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Sarmah K, Sharma A, Sarma K, Alam ST, Dutta BS, Deka E, Laskar SA, Tishya NS, Lakshmi Priya MS, Baishya AC. Genomic analysis of Varicella zoster virus strains during an outbreak with atypical clinical presentations in Biswanath district of Assam, India. Virus Genes 2025:10.1007/s11262-025-02156-0. [PMID: 40220111 DOI: 10.1007/s11262-025-02156-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/05/2025] [Indexed: 04/14/2025]
Abstract
Chickenpox, caused by the Varicella Zoster Virus (VZV), presents as varicella (chickenpox) during primary infection and as herpes zoster (shingles) upon reactivation. With a high infectivity rate and transmission through airborne droplets and contact, VZV poses a significant public health challenge. While the disease is self-limiting, complications such as encephalitis and pneumonia can occur, particularly in unimmunized individuals and those with weakened immune systems. The introduction of varicella vaccination has significantly reduced incidence and complications in countries with universal vaccination programs, but India is yet to incorporate this vaccine into its national immunization schedule. In June 2023, an outbreak of varicella was reported in Biswanath district, Assam, affecting 18 individuals. The outbreak highlighted the impact of factors such as overcrowding, poor ventilation, and inadequate medical intervention. Clinical symptoms included fever, vesicular rash, and severe abdominal pain, with three fatalities linked to severe complications. Molecular and serological investigations confirmed VZV infection in the cases, and whole genome sequencing (WGS) identified the strain as belonging to Clade 5. Phylogenetic analysis revealed the strain's similarity to other Indian VZV sequences, aligning with the established VZV clade nomenclature. The outbreak investigation underscored the importance of timely medical intervention and effective vaccination strategies. Enhanced surveillance, community awareness, and a coordinated response involving various health stakeholders are crucial for managing varicella outbreaks and improving vaccination coverage. This study represents the first comprehensive genomic analysis of VZV from Northeast India, providing valuable insights into the strain circulation and reinforcing the need for vaccination and preventive measures.
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Affiliation(s)
- Kimmi Sarmah
- Department of Microbiology, Gauhati Medical College and Hospital, State Level VRDL, Guwahati, 32, India
| | - Ajanta Sharma
- Department of Microbiology, Gauhati Medical College and Hospital, State Level VRDL, Guwahati, 32, India.
| | - Kishore Sarma
- Department of Computational Biology and Biotechnology, Mahapurusha Srimanta Sankaradeva Viswavidyalaya, Nagaon, India
| | - Syed Tanwir Alam
- Department of Microbiology, Gauhati Medical College and Hospital, State Level VRDL, Guwahati, 32, India
| | - Bornali Sarmah Dutta
- Department of Microbiology, Gauhati Medical College and Hospital, State Level VRDL, Guwahati, 32, India
| | - Eliza Deka
- District Surveillance Office, IDSP, Biswanath Chariali, Assam, India
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Paião HGO, da Costa AC, Ferreira NE, Honorato L, dos Santos BM, de Matos MLM, Domingues RB, Senne CA, Lopes ADO, de Paula VS, Witkin SS, Tozetto-Mendoza TR, Mendes-Correa MC. Phylogenetic Analysis of Varicella-Zoster Virus in Cerebrospinal Fluid from Individuals with Acute Central Nervous System Infection: An Exploratory Study. Viruses 2025; 17:286. [PMID: 40007041 PMCID: PMC11860453 DOI: 10.3390/v17020286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/15/2025] [Accepted: 02/16/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND There is scarce information on Varicella-Zoster virus genetic variability in individuals with acute central nervous system infection in Brazil. The objective of this study was the molecular characterization of Varicella-Zoster virus isolates in cerebrospinal fluid from individuals with acute central nervous system infection. METHODS Cerebrospinal fluid samples were collected from individuals evaluated in emergency and community healthcare services in São Paulo, Brazil. Varicella-Zoster virus identification was performed using commercial platforms Biofire-FilmArray Meningitis/Encephalitis (BioMérieux, Craponne, France) and XGEN-UMLTI-N9® (Mobius Life, Pinhais, Brazil). Positive samples were further characterized as wild-type or vaccine-strain by a real-time polymerase chain reaction assay that targeted a single nucleotide polymorphism in open reading frame 62. We also estimated the mean genetic distance and phylogenetic reconstruction based on open reading frames 22, 38, 54, and 62 in relation to sequences of intercontinentally circulating Varicella-Zoster virus isolates. RESULTS Among the 600 cerebrospinal fluid samples, we identified Varicella-Zoster virus in 30 (5%) samples. None were positive for the vaccine-strain. Twelve samples were sequenced and phylogenetically classified into Clades 1 (41.7%), 2 (25%), 3 (8.3%), 5 (16.7%), or 6 (8%). CONCLUSION Enhanced characterization of circulating Varicella-Zoster virus Clades in Brazil identified previously unreported Clades 2 and 6 as well as three other Clades disseminated intercontinentally. These findings reinforce the importance of Varicella-Zoster virus molecular surveillance in cerebrospinal fluid.
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Affiliation(s)
- Heuder G. O. Paião
- Laboratório de Virologia (LIM52), Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Enéas de Carvalho Aguiar, 470, São Paulo 05403-000, Brazil; (A.C.d.C.); (N.E.F.); (L.H.); (S.S.W.); (T.R.T.-M.); (M.C.M.-C.)
- Departamento de Infectologia e Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Arnaldo, 455, São Paulo 01246-903, Brazil
| | - Antônio C. da Costa
- Laboratório de Virologia (LIM52), Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Enéas de Carvalho Aguiar, 470, São Paulo 05403-000, Brazil; (A.C.d.C.); (N.E.F.); (L.H.); (S.S.W.); (T.R.T.-M.); (M.C.M.-C.)
| | - Noely E. Ferreira
- Laboratório de Virologia (LIM52), Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Enéas de Carvalho Aguiar, 470, São Paulo 05403-000, Brazil; (A.C.d.C.); (N.E.F.); (L.H.); (S.S.W.); (T.R.T.-M.); (M.C.M.-C.)
- Departamento de Infectologia e Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Arnaldo, 455, São Paulo 01246-903, Brazil
| | - Layla Honorato
- Laboratório de Virologia (LIM52), Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Enéas de Carvalho Aguiar, 470, São Paulo 05403-000, Brazil; (A.C.d.C.); (N.E.F.); (L.H.); (S.S.W.); (T.R.T.-M.); (M.C.M.-C.)
- Departamento de Infectologia e Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Arnaldo, 455, São Paulo 01246-903, Brazil
| | - Bianca M. dos Santos
- Serviço de Cuidados Paliativos do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, R. Cotoxó, 1142, São Paulo 05021-001, Brazil;
| | - Maria L. M. de Matos
- Faculdade de Medicina, Universidade de São Caetano do Sul, R. Santo Antônio, 50, São Caetano do Sul 09521-160, Brazil;
| | - Renan B. Domingues
- Laboratório Senne Liquor, Av. Angélica, 2071, São Paulo 01239-030, Brazil; (R.B.D.); (C.A.S.)
| | - Carlos A. Senne
- Laboratório Senne Liquor, Av. Angélica, 2071, São Paulo 01239-030, Brazil; (R.B.D.); (C.A.S.)
| | - Amanda de O. Lopes
- Laboratório de Virologia Molecular do Instituto Oswaldo Cruz, Av. Brasil, 4365, Rio de Janeiro 21040-900, Brazil; (A.d.O.L.); (V.S.d.P.)
| | - Vanessa S. de Paula
- Laboratório de Virologia Molecular do Instituto Oswaldo Cruz, Av. Brasil, 4365, Rio de Janeiro 21040-900, Brazil; (A.d.O.L.); (V.S.d.P.)
| | - Steven S. Witkin
- Laboratório de Virologia (LIM52), Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Enéas de Carvalho Aguiar, 470, São Paulo 05403-000, Brazil; (A.C.d.C.); (N.E.F.); (L.H.); (S.S.W.); (T.R.T.-M.); (M.C.M.-C.)
- Departamento de Infectologia e Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Arnaldo, 455, São Paulo 01246-903, Brazil
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10001, USA
| | - Tânia R. Tozetto-Mendoza
- Laboratório de Virologia (LIM52), Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Enéas de Carvalho Aguiar, 470, São Paulo 05403-000, Brazil; (A.C.d.C.); (N.E.F.); (L.H.); (S.S.W.); (T.R.T.-M.); (M.C.M.-C.)
- Departamento de Infectologia e Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Arnaldo, 455, São Paulo 01246-903, Brazil
| | - Maria Cássia Mendes-Correa
- Laboratório de Virologia (LIM52), Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Enéas de Carvalho Aguiar, 470, São Paulo 05403-000, Brazil; (A.C.d.C.); (N.E.F.); (L.H.); (S.S.W.); (T.R.T.-M.); (M.C.M.-C.)
- Departamento de Infectologia e Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Av. Dr Arnaldo, 455, São Paulo 01246-903, Brazil
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Li J, Wang D, Qi L, Yang Y, Pei J, Dong Y, Wang Y, Yao M, Zhang F, Lei Y, Cheng L, Ye W. Genomic sequencing revealed recombination event between clade 1 and clade 2 occurs in circulating varicella-zoster virus in China. Braz J Microbiol 2024; 55:125-132. [PMID: 38052769 PMCID: PMC10920497 DOI: 10.1007/s42770-023-01206-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/29/2023] [Indexed: 12/07/2023] Open
Abstract
Varicella-zoster virus (VZV), a member of the Alphaherpesvirinae subfamily, causes varicella in primary infections and establishing a latent stage in sensory ganglia. Upon reactivation, VZV causes herpes zoster with severe neuralgia, especially in elderly patients. The mutation rate for VZV is comparatively lower than the other members of other alpha herpesviruses. Due to geographic isolation, different genotypes of VZV are circulating on separate continents. Here, we successfully isolated a VZV from the vesicular fluid of a youth zoster patient. Based on the single-nucleotide polymorphism profiles of different open reading frames that define the genotype, this newly isolated VZV primarily represents genotype clade 2 but also has characteristics of genotype clade 1. The next-generation sequencing provided a nearly full-length sequence, and further phylogenetic analysis revealed that this VZV isolate is distinct from clades 1 and 2. The Recombination Detection Program indicates that a possible recombinant event may occur between the VZV isolate and clade 1. In summary, we found that there is a circulating VZV isolate in China that may represent a recombinant between clade 1 and clade 2, providing new concerns that need to be considered in the future VZV vaccination program.
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Affiliation(s)
- Jia Li
- Department of Neurology, Xi'an International Medical Center Hospital, Xi'an, 710100, Shaanxi, China
| | - Dan Wang
- Second Affiliated Hospital, Xi'an Medical University, 167th Textile East Street, Xi'an, China
| | - Libin Qi
- Cadet Brigade, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, 710032, China
| | - Yuewu Yang
- Cadet Brigade, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, 710032, China
| | - Jiawei Pei
- Bone Metabolism Lab, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Yangchao Dong
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yuan Wang
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Min Yao
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Fanglin Zhang
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yingfeng Lei
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Linfeng Cheng
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Wei Ye
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China.
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Banerjee S, Nath A, Kumar H, Mukherjee D, Soni NP, Dey D, Akilimali A. Evolving VZV Strains: Necessity for Continuous Surveillance and Adaptation of Vaccination Strategies in India. Microbiol Insights 2024; 17:11786361231220122. [PMID: 38533272 PMCID: PMC10961988 DOI: 10.1177/11786361231220122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 11/25/2020] [Indexed: 03/28/2024] Open
Affiliation(s)
| | - Arghya Nath
- ICMR-DHR Viral Research & Diagnostic Laboratory, Burdwan Medical College, Burdwan, India
| | | | | | | | - Debankur Dey
- Calcutta Medical College and Hospital, Kolkata, India
| | - Aymar Akilimali
- Department of Research, Medical Research Circle, Bukavu, DR Congo
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Kumar A, Rajan LS, Sabarinath PS K, Shete AM, Sahay RR, Patil DY, Ingole N, K K, Padinakarai AC, GB S, Shastri J, Padukone S, Joshi Y, Patil S, Majumdar T, Verma A, Yemul J, Shende N, Kumari V, Vedpathak P, Sathe S, Gawande P, Yadav PD. First detection of Varicella Zoster Virus clade 9 cases in India during mpox surveillance. Ann Med 2023; 55:2253733. [PMID: 37672487 PMCID: PMC10484040 DOI: 10.1080/07853890.2023.2253733] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/01/2023] [Accepted: 08/27/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND The multi-country mpox outbreak across the globe has led to the systematic surveillance of mpox cases in India. During the surveillance of mpox, we encountered cases of Varicella Zoster Virus (VZV) in suspected mpox cases amongst children & adults. This study focused on the genomic characterization of VZV in India. METHODS A total of 331 mpox suspected cases were tested for VZV through real-time PCR, and the positive samples were subjected to next-generation sequencing to retrieve the whole genome of VZV using CLC genomics software. Phylogenetic analysis has been done in MEGA 11.0 software to identify circulating clades. RESULT Of the 331 suspected cases, 28 cases with vesicular rashes were found to be positive for VZV. The maximum genome could be retrieved from the clinical specimens of 16 cases with coverage greater than 98% when mapped with reference strain Dumas (NC 001348). The phylogenetic analyses of these sequences determined the circulation of clades 1, 5, and 9 in India. Further, the sequence analysis demonstrated non-synonymous single nucleotide polymorphism (SNPs) among specific ORF of VZV including ORF 14, ORF 22, ORF 36, ORF 37 and ORF 51. Although clade 1 and 5 has been reported earlier, the circulation of clade 9 of VZV has been determined for the first time in India. CONCLUSION Although the circulation of different clades of VZV was reported from India, the presence of clade 9 was detected for the first time during the mpox surveillance.
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Affiliation(s)
- Abhinendra Kumar
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Lekshmi S. Rajan
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | | | - Anita M. Shete
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Rima R. Sahay
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Deepak Y. Patil
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Nayana Ingole
- Virus Research and Diagnostic Laboratory, Kasturba Hospital for Infectious Diseases, Mumbai, India
| | - Kaveri K
- King Institute of Preventive Medicine and Research, Chennai, India
| | | | - Shantala GB
- Bangalore Medical College and Research Institute, Bengaluru, India
| | - Jayanthi Shastri
- Virus Research and Diagnostic Laboratory, Kasturba Hospital for Infectious Diseases, Mumbai, India
| | | | - Yash Joshi
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Savita Patil
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Triparna Majumdar
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Ajay Verma
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Jyoti Yemul
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Nandini Shende
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Vaishnavi Kumari
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Pratiksha Vedpathak
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Shubhangi Sathe
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Pranita Gawande
- Indian Council of Medical Research-National Institute of Virology, Pune, India
| | - Pragya D. Yadav
- Indian Council of Medical Research-National Institute of Virology, Pune, India
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Supangat, Sari YL, Prasetyo FA, Widoretno N, Tursina MQ. Intussusception related to Ogilvie's syndrome caused by herpes zoster infection. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2022. [DOI: 10.1016/j.epsc.2022.102482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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Sadaoka T, Depledge DP, Rajbhandari L, Breuer J, Venkatesan A, Cohen JI. A Variant Allele in Varicella-Zoster Virus Glycoprotein B Selected during Production of the Varicella Vaccine Contributes to Its Attenuation. mBio 2022; 13:e0186422. [PMID: 35916400 PMCID: PMC9426484 DOI: 10.1128/mbio.01864-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 07/13/2022] [Indexed: 11/20/2022] Open
Abstract
Attenuation of the live varicella Oka vaccine (vOka) has been attributed to mutations in the genome acquired during cell culture passage of pOka (parent strain); however, the precise mechanisms of attenuation remain unknown. Comparative sequence analyses of several vaccine batches showed that over 100 single-nucleotide polymorphisms (SNPs) are conserved across all vaccine batches; 6 SNPs are nearly fixed, suggesting that these SNPs are responsible for attenuation. By contrast, prior analysis of chimeric vOka and pOka recombinants indicates that loci other than these six SNPs contribute to attenuation. Here, we report that pOka consists of a heterogenous population of virus sequences with two nearly equally represented bases, guanine (G) or adenine (A), at nucleotide 2096 of the ORF31 coding sequence, which encodes glycoprotein B (gB) resulting in arginine (R) or glutamine (Q), respectively, at amino acid 699 of gB. By contrast, 2096A/699Q is dominant in vOka (>99.98%). gB699Q/gH/gL showed significantly less fusion activity than gB699R/gH/gL in a cell-based fusion assay. Recombinant pOka with gB669Q (rpOka_gB699Q) had a similar growth phenotype as vOka during lytic infection in cell culture including human primary skin cells; however, rpOka_gB699R showed a growth phenotype similar to pOka. rpOka_gB699R entered neurons from axonal terminals more efficiently than rpOka_gB699Q in the presence of cell membrane-derived vesicles containing gB. Strikingly, when a mixture of pOka with both alleles equally represented was used to infect human neurons from axon terminals, pOka with gB699R was dominant for virus entry. These results identify a variant allele in gB that contributes to attenuation of vOka. IMPORTANCE The live-attenuated varicella vaccine has reduced the burden of chickenpox. Despite its development in 1974, the molecular basis for its attenuation is still not well understood. Since the live-attenuated varicella vaccine is the only licensed human herpesvirus vaccine that prevents primary disease, it is important to understand the mechanism for its attenuation. Here we identify that a variant allele in glycoprotein B (gB) selected during generation of the varicella vaccine contributes to its attenuation. This variant is impaired for fusion, virus entry into neurons from nerve terminals, and replication in human skin cells. Identification of a variant allele in gB, one of the essential herpesvirus core genes, that contributes to its attenuation may provide insights that assist in the development of other herpesvirus vaccines.
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Affiliation(s)
- Tomohiko Sadaoka
- Division of Clinical Virology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
- Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Daniel P. Depledge
- Department of Microbiology, New York University School of Medicine, New York, USA
- Institute for Virology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Hannover, Germany
| | - Labchan Rajbhandari
- Division of Neuroimmunology and Neuroinfectious Diseases, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Judith Breuer
- MRC Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, United Kingdom
| | - Arun Venkatesan
- Division of Neuroimmunology and Neuroinfectious Diseases, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jeffrey I. Cohen
- Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Shin D, Shin Y, Kim E, Nam H, Nan H, Lee J. Immunological characteristics of MAV/06 strain of varicella-zoster virus vaccine in an animal model. BMC Immunol 2022; 23:27. [PMID: 35658899 PMCID: PMC9166591 DOI: 10.1186/s12865-022-00503-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/28/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Varicella-zoster virus (VZV) is a pathogen that causes chickenpox and shingles in humans. Different types of the varicella vaccines derived from the Oka and MAV/06 strains are commercially available worldwide. Although the MAV/06 vaccine was introduced in 1990s, little was known about immunological characteristics. RESULTS Here, we evaluated B and T cell immune response in animals inoculated with the Oka and MAV/06 vaccines as well as a new formulation of the MAV/06 vaccine. A variety of test methods were applied to evaluate T and B cell immune response. Plaque reduction neutralization test (PRNT) and fluorescent antibody to membrane antigen (FAMA) assay were conducted to measure the MAV/06 vaccine-induced antibody activity against various VZVs. Glycoprotein enzyme-linked immunosorbent assay (gpELISA) was used to compare the degree of the antibody responses induced by the two available commercial VZV vaccines and the MAV/06 vaccine. Interferon-gamma enzyme-linked immunosorbent spot (IFN-γ ELISpot) assays and cytokine bead array (CBA) assays were conducted to investigate T cell immune responses. Antibodies induced by MAV/06 vaccination showed immunogenicity against a variety of varicella-zoster virus and cross-reactivity among the virus clades. CONCLUSIONS It is indicating the similarity of the antibody responses induced by commercial varicella vaccines and the MAV/06 vaccine. Moreover, VZV-specific T cell immune response from MAV/06 vaccination was increased via Th1 cell response. MAV/06 varicella vaccine induced both humoral and cellular immune response via Th1 cell mediated response.
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Affiliation(s)
- Duckhyang Shin
- GC Biopharma Corp., 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea
| | - Younchul Shin
- GC Biopharma Corp., 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Eunmi Kim
- MOGAM Institute for Biomedical Research, 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Hyojung Nam
- GC Biopharma Corp., 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Haiyan Nan
- GC Biopharma Corp., 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Jaewoo Lee
- GC Biopharma Corp., 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
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Palmer WH, Telford M, Navarro A, Santpere G, Norman PJ. Human herpesvirus diversity is altered in HLA class I binding peptides. Proc Natl Acad Sci U S A 2022; 119:e2123248119. [PMID: 35486690 PMCID: PMC9170163 DOI: 10.1073/pnas.2123248119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/30/2022] [Indexed: 11/18/2022] Open
Abstract
Herpesviruses are ubiquitous, genetically diverse DNA viruses, with long-term presence in humans associated with infrequent but significant pathology. Human leukocyte antigen (HLA) class I presents intracellularly derived peptide fragments from infected tissue cells to CD8+ T and natural killer cells, thereby directing antiviral immunity. Allotypes of highly polymorphic HLA class I are distinguished by their peptide binding repertoires. Because this HLA class I variation is a major determinant of herpesvirus disease, we examined if sequence diversity of virus proteins reflects evasion of HLA presentation. Using population genomic data from Epstein–Barr virus (EBV), human cytomegalovirus (HCMV), and Varicella–Zoster virus, we tested whether diversity differed between the regions of herpesvirus proteins that can be recognized, or not, by HLA class I. Herpesviruses exhibit lytic and latent infection stages, with the latter better enabling immune evasion. Whereas HLA binding peptides of lytic proteins are conserved, we found that EBV and HCMV proteins expressed during latency have increased peptide sequence diversity. Similarly, latent, but not lytic, herpesvirus proteins have greater population structure in HLA binding than nonbinding peptides. Finally, we found patterns consistent with EBV adaption to the local HLA environment, with less efficient recognition of EBV isolates by high-frequency HLA class I allotypes. Here, the frequency of CD8+ T cell epitopes inversely correlated with the frequency of HLA class I recognition. Previous analyses have shown that pathogen-mediated natural selection maintains exceptional polymorphism in HLA residues that determine peptide recognition. Here, we show that HLA class I peptide recognition impacts diversity of globally widespread pathogens.
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Affiliation(s)
- William H. Palmer
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO 80045
- Department of Immunology and Microbiology, University of Colorado, Aurora, CO 80045
| | - Marco Telford
- Neurogenomics Group, Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510
| | - Arcadi Navarro
- Institut de Biologia Evolutiva (Universitat Pompeu Fabra - Consejo Superior de Investigaciones Científicas), Department of Medicine and Life Sciences (MELIS), Barcelona Biomedical Research Park, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats and Universitat Pompeu Fabra, 08010 Barcelona, Spain
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain
- Barcelona Beta Brain Research Center, Pasqual Maragall Foundation, 08005 Barcelona, Spain
| | - Gabriel Santpere
- Neurogenomics Group, Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510
| | - Paul J. Norman
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO 80045
- Department of Immunology and Microbiology, University of Colorado, Aurora, CO 80045
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10
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Skripchenko E, Zheleznikova G, Skripchenko N, Alekseeva L, Goleva O, Bessonova T, Zhirkov A. Immunopatological and genetic aspects of pathogenesis of CNS lesions in VZV infection. Zh Nevrol Psikhiatr Im S S Korsakova 2022; 122:46-56. [DOI: 10.17116/jnevro202212210146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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11
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Depledge DP, Breuer J. Varicella-Zoster Virus-Genetics, Molecular Evolution and Recombination. Curr Top Microbiol Immunol 2021; 438:1-23. [PMID: 34374828 DOI: 10.1007/82_2021_238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
This chapter first details the structure, organization and coding content of the VZV genome to provide a foundation on which the molecular evolution of the virus can be projected. We subsequently describe the evolution of molecular profiling approaches from restriction fragment length polymorphisms to single nucleotide polymorphism profiling to modern day high-throughput sequencing approaches. We describe how the application of these methodologies led to our current model of VZV phylogeograpy including the number and structure of geographic clades and the role of recombination in reshaping these.
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Affiliation(s)
- Daniel P Depledge
- Institute of Virology, Hannover Medical School (MHH), Hannover, Germany. .,Department of Microbiology, NYU School of Medicine, New York, USA.
| | - Judith Breuer
- Department of Infection & Immunology, University College London, London, UK
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12
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Viral and Prion Infections Associated with Central Nervous System Syndromes in Brazil. Viruses 2021; 13:v13071370. [PMID: 34372576 PMCID: PMC8310075 DOI: 10.3390/v13071370] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/05/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022] Open
Abstract
Virus-induced infections of the central nervous system (CNS) are among the most serious problems in public health and can be associated with high rates of morbidity and mortality, mainly in low- and middle-income countries, where these manifestations have been neglected. Typically, herpes simplex virus 1 and 2, varicella-zoster, and enterovirus are responsible for a high number of cases in immunocompetent hosts, whereas other herpesviruses (for example, cytomegalovirus) are the most common in immunocompromised individuals. Arboviruses have also been associated with outbreaks with a high burden of neurological disorders, such as the Zika virus epidemic in Brazil. There is a current lack of understanding in Brazil about the most common viruses involved in CNS infections. In this review, we briefly summarize the most recent studies and findings associated with the CNS, in addition to epidemiological data that provide extensive information on the circulation and diversity of the most common neuro-invasive viruses in Brazil. We also highlight important aspects of the prion-associated diseases. This review provides readers with better knowledge of virus-associated CNS infections. A deeper understanding of these infections will support the improvement of the current surveillance strategies to allow the timely monitoring of the emergence/re-emergence of neurotropic viruses.
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13
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Metagenomic analysis of a throat swab sample collected in China on a patient infected with Varicella Zoster Virus. Sci Rep 2021; 11:13874. [PMID: 34230529 PMCID: PMC8260771 DOI: 10.1038/s41598-021-93230-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 06/15/2021] [Indexed: 12/26/2022] Open
Abstract
Varicella Zoster Virus (VZV) is endemic worldwide, causing varicella in children and zoster upon reactivation in adults. This study concerned a metagenomic analysis of a throat swab sample collected in China, on a young patient suffering from Systemic Lupus Erythematosus (SLE) and diagnosed with varicella. The complete genome sequence of a VZV strain of clade 2 has been generated. Clade 2 strains are the most prevalent in Asian countries. A comparison of 223 VZV genomes identified 77 clade specific markers, 20 of them specific to clade 2. The metagenomic analysis also identified sequences covering most of the genome of the bacteria Schaalia odontolytica also known as Actinomyces odontolyticus. VZV infection and bacterial infection in the context of SLE is further discussed. Even though the patient presented only mild symptoms, this study is a reminder that vaccination against VZV is critical to avoid severe complications like bacterial superinfection or even death in the case of immunodeficiency.
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14
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Pontremoli C, Forni D, Clerici M, Cagliani R, Sironi M. Possible European Origin of Circulating Varicella Zoster Virus Strains. J Infect Dis 2021; 221:1286-1294. [PMID: 31051029 DOI: 10.1093/infdis/jiz227] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 05/02/2019] [Indexed: 11/13/2022] Open
Abstract
Varicella zoster virus (VZV) is the causative agent of chickenpox and shingles. The geographic distribution of VZV clades was taken as evidence that VZV migrated out of Africa with human populations. We show that extant VZV strains most likely originated in Europe and not in Africa. Europe was also identified as the ancestral location for most internal nodes of the VZV phylogeny, including the ancestor of clade 5 strains. We also show that strains from clades 1, 2, 3, and 5 derived a major proportion of their ancestry from each of 4 ancestral populations. Conversely, viruses from other clades displayed variable levels of admixture. Some low-level admixture was also observed for clade 5 genomes, but only for non-African viruses. This pattern indicates that the clade 5 VZV strains do not represent recent introductions from Africa due to migratory fluxes. These data have also relevance for the definition and classification of VZV clades.
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Affiliation(s)
- Chiara Pontremoli
- Istituto di ricovero e cura a carattere scientifico (IRCCS) E. Medea, Bioinformatics, Bosisio Parini, Milan, Italy
| | - Diego Forni
- Istituto di ricovero e cura a carattere scientifico (IRCCS) E. Medea, Bioinformatics, Bosisio Parini, Milan, Italy
| | - Mario Clerici
- Department of Physiopathology and Transplantation, University of Milan, Milan, Italy.,IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
| | - Rachele Cagliani
- Istituto di ricovero e cura a carattere scientifico (IRCCS) E. Medea, Bioinformatics, Bosisio Parini, Milan, Italy
| | - Manuela Sironi
- Istituto di ricovero e cura a carattere scientifico (IRCCS) E. Medea, Bioinformatics, Bosisio Parini, Milan, Italy
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15
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Abstract
Alphaherpesviruses, as large double-stranded DNA viruses, were long considered to be genetically stable and to exist in a homogeneous state. Recently, the proliferation of high-throughput sequencing (HTS) and bioinformatics analysis has expanded our understanding of herpesvirus genomes and the variations found therein. Recent data indicate that herpesviruses exist as diverse populations, both in culture and in vivo, in a manner reminiscent of RNA viruses. In this review, we discuss the past, present, and potential future of alphaherpesvirus genomics, including the technical challenges that face the field. We also review how recent data has enabled genome-wide comparisons of sequence diversity, recombination, allele frequency, and selective pressures, including those introduced by cell culture. While we focus on the human alphaherpesviruses, we draw key insights from related veterinary species and from the beta- and gamma-subfamilies of herpesviruses. Promising technologies and potential future directions for herpesvirus genomics are highlighted as well, including the potential to link viral genetic differences to phenotypic and disease outcomes.
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Affiliation(s)
- Chad V. Kuny
- Departments of Biology, and Biochemistry and Molecular Biology, Center for Infectious Disease Dynamics, and the Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania, 16802, USA
| | - Moriah L. Szpara
- Departments of Biology, and Biochemistry and Molecular Biology, Center for Infectious Disease Dynamics, and the Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania, 16802, USA
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16
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Harbecke R, Jensen NJ, Depledge DP, Johnson GR, Ashbaugh ME, Schmid DS, Breuer J, Levin MJ, Oxman MN. Recurrent herpes zoster in the Shingles Prevention Study: Are second episodes caused by the same varicella-zoster virus strain? Vaccine 2020; 38:150-157. [PMID: 31679866 DOI: 10.1016/j.vaccine.2019.10.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 10/01/2019] [Accepted: 10/15/2019] [Indexed: 11/17/2022]
Abstract
Herpes zoster (HZ) is caused by reactivation of varicella zoster virus (VZV) that established latency in sensory and autonomic neurons during primary infection. In the Shingles Prevention Study (SPS), a large efficacy trial of live attenuated Oka/Merck zoster vaccine (ZVL), PCR-confirmed second episodes of HZ occurred in two of 660 placebo and one of 321 ZVL recipients with documented HZ during a mean follow-up of 3.13 years. An additional two ZVL recipients experienced a second episode of HZ in the Long-Term Persistence Substudy. All episodes of HZ were caused by wild-type VZV. The first and second episodes of HZ occurred in different dermatomes in each of these five participants, with contralateral recurrences in two. Time between first and second episodes ranged from 12 to 28 months. One of the five participants, who was immunocompetent on study enrollment, was immunocompromised at the onset of his first and second episodes of HZ. VZV DNA isolated from rash lesions from the first and second episodes of HZ was used to sequence the full-length VZV genomes. For the unique-sequence regions of the VZV genome, we employed target enrichment of VZV DNA, followed by deep sequencing. For the reiteration regions, we used PCR amplification and Sanger sequencing. Our analysis and comparison of the VZV genomes from the first and second episodes of HZ in each of the five participants indicate that both episodes were caused by the same VZV strain. This is consistent with the extraordinary stability of VZV during the replication phase of varicella and the subsequent establishment of latency in sensory ganglia throughout the body. Our observations also indicate that VZV is stable during the persistence of latency and the subsequent reactivation and replication that results in HZ.
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Affiliation(s)
- Ruth Harbecke
- Department of Veterans Affairs (VA) San Diego Healthcare System, San Diego, CA, USA; Department of Medicine, University of California San Diego, San Diego, CA, USA.
| | - Nancy J Jensen
- Centers for Disease Control and Prevention, Division of Viral Diseases, Atlanta, GA, USA
| | - Daniel P Depledge
- Division of Infection and Immunity, University College London, London, UK; Department of Medicine, New York University School of Medicine, New York, NY, USA
| | - Gary R Johnson
- Cooperative Studies Program Coordinating Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
| | - Mark E Ashbaugh
- Department of Veterans Affairs (VA) San Diego Healthcare System, San Diego, CA, USA
| | - D Scott Schmid
- Centers for Disease Control and Prevention, Division of Viral Diseases, Atlanta, GA, USA
| | - Judith Breuer
- Division of Infection and Immunity, University College London, London, UK
| | - Myron J Levin
- Department of Medicine and Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Michael N Oxman
- Department of Veterans Affairs (VA) San Diego Healthcare System, San Diego, CA, USA; Department of Medicine, University of California San Diego, San Diego, CA, USA
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17
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Breuer J. Molecular Genetic Insights Into Varicella Zoster Virus (VZV), the vOka Vaccine Strain, and the Pathogenesis of Latency and Reactivation. J Infect Dis 2019; 218:S75-S80. [PMID: 30247591 DOI: 10.1093/infdis/jiy279] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Genetic tools for molecular typing of varicella zoster virus (VZV) have been used to understand the spread of virus, to differentiate wild-type and vaccine strains, and to understand the natural history of VZV infection in its cognate host. Molecular genetics has identified 7 clades of VZV (1-6 and 9), with 2 more mooted. Differences between the vOka vaccine strain and wild-type VZVs have been used to distinguish the cause of postimmunization events and to provide insight into the natural history of VZV infections. Importantly molecular genetics has shown that reinfection with establishment of latency by the reinfecting strain is common, that dual infections with different viruses can occur, and that reactivation of the superinfecting genotype can both occur. Whole-genome sequencing of the vOka vaccine has been used to show that vesicles form from a single virion, that latency is established within a few days of inoculation, and that all vaccine strains are capable of establishing latency and reactivating. Novel molecular tools have characterized the transcripts expressed during latent infection in vitro.
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Affiliation(s)
- Judith Breuer
- Division of Infection and Immunity, University College London, United Kingdom
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18
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Breuer J. The Origin and Migration of Varicella Zoster Virus Strains. J Infect Dis 2019; 221:1213-1215. [DOI: 10.1093/infdis/jiz232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 05/02/2019] [Indexed: 11/13/2022] Open
Affiliation(s)
- Judith Breuer
- Division of Infection and Immunity, University College London, United Kingdom
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19
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Depledge DP, Sadaoka T, Ouwendijk WJD. Molecular Aspects of Varicella-Zoster Virus Latency. Viruses 2018; 10:v10070349. [PMID: 29958408 PMCID: PMC6070824 DOI: 10.3390/v10070349] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 06/19/2018] [Accepted: 06/27/2018] [Indexed: 02/07/2023] Open
Abstract
Primary varicella-zoster virus (VZV) infection causes varicella (chickenpox) and the establishment of a lifelong latent infection in ganglionic neurons. VZV reactivates in about one-third of infected individuals to cause herpes zoster, often accompanied by neurological complications. The restricted host range of VZV and, until recently, a lack of suitable in vitro models have seriously hampered molecular studies of VZV latency. Nevertheless, recent technological advances facilitated a series of exciting studies that resulted in the discovery of a VZV latency-associated transcript (VLT) and provide novel insights into our understanding of VZV latency and factors that may initiate reactivation. Deducing the function(s) of VLT and the molecular mechanisms involved should now be considered a priority to improve our understanding of factors that govern VZV latency and reactivation. In this review, we summarize the implications of recent discoveries in the VZV latency field from both a virus and host perspective and provide a roadmap for future studies.
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Affiliation(s)
- Daniel P Depledge
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
| | - Tomohiko Sadaoka
- Division of Clinical Virology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Werner J D Ouwendijk
- Department of Viroscience, Erasmus Medical Centre, 3015 CN Rotterdam, The Netherlands.
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20
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Anaya-Prado R, Pérez-Navarro JV, Corona-Nakamura A, Anaya-Fernández MM, Anaya-Fernández R, Izaguirre-Pérez ME. Intestinal pseudo-obstruction caused by herpes zoster: Case report and pathophysiology. World J Clin Cases 2018; 6:132-138. [PMID: 29988868 PMCID: PMC6033747 DOI: 10.12998/wjcc.v6.i6.132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/27/2018] [Accepted: 05/15/2018] [Indexed: 02/05/2023] Open
Abstract
Herpes zoster (HZ) infection occurs in approximately 10% to 30% of individuals. Visceral neuropathies secondary to HZ can cause cystitis and urinary retention. But colonic pseudo-obstruction can also occur. Peripheral neuropathy may reveal segmental motor paresis of either upper or lower limbs, the abdominal muscles or the diaphragm. We report the case of a 62-year-old male patient who presented with abdominal distention and cutaneous vesicular eruption on the left side of the abdominal wall. Plain X-rays and computed tomography scan showed distended small bowel. A diagnosis of intestinal pseudo-obstruction was made secondary to segmental paresis of the small intestine and visceral neuropathy. Conservative management was successful and the patient was discharged uneventfully. Intestinal pseudo-obstruction ought to be considered when dealing with non-obstructive (adynamic) conditions of the digestive tract associated with HZ infection; since early recognition may help to avoid unnecessary surgery.
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Affiliation(s)
- Roberto Anaya-Prado
- Department of Surgery at Western Medical Center, the Mexican Institute of Social Security, Guadalajara, JAL 44340, México
- Division of Research at Autonomous University of Guadalajara, Guadalajara, JAL 45200, México
| | - José V Pérez-Navarro
- Department of Surgery at Western Medical Center, the Mexican Institute of Social Security, Guadalajara, JAL 44340, México
| | - Ana Corona-Nakamura
- Department of Infectious Diseases at Western Medical Center, the Mexican Institute of Social Security, Guadalajara, JAL 44340, México
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21
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Genomic, Recombinational and Phylogenetic Characterization of Global Feline Herpesvirus 1 Isolates. Virology 2018; 518:385-397. [PMID: 29605685 DOI: 10.1016/j.virol.2018.03.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 03/20/2018] [Accepted: 03/21/2018] [Indexed: 11/23/2022]
Abstract
Feline herpes virus type 1 (FHV-1) is widely considered to be the leading cause of ocular disease in cats and has been implicated in upper respiratory tract infections. Little, however is known about interstrain phylogenetic relationships, and details of the genomic structure. For the present study, twenty-six FHV-1 isolates from different cats in animal shelters were collected from eight separate locations in the USA, and the genomes sequenced. Genomic characterization of these isolates includied short sequence repeat (SSR) detection, with fewer SSRs detected, compared to herpes simplex viruses type 1 and 2. For phylogenetic and recombination analysis, 27 previously sequenced isolates of FHV-1 were combined with the 26 strains sequenced for the present study. The overall genomic interstrain genetic distance between all available isolates was 0.093%. Phylogenetic analysis identified four main FHV-1 clades primarily corresponding to geographical collection site. Recombination analysis suggested that interclade recombination has occurred.
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22
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Bryant NA, Wilkie GS, Russell CA, Compston L, Grafham D, Clissold L, McLay K, Medcalf L, Newton R, Davison AJ, Elton DM. Genetic diversity of equine herpesvirus 1 isolated from neurological, abortigenic and respiratory disease outbreaks. Transbound Emerg Dis 2018; 65:817-832. [PMID: 29423949 PMCID: PMC5947664 DOI: 10.1111/tbed.12809] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Indexed: 12/14/2022]
Abstract
Equine herpesvirus 1 (EHV‐1) causes respiratory disease, abortion, neonatal death and neurological disease in equines and is endemic in most countries. The viral factors that influence EHV‐1 disease severity are poorly understood, and this has hampered vaccine development. However, the N752D substitution in the viral DNA polymerase catalytic subunit has been shown statistically to be associated with neurological disease. This has given rise to the term “neuropathic strain,” even though strains lacking the polymorphism have been recovered from cases of neurological disease. To broaden understanding of EHV‐1 diversity in the field, 78 EHV‐1 strains isolated over a period of 35 years were sequenced. The great majority of isolates originated from the United Kingdom and included in the collection were low passage isolates from respiratory, abortigenic and neurological outbreaks. Phylogenetic analysis of regions spanning 80% of the genome showed that up to 13 viral clades have been circulating in the United Kingdom and that most of these are continuing to circulate. Abortion isolates grouped into nine clades, and neurological isolates grouped into five. Most neurological isolates had the N752D substitution, whereas most abortion isolates did not, although three of the neurological isolates from linked outbreaks had a different polymorphism. Finally, bioinformatic analysis suggested that recombination has occurred between EHV‐1 clades, between EHV‐1 and equine herpesvirus 4, and between EHV‐1 and equine herpesvirus 8.
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Affiliation(s)
- N A Bryant
- Animal Health Trust, Kentford, Newmarket, Suffolk, UK
| | - G S Wilkie
- MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
| | - C A Russell
- Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
| | - L Compston
- Animal Health Trust, Kentford, Newmarket, Suffolk, UK
| | - D Grafham
- Sheffield Children's NHS Foundation Trust, Sheffield, South Yorkshire, UK
| | - L Clissold
- Earlham Institute, Norwich Research Park, Norwich, Norfolk, UK
| | - K McLay
- Earlham Institute, Norwich Research Park, Norwich, Norfolk, UK
| | - L Medcalf
- Animal Health Trust, Kentford, Newmarket, Suffolk, UK
| | - R Newton
- Animal Health Trust, Kentford, Newmarket, Suffolk, UK
| | - A J Davison
- MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
| | - D M Elton
- Animal Health Trust, Kentford, Newmarket, Suffolk, UK
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23
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Impacts of Genome-Wide Analyses on Our Understanding of Human Herpesvirus Diversity and Evolution. J Virol 2017; 92:JVI.00908-17. [PMID: 29046445 PMCID: PMC5730764 DOI: 10.1128/jvi.00908-17] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Until fairly recently, genome-wide evolutionary dynamics and within-host diversity were more commonly examined in the context of small viruses than in the context of large double-stranded DNA viruses such as herpesviruses. The high mutation rates and more compact genomes of RNA viruses have inspired the investigation of population dynamics for these species, and recent data now suggest that herpesviruses might also be considered candidates for population modeling. High-throughput sequencing (HTS) and bioinformatics have expanded our understanding of herpesviruses through genome-wide comparisons of sequence diversity, recombination, allele frequency, and selective pressures. Here we discuss recent data on the mechanisms that generate herpesvirus genomic diversity and underlie the evolution of these virus families. We focus on human herpesviruses, with key insights drawn from veterinary herpesviruses and other large DNA virus families. We consider the impacts of cell culture on herpesvirus genomes and how to accurately describe the viral populations under study. The need for a strong foundation of high-quality genomes is also discussed, since it underlies all secondary genomic analyses such as RNA sequencing (RNA-Seq), chromatin immunoprecipitation, and ribosome profiling. Areas where we foresee future progress, such as the linking of viral genetic differences to phenotypic or clinical outcomes, are highlighted as well.
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24
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Ba Abdullah MM, Palermo RD, Palser AL, Grayson NE, Kellam P, Correia S, Szymula A, White RE. Heterogeneity of the Epstein-Barr Virus (EBV) Major Internal Repeat Reveals Evolutionary Mechanisms of EBV and a Functional Defect in the Prototype EBV Strain B95-8. J Virol 2017; 91:e00920-17. [PMID: 28904201 PMCID: PMC5686732 DOI: 10.1128/jvi.00920-17] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 09/02/2017] [Indexed: 12/28/2022] Open
Abstract
Epstein-Barr virus (EBV) is a ubiquitous pathogen of humans that can cause several types of lymphoma and carcinoma. Like other herpesviruses, EBV has diversified through both coevolution with its host and genetic exchange between virus strains. Sequence analysis of the EBV genome is unusually challenging because of the large number and lengths of repeat regions within the virus. Here we describe the sequence assembly and analysis of the large internal repeat 1 of EBV (IR1; also known as the BamW repeats) for more than 70 strains. The diversity of the latency protein EBV nuclear antigen leader protein (EBNA-LP) resides predominantly within the exons downstream of IR1. The integrity of the putative BWRF1 open reading frame (ORF) is retained in over 80% of strains, and deletions truncating IR1 always spare BWRF1. Conserved regions include the IR1 latency promoter (Wp) and one zone upstream of and two within BWRF1. IR1 is heterogeneous in 70% of strains, and this heterogeneity arises from sequence exchange between strains as well as from spontaneous mutation, with interstrain recombination being more common in tumor-derived viruses. This genetic exchange often incorporates regions of <1 kb, and allelic gene conversion changes the frequency of small regions within the repeat but not close to the flanks. These observations suggest that IR1-and, by extension, EBV-diversifies through both recombination and breakpoint repair, while concerted evolution of IR1 is driven by gene conversion of small regions. Finally, the prototype EBV strain B95-8 contains four nonconsensus variants within a single IR1 repeat unit, including a stop codon in the EBNA-LP gene. Repairing IR1 improves EBNA-LP levels and the quality of transformation by the B95-8 bacterial artificial chromosome (BAC).IMPORTANCE Epstein-Barr virus (EBV) infects the majority of the world population but causes illness in only a small minority of people. Nevertheless, over 1% of cancers worldwide are attributable to EBV. Recent sequencing projects investigating virus diversity to see if different strains have different disease impacts have excluded regions of repeating sequence, as they are more technically challenging. Here we analyze the sequence of the largest repeat in EBV (IR1). We first characterized the variations in protein sequences encoded across IR1. In studying variations within the repeat of each strain, we identified a mutation in the main laboratory strain of EBV that impairs virus function, and we suggest that tumor-associated viruses may be more likely to contain DNA mixed from two strains. The patterns of this mixing suggest that sequences can spread between strains (and also within the repeat) by copying sequence from another strain (or repeat unit) to repair DNA damage.
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Affiliation(s)
- Mohammed M Ba Abdullah
- Section of Virology, Imperial College Faculty of Medicine, St. Mary's Hospital, Norfolk Place, London, United Kingdom
| | - Richard D Palermo
- Section of Virology, Imperial College Faculty of Medicine, St. Mary's Hospital, Norfolk Place, London, United Kingdom
| | - Anne L Palser
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
| | | | - Paul Kellam
- Section of Virology, Imperial College Faculty of Medicine, St. Mary's Hospital, Norfolk Place, London, United Kingdom
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
- Kymab, Babraham Research Campus, Cambridge, United Kingdom
| | - Samantha Correia
- Section of Virology, Imperial College Faculty of Medicine, St. Mary's Hospital, Norfolk Place, London, United Kingdom
| | - Agnieszka Szymula
- Section of Virology, Imperial College Faculty of Medicine, St. Mary's Hospital, Norfolk Place, London, United Kingdom
| | - Robert E White
- Section of Virology, Imperial College Faculty of Medicine, St. Mary's Hospital, Norfolk Place, London, United Kingdom
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Characterization and phylogenetic analysis of Varicella-zoster virus strains isolated from Korean patients. J Microbiol 2017; 55:665-672. [PMID: 28752294 DOI: 10.1007/s12275-017-7171-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 06/15/2017] [Accepted: 06/22/2017] [Indexed: 12/24/2022]
Abstract
Varicella-zoster virus (VZV) is a causative agent of chickenpox in primary infection and shingles after its reactivation from latency. Complete or almost-complete genomic DNA sequences for various VZV strains have been reported. Recently, clinical VZV strains were isolated from Korean patients whose genome was sequenced using high-throughput sequencing technology. In this study, we analyzed single nucleotide polymorphism (SNP) of VZV strains to genetically characterize Korean clinical isolates. Phylogenetic analyses revealed that three Korean strains, YC01, YC02, and YC03, were linked to clade 2. Comprehensive SNP analysis identified 86 sites specific for the 5 VZV clades. VZV strains isolated from Korea did not form a phylogenetic cluster. Rather, YC02 and YC03 clustered strongly with Chinese strain 84-7 within clade 2, more specifically cluster 2a. Signature sequences for the cluster 2a were identified and found to play an important role in the separation of cluster 2a strains from other clade 2 strains, as shown in substitution studies. Further genetic analysis with additional strains isolated from Japan, China, and other Asian countries would provide a novel insight into the significance of two distinct subclades within clade 2.
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Differentiation between wild-type and vaccines strains of varicella zoster virus (VZV) based on four single nucleotide polymorphisms. Epidemiol Infect 2017; 145:2618-2625. [PMID: 28748773 DOI: 10.1017/s0950268817001509] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Varicella-zoster virus (VZV) infection (chickenpox) results in latency and subsequent reactivation manifests as shingles. Effective attenuated vaccines (vOka) are available for prevention of both illnesses. In this study, an amplicon-based sequencing method capable of differentiating between VZV wild-type (wt) strains and vOka vaccine is described. A total of 44 vesicular fluid specimens collected from 43 patients (16 from China and 27 from the UK) with either chickenpox or shingles were investigated, of which 10 had received previous vaccination. Four sets of polymerase chain reactions were set up simultaneously with primers amplifying regions encompassing four single nucleotide polymorphisms (SNPs), '69349-106262-107252-108111'. Nucleotide sequences were generated by Sanger sequencing. All samples except one had a wt SNP profile of 'A-T-T-T'. The sample collected from a patient who received vaccine 7-10 days ago, along with VZV vaccine preparations, Zostavax and Baike-varicella gave a SNP profile 'G-C-C-C'. The results show that this method can distinguish vaccine-derived virus from wt viruses from main four clades, (clades 1-4) and should be of utility worldwide.
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Abstract
The most common specimens from immunocompromised patients that are analyzed for detection of herpes simplex virus (HSV) or varicella-zoster virus (VZV) are from skin lesions. Many types of assays are applicable to these samples, but some, such as virus isolation and direct fluorescent antibody testing, are useful only in the early phases of the lesions. In contrast, nucleic acid (NA) detection methods, which generally have superior sensitivity and specificity, can be applied to skin lesions at any stage of progression. NA methods are also the best choice, and sometimes the only choice, for detecting HSV or VZV in blood, cerebrospinal fluid, aqueous or vitreous humor, and from mucosal surfaces. NA methods provide the best performance when reliability and speed (within 24 hours) are considered together. They readily distinguish the type of HSV detected or the source of VZV detected (wild type or vaccine strain). Nucleic acid detection methods are constantly being improved with respect to speed and ease of performance. Broader applications are under study, such as the use of quantitative results of viral load for prognosis and to assess the efficacy of antiviral therapy.
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Jensen NJ, Rivailler P, Tseng HF, Quinlivan ML, Radford K, Folster J, Harpaz R, LaRussa P, Jacobsen S, Scott Schmid D. Revisiting the genotyping scheme for varicella-zoster viruses based on whole-genome comparisons. J Gen Virol 2017; 98:1434-1438. [PMID: 28613146 DOI: 10.1099/jgv.0.000772] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
We report whole-genome sequences (WGSs) for four varicella-zoster virus (VZV) samples from a shingles study conducted by Kaiser Permanente of Southern California. Comparative genomics and phylogenetic analysis of all published VZV WGSs revealed that strain KY037798 is in clade IX, which shall henceforth be designated clade 9. Previously published single nucleotide polymorphisms (SNP)-based genotyping schemes fail to discriminate between clades 6 and VIII and employ positions that are not clade-specific. We provide an updated list of clade-specific positions that supersedes the list determined at the 2008 VZV nomenclature meeting. Finally, we propose a new targeted genotyping scheme that will discriminate the circulating VZV clades with at least a twofold redundancy. Genotyping strategies using a limited set of targeted SNPs will continue to provide an efficient 'first pass' method for VZV strain surveillance as vaccination programmes for varicella and zoster influence the dynamics of VZV transmission.
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Affiliation(s)
- Nancy J Jensen
- Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases, Division of Viral Diseases, Atlanta, GA, USA
| | - Pierre Rivailler
- Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases, Division of Viral Diseases, Atlanta, GA, USA
| | - Hung Fu Tseng
- Kaiser Permanente of Southern California, Department of Research and Evaluation, Pasadena, CA, USA
| | - Mark L Quinlivan
- Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases, Division of Viral Diseases, Atlanta, GA, USA.,Present address: Labtech International Ltd, Uckfield, East Sussex, UK
| | - Kay Radford
- Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases, Division of Viral Diseases, Atlanta, GA, USA
| | - Jennifer Folster
- Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases, Division of Viral Diseases, Atlanta, GA, USA
| | - Rafael Harpaz
- Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases, Division of Viral Diseases, Atlanta, GA, USA
| | - Philip LaRussa
- Department of Pediatrics, Columbia University, College of Physicians and Surgeons,, New York, NY, USA
| | - Steven Jacobsen
- Kaiser Permanente of Southern California, Department of Research and Evaluation, Pasadena, CA, USA
| | - D Scott Schmid
- Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases, Division of Viral Diseases, Atlanta, GA, USA
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Natural recombination in alphaherpesviruses: Insights into viral evolution through full genome sequencing and sequence analysis. INFECTION GENETICS AND EVOLUTION 2017; 49:174-185. [DOI: 10.1016/j.meegid.2016.12.022] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 12/20/2016] [Accepted: 12/21/2016] [Indexed: 01/05/2023]
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Pfaff F, Groth M, Sauerbrei A, Zell R. Genotyping of herpes simplex virus type 1 by whole-genome sequencing. J Gen Virol 2016; 97:2732-2741. [PMID: 27558891 DOI: 10.1099/jgv.0.000589] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
A previous phylogenetic analysis based on 32 full-length sequences of herpes simplex virus type 1 (HSV-1) suggested three major phylogenetic groups (phylogroups) with distinct geographic distribution: (1) western strains from Europe and North America, (2) isolates from Asia and one American strain and (3) isolates from Africa only. Here, we sequenced the genomes of additional 10 clinical HSV-1 isolates from Germany, and subsequently compared these sequences to 40 published HSV-1 genomes. The present data demonstrate that HSV-1 is the most diverse human alphaherpesvirus (mean pairwise p-distance of 0.756 %) and confirm the tripartite tree. However, as the German isolates cluster with strains of both phylogroups I and II, it is demonstrated that the latter is also present in Europe and thus is a Eurasian phylogroup. Tree-order scans indicate that HSV-1 evolution is massively influenced by recombination including all investigated strains regardless of the areal distribution of the phylogroups. Numerous recombination events in the evolution of HSV-1 may also influence genotyping as the present HSV-1 genotyping schemes do not yield results consistent with phylogroup classification. Genotyping of HSV-1 is currently based on analyses of intragenic sequence polymorphisms of US2, glycoprotein G (gG, US4) and gI (US7). Each of the 10 German HSV-1 isolates displayed a different US2/gG/gI-genotype combination, but clustered either in phylogroup I or II. In conclusion, the phylogroup concept provides a HSV-1 typing scheme that largely reflects human migration history, whereas the analysis of single-nucleotide polymorphisms fails to render significant biological properties, but allows description of individual genetic traits.
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Affiliation(s)
- Florian Pfaff
- Department of Virology and Antiviral Therapy, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
| | - Marco Groth
- Genome Analysis, Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
| | - Andreas Sauerbrei
- Department of Virology and Antiviral Therapy, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
| | - Roland Zell
- Department of Virology and Antiviral Therapy, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
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Abstract
Since the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2'-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2'-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide.
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Affiliation(s)
- Erik De Clercq
- KU Leuven-University of Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology, Leuven, Belgium
| | - Guangdi Li
- KU Leuven-University of Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology, Leuven, Belgium Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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32
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Jeon JS, Won YH, Kim IK, Ahn JH, Shin OS, Kim JH, Lee CH. Analysis of single nucleotide polymorphism among Varicella-Zoster Virus and identification of vaccine-specific sites. Virology 2016; 496:277-286. [PMID: 27376245 DOI: 10.1016/j.virol.2016.06.017] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 06/11/2016] [Accepted: 06/21/2016] [Indexed: 12/30/2022]
Abstract
Varicella-zoster virus (VZV) is a causative agent for chickenpox and zoster. Live attenuated vaccines have been developed based on Oka and MAV/06 strains. In order to understand the molecular mechanisms of attenuation, complete genome sequences of vaccine and wild-type strains were compared and single nucleotide polymorphism (SNP) was analyzed. ORF22 and ORF62 contained the highest number of SNPs. The detailed analysis of the SNPs suggested 24 potential vaccine-specific sites. All the mutational events found in vaccine-specific sites were transitional, and most of them were substitution of AT to GC pair. Interestingly, 18 of the vaccine-specific sites of the vaccine strains appeared to be genetically heterogeneous. The probability of a single genome of vaccine strain to contain all 24 vaccine-type sequences was calculated to be less than 4%. The average codon adaptation index (CAI) value of the vaccine strains was significantly lower than the CAI value of the clinical strains.
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Affiliation(s)
- Jeong Seon Jeon
- Department of Microbiology, Chungbuk National University, Cheongju, South Korea
| | - Youn Hee Won
- Department of Microbiology, Chungbuk National University, Cheongju, South Korea
| | - In Kyo Kim
- Department of Microbiology, Chungbuk National University, Cheongju, South Korea
| | - Jin Hyun Ahn
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea
| | - Ok Sarah Shin
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, South Korea
| | - Jung Hwan Kim
- Mogam Biotechnology Research Institute, Yongin, South Korea
| | - Chan Hee Lee
- Department of Microbiology, Chungbuk National University, Cheongju, South Korea.
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33
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Zhang XS. Epidemic cycling in a multi-strain SIRS epidemic network model. Theor Biol Med Model 2016; 13:14. [PMID: 27090782 PMCID: PMC4836137 DOI: 10.1186/s12976-016-0040-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 04/11/2016] [Indexed: 12/27/2022] Open
Abstract
Background One common observation in infectious diseases caused by multi-strain pathogens is that both the incidence of all infections and the relative fraction of infection with each strain oscillate with time (i.e., so-called Epidemic cycling). Many different mechanisms have been proposed for the pervasive nature of epidemic cycling. Nevertheless, the two facts that people contact each other through a network rather than following a simple mass-action law and most infectious diseases involve multiple strains have not been considered together for their influence on the epidemic cycling. Methods To demonstrate how the structural contacts among people influences the dynamical patterns of multi-strain pathogens, we investigate a two strain epidemic model in a network where every individual randomly contacts with a fixed number of other individuals. The standard pair approximation is applied to describe the changing numbers of individuals in different infection states and contact pairs. Results We show that spatial correlation due to contact network and interactions between strains through both ecological interference and immune response interact to generate epidemic cycling. Compared to one strain epidemic model, the two strain model presented here can generate epidemic cycling within a much wider parameter range that covers many infectious diseases. Conclusion Our results suggest that co-circulation of multiple strains within a contact network provides an explanation for epidemic cycling.
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Affiliation(s)
- Xu-Sheng Zhang
- Department of Statistics, Modelling and Economics, Centre for Infectious Disease Surveillance and Control, Public Health England, 61 Colindale Avenue, London, NW9 5EQ, UK. .,Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College School of Public Health, Norfolk Place, London, W2 1PG, UK.
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34
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Vaz PK, Horsington J, Hartley CA, Browning GF, Ficorilli NP, Studdert MJ, Gilkerson JR, Devlin JM. Evidence of widespread natural recombination among field isolates of equine herpesvirus 4 but not among field isolates of equine herpesvirus 1. J Gen Virol 2015; 97:747-755. [PMID: 26691326 DOI: 10.1099/jgv.0.000378] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Recombination in alphaherpesviruses allows evolution to occur in viruses that have an otherwise stable DNA genome with a low rate of nucleotide substitution. High-throughput sequencing of complete viral genomes has recently allowed natural (field) recombination to be studied in a number of different alphaherpesviruses, however, such studies have not been applied to equine herpesvirus 1 (EHV-1) or equine herpesvirus 4 (EHV-4). These two equine alphaherpesviruses are genetically similar, but differ in their pathogenesis and epidemiology. Both cause economically significant disease in horse populations worldwide. This study used high-throughput sequencing to determine the full genome sequences of EHV-1 and EHV-4 isolates (11 and 14 isolates, respectively) from Australian or New Zealand horses. These sequences were then analysed and examined for evidence of recombination. Evidence of widespread recombination was detected in the genomes of the EHV-4 isolates. Only one potential recombination event was detected in the genomes of the EHV-1 isolates, even when the genomes from an additional 11 international EHV-1 isolates were analysed. The results from this study reveal another fundamental difference between the biology of EHV-1 and EHV-4. The results may also be used to help inform the future safe use of attenuated equine herpesvirus vaccines.
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Affiliation(s)
- P K Vaz
- Asia-Pacific Centre for Animal Health, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - J Horsington
- Asia-Pacific Centre for Animal Health, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - C A Hartley
- Asia-Pacific Centre for Animal Health, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - G F Browning
- Asia-Pacific Centre for Animal Health, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - N P Ficorilli
- Centre for Equine Infectious Diseases, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - M J Studdert
- Centre for Equine Infectious Diseases, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - J R Gilkerson
- Centre for Equine Infectious Diseases, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - J M Devlin
- Asia-Pacific Centre for Animal Health, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
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35
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Sun Z, Guo Y, Li M, Yao Z. Genotype analysis of varicella-zoster virus isolates from suburban Shanghai Municipal Province, China. J Med Microbiol 2015; 65:123-128. [PMID: 26654224 DOI: 10.1099/jmm.0.000208] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
To determine the predominant genotype of the varicella-zoster virus (VZV) in suburban Shanghai Municipal Province, specimens were collected from the lesions of 95 outpatients clinically diagnosed with varicella or herpes zoster. Of these, 69 patients (72.6%) were positive for VZV DNA. The 69 isolates were all genotyped as the genotype J1/clade 2. Based on sequencing of the 447 bp sequence in ORF22, 66 isolates were identified as genotype J/clade 2 strains and three were identified as type M2/clade 4 strains. To confirm the classification of these three strains, we determined the presence of 27 single-nucleotide polymorphisms (SNPs) and found that isolates 1270/1450 shared seven SNPs that differed from those of clade 2, in which three SNPs were unique to clade 3 and another three were unique to clade 4. Isolate 1456 had two markers of clade 4 that differed from clade 2. The phylogenetic tree showed that our isolates clustered primarily with clade 2 and that the three M2/J1 strains clustered between clades 2 and 4. It is likely that isolates 1270/1450/1446 may represent a new subclade of either clade 2 or 4, or some recombinant events. In addition, our isolates were WT strains. We also observed significant inter-strain variations.
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Affiliation(s)
- Z Sun
- Department of Dermatology, Fengxian Institute of Dermatosis Prevention, Shanghai, PR China
| | - Y Guo
- Department of Dermatology, Fengxian Institute of Dermatosis Prevention, Shanghai, PR China
| | - M Li
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Z Yao
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
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36
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Abstract
UNLABELLED Varicella-zoster virus (VZV) is a human herpesvirus, which during primary infection typically causes varicella (chicken pox) and establishes lifelong latency in sensory and autonomic ganglia. Later in life, the virus may reactivate to cause herpes zoster (HZ; also known as shingles). To prevent these diseases, a live-attenuated heterogeneous vaccine preparation, vOka, is used routinely in many countries worldwide. Recent studies of another alphaherpes virus, infectious laryngotracheitis virus, demonstrate that live-attenuated vaccine strains can recombine in vivo, creating virulent progeny. These findings raised concerns about using attenuated herpesvirus vaccines under conditions that favor recombination. To investigate whether VZV may undergo recombination, which is a prerequisite for VZV vaccination to create such conditions, we here analyzed 115 complete VZV genomes. Our results demonstrate that recombination occurs frequently for VZV. It thus seems that VZV is fully capable of recombination if given the opportunity, which may have important implications for continued VZV vaccination. Although no interclade vaccine wild-type recombinant strains were found, intraclade recombinants were frequently detected in clade 2, which harbors the vaccine strains, suggesting that the vaccine strains have already been involved in recombination events, either in vivo or in vitro during passages in cell culture. Finally, previous partial and complete genomic studies have described strains that do not cluster phylogenetically to any of the five established clades. The additional VZV strains sequenced here, in combination with those previously published, have enabled us to formally define a novel sixth VZV clade. IMPORTANCE Although genetic recombination has been demonstrated to frequently occur for other human alphaherpesviruses, herpes simplex viruses 1 and 2, only a few ancient and isolated recent recombination events have hitherto been demonstrated for VZV. In the present study, we demonstrate that VZV also frequently undergoes genetic recombination, including strains belonging to the clade containing the vOKA strain.
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Full-Genome Sequence of a Novel Varicella-Zoster Virus Clade Isolated in Mexico. GENOME ANNOUNCEMENTS 2015; 3:3/4/e00752-15. [PMID: 26159533 PMCID: PMC4498119 DOI: 10.1128/genomea.00752-15] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Varicella-zoster virus (VZV) is a member of the Herpesviridae family, which causes varicella (chicken pox) and herpes zoster (shingles) in humans. Here, we report the complete genome sequence of varicella-zoster virus, isolated from a vesicular fluid sample, revealing the circulation of VZV clade VIII in Mexico.
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38
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Weinert LA, Depledge DP, Kundu S, Gershon AA, Nichols RA, Balloux F, Welch JJ, Breuer J. Rates of vaccine evolution show strong effects of latency: implications for varicella zoster virus epidemiology. Mol Biol Evol 2015; 32:1020-8. [PMID: 25568346 PMCID: PMC4379407 DOI: 10.1093/molbev/msu406] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Varicella-zoster virus (VZV) causes chickenpox and shingles, and is found in human populations worldwide. The lack of temporal signal in the diversity of VZV makes substitution rate estimates unreliable, which is a barrier to understanding the context of its global spread. Here, we estimate rates of evolution by studying live attenuated vaccines, which evolved in 22 vaccinated patients for known periods of time, sometimes, but not always undergoing latency. We show that the attenuated virus evolves rapidly (∼ 10(-6) substitutions/site/day), but that rates decrease dramatically when the virus undergoes latency. These data are best explained by a model in which viral populations evolve for around 13 days before becoming latent, but then undergo no replication during latency. This implies that rates of viral evolution will depend strongly on transmission patterns. Nevertheless, we show that implausibly long latency periods are required to date the most recent common ancestor of extant VZV to an "out-of-Africa" migration with humans, as has been previously suggested.
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Affiliation(s)
- Lucy A Weinert
- Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom Department of Genetics, Evolution and Environment, UCL, London, United Kingdom
| | - Daniel P Depledge
- Division of Infection and Immunity, MRC Centre for Medical Molecular Virology, UCL, London, United Kingdom
| | - Samit Kundu
- Division of Infection and Immunity, MRC Centre for Medical Molecular Virology, UCL, London, United Kingdom
| | - Anne A Gershon
- Division of Infectious Disease, Columbia University Medical Centre, New York, USA
| | - Richard A Nichols
- School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom
| | - Francois Balloux
- Department of Genetics, Evolution and Environment, UCL, London, United Kingdom
| | - John J Welch
- Department of Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Judith Breuer
- Division of Infection and Immunity, MRC Centre for Medical Molecular Virology, UCL, London, United Kingdom
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Tang KW, Norberg P, Holmudden M, Elias P, Liljeqvist JÅ. Rad51 and Rad52 are involved in homologous recombination of replicating herpes simplex virus DNA. PLoS One 2014; 9:e111584. [PMID: 25365323 PMCID: PMC4218770 DOI: 10.1371/journal.pone.0111584] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 10/04/2014] [Indexed: 12/27/2022] Open
Abstract
Replication of herpes simplex virus 1 is coupled to recombination, but the molecular mechanisms underlying this process are poorly characterized. The role of Rad51 and Rad52 recombinases in viral recombination was examined in human fibroblast cells 1BR.3.N (wild type) and in GM16097 with replication defects caused by mutations in DNA ligase I. Intermolecular recombination between viruses, tsS and tsK, harboring genetic markers gave rise to ∼17% recombinants in both cell lines. Knock-down of Rad51 and Rad52 by siRNA reduced production of recombinants to 11% and 5%, respectively, in wild type cells and to 3% and 5%, respectively, in GM16097 cells. The results indicate a specific role for Rad51 and Rad52 in recombination of replicating herpes simplex virus 1 DNA. Mixed infections using clinical isolates with restriction enzyme polymorphisms in the US4 and US7 genes revealed recombination frequencies of 0.7%/kbp in wild type cells and 4%/kbp in GM16097 cells. Finally, tandem repeats in the US7 gene remained stable upon serial passage, indicating a high fidelity of recombination in infected cells.
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Affiliation(s)
- Ka-Wei Tang
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Peter Norberg
- Department of Infectious Diseases, Section of Virology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martin Holmudden
- Department of Infectious Diseases, Section of Virology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Per Elias
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jan-Åke Liljeqvist
- Department of Infectious Diseases, Section of Virology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Evolution of cocirculating varicella-zoster virus genotypes during a chickenpox outbreak in Guinea-Bissau. J Virol 2014; 88:13936-46. [PMID: 25275123 PMCID: PMC4249134 DOI: 10.1128/jvi.02337-14] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Varicella-zoster virus (VZV), a double-stranded DNA alphaherpesvirus, is associated with seasonal outbreaks of varicella in nonimmunized populations. Little is known about whether these outbreaks are associated with a single or multiple viral genotypes and whether new mutations rapidly accumulate during transmission. Here, we take advantage of a well-characterized population cohort in Guinea-Bissau and produce a unique set of 23 full-length genome sequences, collected over 7 months from eight households. Comparative sequence analysis reveals that four distinct genotypes cocirculated among the population, three of which were present during the first week of the outbreak, although no patients were coinfected, which indicates that exposure to infectious virus from multiple sources is common during VZV outbreaks. Transmission of VZV was associated with length polymorphisms in the R1 repeat region and the origin of DNA replication. In two cases, these were associated with the formation of distinct lineages and point to the possible coevolution of these loci, despite the lack of any known functional link in VZV or related herpesviruses. We show that these and all other sequenced clade 5 viruses possess a distinct R1 repeat motif that increases the acidity of an ORF11p protein domain and postulate that this has either arisen or been lost following divergence of the major clades. Thus, sequencing of whole VZV genomes collected during an outbreak has provided novel insights into VZV biology, transmission patterns, and (recent) natural history. IMPORTANCE VZV is a highly infectious virus and the causative agent of chickenpox and shingles, the latter being particularly associated with the risk of painful complications. Seasonal outbreaks of chickenpox are very common among young children, yet little is known about the dynamics of the virus during person-to-person to transmission or whether multiple distinct viruses seed and/or cocirculate during an outbreak. In this study, we have sequenced chickenpox viruses from an outbreak in Guinea-Bissau that are supported by detailed epidemiological data. Our data show that multiple different virus strains seeded and were maintained throughout the 6-month outbreak period and that viruses transmitted between individuals accumulated new mutations in specific genomic regions. Of particular interest is the potential coevolution of two distinct parts of the genomes and our calculations of the rate of viral mutation, both of which increase our understanding of how VZV evolves over short periods of time in human populations.
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Quinlivan M, Breuer J. Clinical and molecular aspects of the live attenuated Oka varicella vaccine. Rev Med Virol 2014; 24:254-73. [PMID: 24687808 DOI: 10.1002/rmv.1789] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Revised: 02/25/2014] [Accepted: 02/26/2014] [Indexed: 12/24/2022]
Abstract
VZV is a ubiquitous member of the Herpesviridae family that causes varicella (chicken pox) and herpes zoster (shingles). Both manifestations can cause great morbidity and mortality and are therefore of significant economic burden. The introduction of varicella vaccination as part of childhood immunization programs has resulted in a remarkable decline in varicella incidence, and associated hospitalizations and deaths, particularly in the USA. The vaccine preparation, vOka, is a live attenuated virus produced by serial passage of a wild-type clinical isolate termed pOka in human and guinea pig cell lines. Although vOka is clinically attenuated, it can cause mild varicella, establish latency, and reactivate to cause herpes zoster. Sequence analysis has shown that vOka differs from pOka by at least 42 loci; however, not all genomes possess the novel vOka change at all positions, creating a heterogeneous population of genetically distinct haplotypes. This, together with the extreme cell-associated nature of VZV replication in cell culture and the lack of an animal model, in which the complete VZV life cycle can be replicated, has limited studies into the molecular basis for vOka attenuation. Comparative studies of vOka with pOka replication in T cells, dorsal root ganglia, and skin indicate that attenuation likely involves multiple mutations within ORF 62 and several other genes. This article presents an overview of the clinical aspects of the vaccine and current progress on understanding the molecular mechanisms that account for the clinical phenotype of reduced virulence.
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Affiliation(s)
- Mark Quinlivan
- Division of Infection and Immunity, University College London, London, UK
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42
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Abstract
Herpes simplex virus 1 (HSV-1) causes a chronic, lifelong infection in >60% of adults. Multiple recent vaccine trials have failed, with viral diversity likely contributing to these failures. To understand HSV-1 diversity better, we comprehensively compared 20 newly sequenced viral genomes from China, Japan, Kenya, and South Korea with six previously sequenced genomes from the United States, Europe, and Japan. In this diverse collection of passaged strains, we found that one-fifth of the newly sequenced members share a gene deletion and one-third exhibit homopolymeric frameshift mutations (HFMs). Individual strains exhibit genotypic and potential phenotypic variation via HFMs, deletions, short sequence repeats, and single-nucleotide polymorphisms, although the protein sequence identity between strains exceeds 90% on average. In the first genome-scale analysis of positive selection in HSV-1, we found signs of selection in specific proteins and residues, including the fusion protein glycoprotein H. We also confirmed previous results suggesting that recombination has occurred with high frequency throughout the HSV-1 genome. Despite this, the HSV-1 strains analyzed clustered by geographic origin during whole-genome distance analysis. These data shed light on likely routes of HSV-1 adaptation to changing environments and will aid in the selection of vaccine antigens that are invariant worldwide.
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Cruz-Rivera M, Forbi JC, Yamasaki LHT, Vazquez-Chacon CA, Martinez-Guarneros A, Carpio-Pedroza JC, Escobar-Gutiérrez A, Ruiz-Tovar K, Fonseca-Coronado S, Vaughan G. Molecular epidemiology of viral diseases in the era of next generation sequencing. J Clin Virol 2013; 57:378-380. [PMID: 23726419 DOI: 10.1016/j.jcv.2013.04.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Revised: 04/22/2013] [Accepted: 04/24/2013] [Indexed: 12/17/2022]
Affiliation(s)
- Mayra Cruz-Rivera
- Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Genetic analysis of clinical VZV isolates collected in China reveals a more homologous profile. BIOMED RESEARCH INTERNATIONAL 2013; 2013:681234. [PMID: 23781507 PMCID: PMC3678451 DOI: 10.1155/2013/681234] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 04/23/2013] [Accepted: 04/23/2013] [Indexed: 12/21/2022]
Abstract
Forty-four varicella-zoster virus (VZV) isolates from China were genotyped by using a scattered single nucleotide polymorphism (SNP) method, including open reading frames (ORFs) 1, 22, 31, 37, 60, 62, 67, and 68. Based on the analysis of the polymorphic markers in the 8 ORFs, all of the 44 isolates can be placed in genotype J defined by the SNP profiles in ORF22 or clade B defined by the SNP profiles in ORFs 31, 37, 60, 62, 67, and 68. The three consecutive nucleotide (CGG) in-frame insertions in ORF 1 were found in 8 (18.2%) isolates, which has not been described in VZV strains from any other part of the world. A novel synonymous A>G substitution in ORF60 was revealed in 4 (9.1%) of the isolates. In addition, a previously described three consecutive nucleotide (ATC) insertion in ORF 60 was found in all the Chinese isolates but not in the US isolate MLS. The results showed all the 44 strains that belong to genotype J/clade B with significantly high homogeneity, and phylogenetic analysis suggested that the 44 Chinese isolates consist of 4 clusters, but interstrain variations also exist. Overall, VZV isolates obtained in China showed significantly higher genetic homogeneity than isolates reported from other countries.
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Quinlivan M, Sengupta N, Papaevangelou V, Sauerbrei A, Grillner L, Rousseva R, Hague R, Lutsar I, Jogi P, Leca A, Grytchol R, Alain S, Breuer J. Use of oral fluid to examine the molecular epidemiology of varicella zoster virus in the United Kingdom and continental Europe. J Infect Dis 2013; 207:588-93. [PMID: 23087434 PMCID: PMC3549596 DOI: 10.1093/infdis/jis649] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 05/14/2012] [Indexed: 12/12/2022] Open
Abstract
We investigated oral fluid (OF) as an alternative to sampling of rashes for varicella zoster virus (VZV) genotyping and further characterized VZV clade prevalence in the United Kingdom and Europe. VZV was detected in up to 91% of OF specimens. Paired OF and vesicle fluid samples contained identical VZV clades. While clades 1 and 3 were the most prevalent across the United Kingdom and Europe, in Western Europe, clade 5 viruses were circulating. Viruses from the same outbreak belonged to different clades, but no clade was associated with a severe-disease phenotype. OF is suitable and convenient for large-scale molecular epidemiological studies of VZV.
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46
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Leal É, Villanova FE, Lin W, Hu F, Liu Q, Liu Y, Cui S. Interclade recombination in porcine parvovirus strains. J Gen Virol 2012; 93:2692-2704. [DOI: 10.1099/vir.0.045765-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
A detailed analysis of the Ns1/Vp1Vp2 genome region of the porcine parvovirus (PPV) strains isolated from vaccinated animals was performed. We found many inconsistencies in the phylogenetic trees of these viral isolates, such as low statistical support and strains with long branches in the phylogenetic trees. Thus, we used distance-based and phylogenetic methods to distinguish de facto recombinants from spurious recombination signals. We found a mosaic virus in which the Ns1 gene was acquired from one PPV clade and the Vp1Vp2 gene was acquired from a distinct phylogenetic clade. We also described the interclade mosaic structure of the Vp1Vp2 gene of a reference strain. If recombination is an adaptive mechanism over the course of PPV evolution, we would likely observe increasing numbers of chimeric strains over time. However, when the PPV sequences isolated from 1964 to 2011 were analysed, only two chimeric strains were detected. Thus, PPV recombination is an independent event, resulting from close contact between animals housed in high-density conditions.
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Affiliation(s)
- Élcio Leal
- Federal University of Pará, Belém, Brazil
| | | | - Wencheng Lin
- Division of Swine Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of CAAS, Heilongjiang, PR China
| | - Feng Hu
- Division of Swine Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of CAAS, Heilongjiang, PR China
| | - Qinfang Liu
- Division of Swine Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of CAAS, Heilongjiang, PR China
| | - Yebing Liu
- China Institute of Veterinary Drug Control, Beijing 100081, PR China
| | - Shangjin Cui
- Division of Swine Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of CAAS, Heilongjiang, PR China
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Chow VT, Tipples GA, Grose C. Bioinformatics of varicella-zoster virus: single nucleotide polymorphisms define clades and attenuated vaccine genotypes. INFECTION GENETICS AND EVOLUTION 2012. [PMID: 23183312 DOI: 10.1016/j.meegid.2012.11.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Varicella zoster virus (VZV) is one of the human herpesviruses. To date, over 40 complete VZV genomes have been sequenced and analyzed. The VZV genome contains around 125,000 base pairs including 70 open reading frames (ORFs). Enumeration of single nucleotide polymorphisms (SNPs) has determined that the following ORFs are the most variable (in descending order): 62, 22, 29, 28, 37, 21, 54, 31, 1 and 55. ORF 62 is the major immediate early regulatory VZV gene. Further SNP analysis across the entire genome has led to the observation that VZV strains can be broadly grouped into clades within a phylogenetic tree. VZV strains collected in Singapore provided important sequence data for construction of the phylogenetic tree. Currently five VZV clades are recognized; they have been designated clades 1 through 5. Clades 1 and 3 include European/North American strains; clade 2 includes Asian strains, especially from Japan; and clade 5 includes strains from India. Clade 4 includes some strains from Europe, but its geographic origins need further documentation. Within clade 1, five variant viruses have been isolated with a missense mutation in the gE (ORF 68) glycoprotein; these strains have an altered increased cell spread phenotype. Bioinformatics analyses of the attenuated vaccine strains have also been performed, with a subsequent discovery of a stop-codon SNP in ORFO as a likely attenuation determinant. Taken together, these VZV bioinformatics analyses have provided enormous insights into VZV phylogenetics as well as VZV SNPs associated with attenuation.
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Affiliation(s)
- Vincent T Chow
- Department of Microbiology, National University of Singapore, Singapore
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Beerenwinkel N, Günthard HF, Roth V, Metzner KJ. Challenges and opportunities in estimating viral genetic diversity from next-generation sequencing data. Front Microbiol 2012; 3:329. [PMID: 22973268 PMCID: PMC3438994 DOI: 10.3389/fmicb.2012.00329] [Citation(s) in RCA: 171] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Accepted: 08/24/2012] [Indexed: 12/17/2022] Open
Abstract
Many viruses, including the clinically relevant RNA viruses HIV (human immunodeficiency virus) and HCV (hepatitis C virus), exist in large populations and display high genetic heterogeneity within and between infected hosts. Assessing intra-patient viral genetic diversity is essential for understanding the evolutionary dynamics of viruses, for designing effective vaccines, and for the success of antiviral therapy. Next-generation sequencing (NGS) technologies allow the rapid and cost-effective acquisition of thousands to millions of short DNA sequences from a single sample. However, this approach entails several challenges in experimental design and computational data analysis. Here, we review the entire process of inferring viral diversity from sample collection to computing measures of genetic diversity. We discuss sample preparation, including reverse transcription and amplification, and the effect of experimental conditions on diversity estimates due to in vitro base substitutions, insertions, deletions, and recombination. The use of different NGS platforms and their sequencing error profiles are compared in the context of various applications of diversity estimation, ranging from the detection of single nucleotide variants (SNVs) to the reconstruction of whole-genome haplotypes. We describe the statistical and computational challenges arising from these technical artifacts, and we review existing approaches, including available software, for their solution. Finally, we discuss open problems, and highlight successful biomedical applications and potential future clinical use of NGS to estimate viral diversity.
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Affiliation(s)
- Niko Beerenwinkel
- Department of Biosystems Science and Engineering, ETH ZurichBasel, Switzerland
- Swiss Institute of BioinformaticsBasel, Switzerland
| | - Huldrych F. Günthard
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of ZurichZurich, Switzerland
| | - Volker Roth
- Department of Mathematics and Computer Science, University of BaselBasel, Switzerland
| | - Karin J. Metzner
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of ZurichZurich, Switzerland
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The attenuated genotype of varicella-zoster virus includes an ORF0 transitional stop codon mutation. J Virol 2012; 86:10695-703. [PMID: 22837206 DOI: 10.1128/jvi.01067-12] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Varicella-zoster virus (VZV) is the first of the human herpesviruses to be attenuated and subsequently approved as a live vaccine to prevent varicella and herpes zoster. Both the attenuated VZV vaccine, called vaccine Oka or vOka, and the parental strain pOka have been completely sequenced. Yet the specific determinants of attenuation are uncertain. The open reading frame (ORF) with the most single nucleotide polymorphisms (SNPs), ORF62, encodes the regulatory protein IE62, but IE62 studies have failed to define a specific SNP associated with attenuation. We have completed next-generation sequencing of the VZV Ellen genome, a strain known to be highly attenuated by its very limited replication in human skin xenografts in the SCID mouse model of VZV pathogenesis. A comparative analysis of the Ellen sequence with all other complete VZV sequences was extremely informative. In particular, an unexpected finding was a stop codon mutation in Ellen ORF0 (herpes simplex virus UL56 homolog) identical to one found in vOka, combined with the absence of polymorphisms in most Ellen ORFs that were known to be mutated in vOka. The mutated ORF0 protein was also imaged in both two dimensions and three dimensions by confocal microscopy. The probability of two VZV strains not connected by a recent common ancestor having an identical ORF0 SNP by chance would be 1 × 10(-8), in other words, extremely unlikely. Taken together, these bioinformatics analyses strongly suggest that the stop codon ORF0 SNP is one of the determinants of the attenuation genotype of live VZV vaccines.
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Pangaea and the Out-of-Africa Model of Varicella-Zoster Virus Evolution and Phylogeography. J Virol 2012; 86:9558-65. [PMID: 22761371 DOI: 10.1128/jvi.00357-12] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The goal of this minireview is to provide an overview of varicella-zoster virus (VZV) phylogenetics and phylogeography when placed in the broad context of geologic time. Planet Earth was formed over 4 billion years ago, and the supercontinent Pangaea coalesced around 400 million years ago (mya). Based on detailed tree-building models, the base of the phylogenetic tree of the Herpesviridae family has been estimated at 400 mya. Subsequently, Pangaea split into Laurasia and Gondwanaland; in turn, Africa rifted from Gondwanaland. Based on available data, the hypothesis of this minireview is that the ancestral alphaherpesvirus VZV coevolved in simians, apes, and hominins in Africa. When anatomically modern humans first crossed over the Red Sea 60,000 years ago, VZV was carried along in their dorsal root ganglia. Currently, there are five VZV clades, distinguishable by single nucleotide polymorphisms. These clades likely represent continued VZV coevolution, as humans with latent VZV infection left Arabia and dispersed into Asia (clades 2 and 5) and Europe (clades 1, 3, and 4). The prototype VZV sequence contains nearly 125,000 bp, divided into 70 open reading frames. Generally, isolates within a clade display >99.9% identity to one another, while members of one clade compared to a second clade show 99.8% identity to one another. Recently, four different VZV genotypes that do not segregate into the previously defined five clades have been identified, a result indicating a wider than anticipated diversity among newly collected VZV strains around the world.
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