide 3-kinase (PI3-kinase) pathways. At 5 days, VZV DNA increased in control and PI3-kinase inhibitor-treated cultures to the same extent, but was significantly more abundant in anti-NGF-treated cultures (p = 0.001). Overall, VZV DNA replication is regulated in part by an NGF pathway that is PI3-kinase-independent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-016-0480-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464606PMC
February 2017

Varicella-Zoster Virus Downregulates Programmed Death Ligand 1 and Major Histocompatibility Complex Class I in Human Brain Vascular Adventitial Fibroblasts, Perineurial Cells, and Lung Fibroblasts.

J Virol 2016 Dec 14;90(23):10527-10534. Epub 2016 Nov 14.

Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA

Varicella-zoster virus (VZV) vasculopathy produces stroke, giant cell arteritis, and granulomatous aortitis, and it develops after virus reactivates from ganglia and spreads transaxonally to arterial adventitia, resulting in persistent inflammation and pathological vascular remodeling. The mechanism(s) by which inflammatory cells persist in VZV-infected arteries is unknown; however, virus-induced dysregulation of programmed death ligand 1 (PD-L1) may play a role. Specifically, PD-L1 can be expressed on virtually all nucleated cells and suppresses the immune system by interacting with the programmed cell death protein receptor 1, found exclusively on immune cells; thus, downregulation of PD-L1 may promote inflammation, as seen in some autoimmune diseases. Both flow cytometry and immunofluorescence analyses to test whether VZV infection of adventitial cells downregulates PD-L1 showed decreased PD-L1 expression in VZV-infected compared to mock-infected human brain vascular adventitial fibroblasts (HBVAFs), perineural cells (HPNCs), and fetal lung fibroblasts (HFLs) at 72 h postinfection. Quantitative RT-PCR analyses showed no change in PD-L1 transcript levels between mock- and VZV-infected cells, indicating a posttranscriptional mechanism for VZV-mediated downregulation of PD-L1. Flow cytometry analyses showed decreased major histocompatibility complex class I (MHC-I) expression in VZV-infected cells and adjacent uninfected cells compared to mock-infected cells. These data suggest that reduced PD-L1 expression in VZV-infected adventitial cells contribute to persistent vascular inflammation observed in virus-infected arteries from patients with VZV vasculopathy, while downregulation of MHC-I prevents viral clearance.

Importance: Here, we provide the first demonstration that VZV downregulates PD-L1 expression in infected HBVAFs, HPNCs, and HFLs, which, together with the noted VZV-mediated downregulation of MHC-I, might foster persistent inflammation in vessels, leading to pathological vascular remodeling during VZV vasculopathy and persistent inflammation in infected lungs to promote subsequent infection of T cells and hematogenous virus spread. Identification of a potential mechanism by which persistent inflammation in the absence of effective viral clearance occurs in VZV vasculopathy and VZV infection of the lung is a step toward targeted therapy of VZV-induced disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.01546-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110195PMC
December 2016

Successful antiviral treatment after 6years of chronic progressive neurological disease attributed to VZV brain infection.

J Neurol Sci 2016 Sep 15;368:240-2. Epub 2016 Jul 15.

Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA.

We describe an extraordinary case of an immunocompetent patient who developed sacral-distribution zoster, followed 3months later by neurological disease that progressed for 6years and was attributed to varicella zoster virus (VZV) infection of the brain. Despite the prolonged infection, neurologic symptoms and signs resolved rapidly and completely after treatment with intravenous acyclovir.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2016.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996351PMC
September 2016

Clinical Reasoning: A 57-year-old woman with ataxia and oscillopsia: Varicella-zoster encephalitis.

Neurology 2016 08;87(7):e61-4

From the Department of Neurology (M.J.B., P.L., S.S.), Vanderbilt University Medical Center, Nashville, TN; and Department of Neurology and Immunology & Microbiology (D.G.), University of Colorado School of Medicine, Aurora.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000002981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999162PMC
August 2016

2016 Colorado alphaherpesvirus latency society symposium.

J Neurovirol 2016 10 12;22(5):703-714. Epub 2016 Jul 12.

Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Ave, Box B182, Aurora, CO, 80045, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-016-0468-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489057PMC
October 2016

Burning mouth syndrome associated with varicella zoster virus.

BMJ Case Rep 2016 Jul 5;2016. Epub 2016 Jul 5.

Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

We present two cases of burning mouth syndrome (BMS)-of 8-month duration in a 61-year-old woman and of 2-year duration in a 63-year-old woman-both associated with increased levels of antivaricella zoster virus (VZV) IgM antibodies in serum and with pain that improved with antiviral treatment. Combined with our previous finding of BMS due to herpes simplex virus type 1 (HSV-1) infection, we recommend evaluation of patients with BMS not only for VZV or HSV-1 DNA in the saliva, but also for serum anti-VZV and anti-HSV-1 IgM antibodies. Both infections are treatable with oral antiviral agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2016-215953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956955PMC
July 2016

Proinflammatory cytokines and matrix metalloproteinases in CSF of patients with VZV vasculopathy.

Neurol Neuroimmunol Neuroinflamm 2016 Aug 13;3(4):e246. Epub 2016 Jun 13.

Departments of Neurology (D.J., E.A., S.S., D.G., M.A.N.) and Immunology and Microbiology (D.G.), University of Colorado School of Medicine, Aurora.

Objective: To determine the levels of proinflammatory cytokines and matrix metalloproteinases (MMPs) in the CSF of patients with virologically verified varicella zoster virus (VZV) vasculopathy.

Methods: CSF from 30 patients with virologically verified VZV vasculopathy was analyzed for levels of proinflammatory cytokines and MMPs using the Meso Scale Discovery multiplex ELISA platform. Positive CNS inflammatory disease controls were provided by CSF from 30 patients with multiple sclerosis. Negative controls were provided by CSF from 20 healthy controls.

Results: Compared to multiple sclerosis CSF and CSF from healthy controls, levels of interleukin (IL)-8, IL-6, and MMP-2 were significantly elevated in VZV vasculopathy CSF.

Conclusions: CSF of patients with VZV vasculopathy revealed a unique profile of elevated proinflammatory cytokines, IL-8 and IL-6, along with elevated MMP-2. The relevance of these cytokines to the pathogenesis of VZV vasculopathy requires further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907802PMC
August 2016

SUNCT headaches after ipsilateral ophthalmic-distribution zoster.

J Neurol Sci 2016 Jul 14;366:207-208. Epub 2016 May 14.

Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. Electronic address:

Nine days after left ophthalmic-distribution zoster, a 47-year-old man developed SUNCT headaches (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing). In contrast to two prior cases of SUNCT that developed after varicella zoster virus (VZV) meningoencephalitis without rash, this case describes an association of SUNCT with overt zoster, thus adding to the spectrum of headache and facial pain syndromes caused by VZV reactivation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2016.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903154PMC
July 2016

Varicella zoster virus infection of human fetal lung cells alters mitochondrial morphology.

J Neurovirol 2016 10 31;22(5):674-682. Epub 2016 May 31.

Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Box B182, Aurora, 80045, CO, USA.

Varicella zoster virus (VZV) is a ubiquitous alphaherpesvirus that establishes latency in ganglionic neurons throughout the neuraxis after primary infection. Here, we show that VZV infection induces a time-dependent significant change in mitochondrial morphology, an important indicator of cellular health, since mitochondria are involved in essential cellular functions. VZV immediate-early protein 63 (IE63) was detected in mitochondria-rich cellular fractions extracted from infected human fetal lung fibroblasts (HFL) by Western blotting. IE63 interacted with cytochrome c oxidase in bacterial 2-hybrid analyses. Confocal microscopy of VZV-infected HFL cells at multiple times after infection revealed the presence of IE63 in the nucleus, mitochondria, and cytoplasm. Our data provide the first evidence that VZV infection induces alterations in mitochondrial morphology, including fragmentation, which may be involved in cellular damage and/or death during virus infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-016-0457-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480379PMC
October 2016

Varicella zoster virus triggers the immunopathology of giant cell arteritis.

Curr Opin Rheumatol 2016 Jul;28(4):376-82

aDepartment of NeurologybDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Purpose Of Review: Giant cell arteritis (GCA) is a severe form of vasculitis in the elderly. The recent discovery of varicella zoster virus (VZV) in the temporal arteries and adjacent skeletal muscle of patients with GCA, and the rationale and strategy for antiviral and corticosteroid treatment for GCA are reviewed.

Recent Findings: The clinical features of GCA include excruciating headache/head pain, often with scalp tenderness, a nodular temporal arteries and decreased temporal artery pulsations. Jaw claudication, night sweats, fever, malaise, and a history of polymyalgia rheumatica (aching and stiffness of large muscles primarily in the shoulder girdle, upper back, and pelvis without objective signs of weakness) are common. ESR and CRP are usually elevated. Diagnosis is confirmed by temporal artery biopsy which reveals vessel wall damage and inflammation, with multinucleated giant cells and/or epithelioid macrophages. Skip lesions are common. Importantly, temporal artery biopsies are pathologically negative in many clinically suspect cases. This review highlights recent virological findings in temporal arteries from patients with pathologically verified GCA and in temporal arteries from patients who manifest clinical and laboratory features of GCA, but whose temporal artery biopsies (Bx) are pathologically negative for GCA (Bx-negative GCA). Virological analysis revealed that VZV is present in most GCA-positive and GCA-negative temporal artery biopsies, mostly in skip areas that correlate with adjacent GCA pathology.

Summary: The presence of VZV in Bx-positive and Bx-negative GCA temporal arteries indicates that VZV triggers the immunopathology of GCA. However, the presence of VZV in about 20% of temporal artery biopsies from non-GCA postmortem controls also suggests that VZV alone is not sufficient to produce disease. Treatment trials should be performed to determine if antiviral agents confer additional benefits to corticosteroids in both Bx-positive and Bx-negative GCA patients. These studies should also examine whether oral antiviral agents and corticosteroids are as effective as intravenous acyclovir and corticosteroids. Appropriate dosage and duration of treatment also remain to be determined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BOR.0000000000000292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896311PMC
July 2016

Alphaherpesvirus DNA replication in dissociated human trigeminal ganglia.

J Neurovirol 2016 10 12;22(5):688-694. Epub 2016 May 12.

Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Mail Stop B182, Aurora, CO, 80045, USA.

Analysis of the frequency and PCR-quantifiable abundance of herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) DNA in multiple biological replicates of cells from dissociated randomly distributed human trigeminal ganglia (TG) of four subjects revealed an increase in both parameters and in both viruses during 5 days of culture, with no further change by 10 days. Dissociated TG provides a platform to analyze initiation of latent virus DNA replication within 5 days of culture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055419PMC
http://dx.doi.org/10.1007/s13365-016-0450-7DOI Listing
October 2016

Varicella Zoster Virus: A Common Cause of Stroke in Children and Adults.

J Stroke Cerebrovasc Dis 2016 Jul 29;25(7):1561-1569. Epub 2016 Apr 29.

Departments of Neurology and Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado.

Background: Varicella zoster virus (VZV) is a neurotropic, exclusively human herpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. As cell-mediated immunity to VZV declines with advancing age and immunosuppression, VZV reactivates to produce zoster (shingles). One of the most serious complications of zoster is VZV vasculopathy.

Methods: We reviewed recent studies of stroke associated with varicella and zoster, how VZV vasculopathy is verified virologically, vaccination to prevent varicella and immunization to prevent zoster, and VZV in giant cell arteritis (GCA).

Findings: We report recent epidemiological studies revealing an increased risk of stroke after zoster; the clinical, laboratory, and imaging features of VZV vasculopathy; that VZV vasculopathy is confirmed by the presence of either VZV DNA or anti-VZV IgG antibody in cerebrospinal fluid; special features of VZV vasculopathy in children; vaccination to prevent varicella and immunization to prevent zoster; and the latest evidence linking VZV to GCA.

Conclusion: In children and adults, VZV is a common cause of stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.03.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912415PMC
July 2016

Blinded search for varicella zoster virus in giant cell arteritis (GCA)-positive and GCA-negative temporal arteries.

J Neurol Sci 2016 May 19;364:141-3. Epub 2016 Mar 19.

Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA.

Recent analysis of archived temporal arteries (TAs) acquired from 13 pathology laboratories in the US, Canada, Iceland, France, Germany and Israel from patients with pathologically-verified giant cell arteritis (GCA-positive) and TAs from patients with clinical features and laboratory abnormalities of GCA but whose TAs were pathologically negative (GCA-negative) revealed VZV antigen in most TAs from both groups. Despite formalin-fixation, VZV DNA was also found in many VZV-antigen positive sections that were scraped, subjected to DNA extraction, and examined by PCR with VZV-specific primers. Importantly, in past studies, the pathological diagnosis (GCA-positive or -negative) was known to the neurovirology laboratory. Herein, GCA-positive and GCA-negative TAs were provided by an outside institution and examined by 4 investigators blinded to the pathological diagnoses. VZV antigen was found in 3/3 GCA-positive TAs and in 4/6 GCA-negative TAs, and VZV DNA in 1/3 VZV antigen-positive, GCA-positive TAs and in 3/4 VZV antigen-positive, GCA-negative TAs. VZV DNA was also detected in one GCA-negative, VZV-antigen negative TA. Overall, the detection of VZV antigen in 78% of GCA-positive and GCA-negative TAs is consistent with previous reports on the prevalence of VZV antigen in patients with clinically suspect GCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2016.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834150PMC
May 2016

Varicella Zoster Virus Infection in Granulomatous Arteritis of the Aorta.

J Infect Dis 2016 06 31;213(12):1866-71. Epub 2016 Mar 31.

Department of Neurology.

Granulomatous arteritis characterizes the pathology of giant cell arteritis, granulomatous aortitis, and intracerebral varicella zoster virus (VZV) vasculopathy. Because intracerebral VZV vasculopathy and giant cell arteritis are strongly associated with productive VZV infection in cerebral and temporal arteries, respectively, we evaluated human aortas for VZV antigen and VZV DNA. Using 3 different anti-VZV antibodies, we identified VZV antigen in 11 of 11 aortas with pathologically verified granulomatous arteritis, in 1 of 1 cases of nongranulomatous arteritis, and in 5 of 18 control aortas (28%) obtained at autopsy. The presence of VZV antigen in granulomatous aortitis was highly significant (P = .0001) as compared to control aortas, in which VZV antigen was never associated with pathology, indicating subclinical reactivation. VZV DNA was found in most aortas containing VZV antigen. The frequent clinical, radiological, and pathological aortic involvement in patients with giant cell arteritis correlates with the significant detection of VZV in granulomatous aortitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiw101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878728PMC
June 2016

VZV in biopsy-positive and -negative giant cell arteritis: Analysis of 100+ temporal arteries.

Neurol Neuroimmunol Neuroinflamm 2016 Apr 9;3(2):e216. Epub 2016 Mar 9.

University of Colorado School of Medicine (D.G., T.W., N.K., M.A.N.), Aurora; and East Carolina University (P.J.B.), Greenville, NC.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794807PMC
April 2016

Varicella Zoster Virus in the Nervous System.

F1000Res 2015 26;4. Epub 2015 Nov 26.

Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, 12700, USA.

Varicella zoster virus (VZV) is a ubiquitous, exclusively human alphaherpesvirus. Primary infection usually results in varicella (chickenpox), after which VZV becomes latent in ganglionic neurons along the entire neuraxis. As VZV-specific cell-mediated immunity declines in elderly and immunocompromised individuals, VZV reactivates and causes herpes zoster (shingles), frequently complicated by postherpetic neuralgia. VZV reactivation also produces multiple serious neurological and ocular diseases, such as cranial nerve palsies, meningoencephalitis, myelopathy, and VZV vasculopathy, including giant cell arteritis, with or without associated rash. Herein, we review the clinical, laboratory, imaging, and pathological features of neurological complications of VZV reactivation as well as diagnostic tests to verify VZV infection of the nervous system. Updates on the physical state of VZV DNA and viral gene expression in latently infected ganglia, neuronal, and primate models to study varicella pathogenesis and immunity are presented along with innovations in the immunization of elderly individuals to prevent VZV reactivation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.7153.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754002PMC
February 2016

Varicella zoster virus and giant cell arteritis.

Curr Opin Infect Dis 2016 06;29(3):275-9

aDepartment of Neurology bDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Purpose Of Review: Giant cell arteritis (GCA) is a serious disease and the most common cause of vasculitis in the elderly. Here, studies describing the recent discovery of varicella zoster virus (VZV) in the temporal arteries of patients with GCA are reviewed.

Recent Findings: GCA is characterized by severe headache/head pain and scalp tenderness. Many patients also have a history of vision loss, jaw claudication, polymyalgia rheumatica, fever, night sweats, weight loss, and fatigue. The erythrocyte sedimentation rate and C-reactive protein are usually elevated. Diagnosis is confirmed by temporal artery biopsy, which reveals vessel wall damage and inflammation, with multinucleated giant cells and/or epithelioid macrophages. Skip lesions are common. Importantly, temporal artery biopsies are pathologically negative in many clinically suspect cases. The present review highlights recent virological findings in temporal arteries from patients with pathologically verified GCA and in temporal arteries from patients who manifest clinical and laboratory features of GCA but whose temporal artery biopsies are pathologically negative for GCA. Virological analysis revealed that VZV is present in most GCA-positive and GCA-negative temporal artery biopsies, particularly in skip areas that correlate with adjacent GCA disease.

Summary: The presence of VZV in GCA-positive and GCA-negative temporal arteries reflects the possible role of VZV in triggering the immunopathology of GCA and indicates that both groups of patients should be treated with antivirals in addition to corticosteroids. Whether oral antiviral agents and steroids are as effective as intravenous acyclovir and steroids, and the dosage and duration of treatment, remain to be determined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QCO.0000000000000258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134838PMC
June 2016

Frequency of varicella zoster virus DNA in human adrenal glands.

J Neurovirol 2016 06 3;22(3):400-2. Epub 2016 Feb 3.

Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Box B-182, Aurora, CO, 80045, USA.

Varicella zoster virus (VZV) becomes latent in ganglionic neurons derived from neural crest cells. Because the adrenal gland also contains medullary chromaffin cells of neural crest origin, we examined human adrenal glands and medullary chromaffin cell tumors (pheochromocytomas) for VZV and herpes simplex virus type 1 (HSV-1). We found VZV, but not HSV-1, DNA in 4/63 (6 %) normal adrenal glands. No VZV transcripts or antigens were detected in the 4 VZV DNA-positive samples. No VZV or HSV-1 DNA was found in 21 pheochromocytomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-016-0425-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654543PMC
June 2016

Developments in Varicella Zoster Virus Vasculopathy.

Curr Neurol Neurosci Rep 2016 Feb;16(2):12

Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Box B182, Aurora, CO, 80045, USA.

Varicella zoster virus (VZV) is a highly neurotropic human herpesvirus. Primary infection usually causes varicella (chicken pox), after which virus becomes latent in ganglionic neurons along the entire neuraxis. VZV reactivation results in zoster (shingles) which is frequently complicated by chronic pain (postherpetic neuralgia). VZV reactivation also causes meningoencephalitis, myelitis, ocular disorders, and vasculopathy, all of which can occur in the absence of rash. This review focuses on the association of VZV and stroke, and on the widening spectrum of disorders produced by VZV vasculopathy in immunocompetent and immunocompromised individuals, including recipients of varicella vaccine. Aside from ischemic stroke, VZV infection of cerebral arteries may lead to development of intracerebral aneurysms, with or without hemorrhage. Moreover, recent clinical-virological case reports and retrospective pathological-virological analyses of temporal arteries positive or negative for giant cell arteritis (GCA) indicate that extracranial VZV vasculopathy triggers the immunopathology of GCA. While many patients with GCA improve after corticosteroid treatment, prolonged corticosteroid use may potentiate VZV infection, leading to fatal vasculopathy in the brain and other organs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11910-015-0614-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489063PMC
February 2016

Risk of Stroke and Myocardial Infarction After Herpes Zoster in Older Adults in a US Community Population.

Mayo Clin Proc 2016 Jan 15;91(1):33-44. Epub 2015 Dec 15.

Department of Neurology, Univerity of Colorado School of Medicine, Aurora, CO; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.

Objective: To assess the risk of stroke and myocardial infarction (MI) after herpes zoster in a US community population of older adults.

Patients And Methods: We performed a community cohort study (January 1, 1986, to October 1, 2011) comparing the risk of stroke and MI in 4862 adult residents of Olmsted County, Minnesota, 50 years and older with and without herpes zoster and 19,433 sex- and age-matched individuals with no history of herpes zoster. Odds ratios are presented for MI and stroke at 3, 6, 12, and 36 months after index herpes zoster plus hazard ratios for long-term risk (up to 28.6 years).

Results: Individuals with herpes zoster had more risk or confounding factors for MI and stroke, suggesting that they had worse health status overall. When controlling for the multiple risk factors, those with herpes zoster were at increased risk for stroke at 3 months after herpes zoster compared with those without a history of herpes zoster (odds ratio, 1.53; 95% CI, 1.10-2.33; P=.04). The association between herpes zoster and MI at 3 months was not robust across analytic methods. Herpes zoster was not associated with an increased risk of stroke or MI at any point beyond 3 months.

Conclusions: Herpes zoster was associated with only a short-term increased risk of stroke, which may be preventable with the prevention of herpes zoster.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mayocp.2015.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856435PMC
January 2016

Characterization of the immune response in ganglia after primary simian varicella virus infection.

J Neurovirol 2016 06 16;22(3):376-88. Epub 2015 Dec 16.

Department of Viroscience, Erasmus MC, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.

Primary simian varicella virus (SVV) infection in non-human primates causes varicella, after which the virus becomes latent in ganglionic neurons and reactivates to cause zoster. The host response in ganglia during establishment of latency is ill-defined. Ganglia from five African green monkeys (AGMs) obtained at 9, 13, and 20 days post-intratracheal SVV inoculation (dpi) were analyzed by ex vivo flow cytometry, immunohistochemistry, and in situ hybridization. Ganglia at 13 and 20 dpi exhibited mild inflammation. Immune infiltrates consisted mostly of CD8(dim) and CD8(bright) memory T cells, some of which expressed granzyme B, and fewer CD11c(+) and CD68(+) cells. Chemoattractant CXCL10 transcripts were expressed in neurons and infiltrating inflammatory cells but did not co-localize with SVV open reading frame 63 (ORF63) RNA expression. Satellite glial cells expressed increased levels of activation markers CD68 and MHC class II at 13 and 20 dpi compared to those at 9 dpi. Overall, local immune responses emerged as viral DNA load in ganglia declined, suggesting that intra-ganglionic immunity contributes to restricting SVV replication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-015-0408-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899505PMC
June 2016

Varicella-Zoster Virus in Giant Cell Arteritis--Reply.

JAMA Neurol 2016 Feb;73(2):239

Department of Neurology, University of Colorado School of Medicine, Aurora2Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2015.3871DOI Listing
February 2016

Varicella-Zoster Virus Infections.

Authors:
Don Gilden

Continuum (Minneap Minn) 2015 Dec;21(6 Neuroinfectious Disease):1692-703

Purpose Of Review: This article describes the clinical features and laboratory and imaging abnormalities of the protean neurologic disorders produced by varicella-zoster virus (VZV) reactivation. Diseases include not only zoster, but also chronic pain (postherpetic neuralgia), meningoencephalitis and cerebellitis, single or multiple cranial nerve palsies (polyneuritis cranialis), myelopathy (myelitis and spinal cord infarction), and VZV vasculopathy of intracerebral and extracerebral arteries that causes ischemic or hemorrhagic stroke, aneurysm, subarachnoid and intracerebral hemorrhage, arterial ectasia, and dissection. The article addresses accurate diagnosis of VZV infection of the nervous system in the absence of rash, and optimal treatment.

Recent Findings: All neurologic disorders produced by VZV can occur in the absence of rash. Diagnosis is confirmed by the presence of VZV DNA or anti-VZV antibodies in CSF. Based on evidence from recent studies, VZV has been implicated as a cause of giant cell arteritis.

Summary: Clinicians must be aware that VZV reactivation produces multiple disorders of the central nervous system (CNS) and peripheral nervous system, often without rash. Rapid virologic verification and prompt treatment with antiviral agents can lead to complete recovery, even in patients with protracted disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/CON.0000000000000246DOI Listing
December 2015

Occupancy of RNA Polymerase II Phosphorylated on Serine 5 (RNAP S5P) and RNAP S2P on Varicella-Zoster Virus Genes 9, 51, and 66 Is Independent of Transcript Abundance and Polymerase Location within the Gene.

J Virol 2016 02 11;90(3):1231-43. Epub 2015 Nov 11.

Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA

Unlabelled: Regulation of gene transcription in varicella-zoster virus (VZV), a ubiquitous human neurotropic alphaherpesvirus, requires coordinated binding of multiple host and virus proteins onto specific regions of the virus genome. Chromatin immunoprecipitation (ChIP) is widely used to determine the location of specific proteins along a genomic region. Since the size range of sheared virus DNA fragments governs the limit of accurate protein localization, particularly for compact herpesvirus genomes, we used a quantitative PCR (qPCR)-based assay to determine the efficiency of VZV DNA shearing before ChIP, after which the assay was used to determine the relationship between transcript abundance and the occupancy of phosphorylated RNA polymerase II (RNAP) on the gene promoter, body, and terminus of VZV genes 9, 51, and 66. The abundance of VZV gene 9, 51, and 66 transcripts in VZV-infected human fetal lung fibroblasts was determined by reverse transcription-linked quantitative PCR. Our results showed that the C-terminal domain of RNAP is hyperphosphorylated at serine 5 (S5(P)) on VZV genes 9, 51, and 66 independently of transcript abundance and the location within the virus gene at both 1 and 3 days postinfection (dpi). In contrast, phosphorylated serine 2 (S2(P))-modified RNAP was not detected at any virus gene location at 3 dpi and was detected at levels only slightly above background levels at 1 dpi.

Importance: Regulation of herpesvirus gene transcription is an elaborate choreography between proteins and DNA that is revealed by chromatin immunoprecipitation (ChIP). We used a quantitative PCR-based assay to determine fragment size after DNA shearing, a critical parameter in ChIP assays, and exposed a basic difference in the mechanism of transcription between mammalian cells and VZV. We found that hyperphosphorylation at serine 5 of the C-terminal domain of RNAP along the lengths of VZV genes (the promoter, body, and transcription termination site) was independent of mRNA abundance. In contrast, little to no enrichment of serine 3 phosphorylation of RNAP was detected at these virus gene regions. This is distinct from the findings for RNAP at highly regulated host genes, where RNAP S5(P) occupancy decreased and S2(P) levels increased as the polymerase transited through the gene. Overall, these results suggest that RNAP associates with human and virus transcriptional units through different mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.02617-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719599PMC
February 2016

2015 Colorado Alphaherpesvirus Latency Society Symposium.

J Neurovirol 2015 Dec 27;21(6):706-16. Epub 2015 Oct 27.

Department of Neurology, University of Colorado Denver School of Medicine, 12700 E. 19th Ave, Box B182, Aurora, CO, 80045, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-015-0396-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480378PMC
December 2015

Zeroing in on zoster: A tale of many disorders produced by one virus.

J Neurol Sci 2015 Nov 3;358(1-2):38-45. Epub 2015 Oct 3.

Departments of Neurology and Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. Electronic address:

While herpes zoster infection has been recognized since antiquity, chickenpox (varicella) was confused with smallpox until the 1800s, when both illnesses became better understood. In the 20th century, varicella zoster virus (VZV) was shown to cause varicella upon primary (first-time) infection and herpes zoster (shingles) after reactivation of latent VZV. Scientific progress over the past 50 years has rapidly advanced the understanding and prevention of disease produced by VZV. Combined imaging and virological studies continue to reveal the protean neurological, ocular and visceral disorders produced by VZV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2015.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628852PMC
November 2015