Publications by authors named "Peter Norberg"

24 Publications

  • Page 1 of 1

Genetic variants and immune responses in a cohort of patients with varicella zoster virus encephalitis.

J Infect Dis 2021 May 11. Epub 2021 May 11.

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.

Background: Infection with varicella zoster virus (VZV) may involve different central nervous system (CNS) manifestations, including meningitis, encephalitis, and vasculitis. In cases where otherwise healthy individuals are affected, an inborn error of immunity may underlie increased susceptibility or severity of infection.

Methods: We collected a cohort of 17 adults who experienced VZV encephalitis and performed whole exome sequencing. Patient PBMCs were infected with VZV and innate antiviral interferon and cytokine responses as well as viral replication was evaluated. Data were analyzed by Mann Whitney U test.

Results: We identified a total of 21 different potentially disease-causing variants in a total of 13 of the 17 patients included. These gene variants were within two major functional clusters: i) innate viral sensors and immune pathways and ii) autophagy pathways. Antiviral interferon (IFN) and cytokine responses were abnormal in the majority of patients, whereas viral replication was increased in only 2/17.

Conclusion: This study identifies a list of variants of pathogenic potential, which may serve as a platform for generating hypotheses for future studies addressing genetic and immunological factors associated with susceptibility to VZV encephalitis. Collectively, these data suggest that disturbances in innate sensing and autophagy pathways may predispose to VZV encephalitis.
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http://dx.doi.org/10.1093/infdis/jiab254DOI Listing
May 2021

Deep Sequencing of Varicella-Zoster Virus in Aqueous Humor From a Patient With Acute Retinal Necrosis Presenting With Acute Glaucoma.

Open Forum Infect Dis 2020 Jun 26;7(6):ofaa198. Epub 2020 May 26.

Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Sweden.

We report a case of acute retinal necrosis presenting with acute glaucoma preceding inflammatory signs by several days. High-throughput sequencing on aqueous humor revealed a low-level diversity in the viral genome comparable to diversity seen in cutaneous vesicles in contrast to high diversity in encephalitis.
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http://dx.doi.org/10.1093/ofid/ofaa198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305702PMC
June 2020

Comparison of Herpes Simplex Virus 1 Strains Circulating in Finland Demonstrates the Uncoupling of Whole-Genome Relatedness and Phenotypic Outcomes of Viral Infection.

J Virol 2019 04 3;93(8). Epub 2019 Apr 3.

Department of Biochemistry and Molecular Biology, Center for Infectious Disease Dynamics, and the Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania, USA

A majority of adults in Finland are seropositive carriers of herpes simplex viruses (HSV). Infection occurs at epithelial or mucosal surfaces, after which virions enter innervating nerve endings, eventually establishing lifelong infection in neurons of the sensory or autonomic nervous system. Recent data have highlighted the genetic diversity of HSV-1 strains and demonstrated apparent geographic patterns in strain similarity. Though multiple HSV-1 genomes have been sequenced from Europe to date, there is a lack of sequenced genomes from the Nordic countries. Finland's history includes at least two major waves of human migration, suggesting the potential for diverse viruses to persist in the population. Here, we used HSV-1 clinical isolates from Finland to test the relationship between viral phylogeny, genetic variation, and phenotypic characteristics. We found that Finnish HSV-1 isolates separated into two distinct phylogenetic groups, potentially reflecting historical waves of human (and viral) migration into Finland. Each HSV-1 isolate harbored a distinct set of phenotypes in cell culture, including differences in the amount of virus production, extracellular virus release, and cell-type-specific fitness. Importantly, the phylogenetic clusters were not predictive of any detectable pattern in phenotypic differences, demonstrating that whole-genome relatedness is not a proxy for overall viral phenotype. Instead, we highlight specific gene-level differences that may contribute to observed phenotypic differences, and we note that strains from different phylogenetic groups can contain the same genetic variations. Herpes simplex viruses (HSV) infect a majority of adults. Recent data have highlighted the genetic diversity of HSV-1 strains and demonstrated apparent genomic relatedness between strains from the same geographic regions. We used HSV-1 clinical isolates from Finland to test the relationship between viral genomic and geographic relationships, differences in specific genes, and characteristics of viral infection. We found that viral isolates from Finland separated into two distinct groups of genomic and geographic relatedness, potentially reflecting historical patterns of human and viral migration into Finland. These Finnish HSV-1 isolates had distinct infection characteristics in multiple cell types tested, which were specific to each isolate and did not group according to genomic and geographic relatedness. This demonstrates that HSV-1 strain differences in specific characteristics of infection are set by a combination of host cell type and specific viral gene-level differences.
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http://dx.doi.org/10.1128/JVI.01824-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450105PMC
April 2019

High Viral Diversity and Mixed Infections in Cerebral Spinal Fluid From Cases of Varicella Zoster Virus Encephalitis.

J Infect Dis 2018 10;218(10):1592-1601

Division of Infection and Immunity, University College London.

Background: Varicella zoster virus (VZV) may cause encephalitis, both with and without rash. Here we investigate whether viruses recovered from the central nervous system (CNS; encephalitis or meningitis) differ genetically from those recovered from non-CNS samples.

Methods: Enrichment-based deep sequencing of 45 VZV genomes from cerebral spinal fluid (CSF), plasma, bronchoalveolar lavage (BAL), and vesicles was carried out with samples collected from 34 patients with and without VZV infection of the CNS.

Results: Viral sequences from multiple sites in the same patient were identical at the consensus level. Virus from vesicle fluid and CSF in cases of meningitis showed low-level diversity. By contrast, plasma, BAL, and encephalitis had higher numbers of variant alleles. Two CSF-encephalitis samples had high genetic diversity, with variant frequency patterns typical of mixed infections with different clades.

Conclusions: Low viral genetic diversity in vesicle fluid is compatible with previous observations that VZV skin lesions arise from single or low numbers of virions. A similar result was observed in VZV from cases of VZV meningitis, a generally self-limiting infection. CSF from cases of encephalitis had higher diversity with evidence for mixed clade infections in 2 cases. We hypothesize that reactivation from multiple neurons may contribute to the pathogenesis of VZV encephalitis.
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http://dx.doi.org/10.1093/infdis/jiy358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173578PMC
October 2018

Worldwide circulation of HSV-2 × HSV-1 recombinant strains.

Sci Rep 2017 03 13;7:44084. Epub 2017 Mar 13.

Department of Medicine, University of Washington, Seattle, WA 98195, USA.

Homo sapiens harbor two distinct, medically significant species of simplexviruses, herpes simplex virus (HSV)-1 and HSV-2, with estimated divergence 6-8 million years ago (MYA). Unexpectedly, we found that circulating HSV-2 strains can contain HSV-1 DNA segments in three distinct genes. Using over 150 genital swabs from North and South America and Africa, we detected recombinants worldwide. Common, widely distributed gene UL39 genotypes are parsimoniously explained by an initial >457 basepair (bp) HSV-1 × HSV-2 crossover followed by back-recombination to HSV-2. Blocks of >244 and >539 bp of HSV-1 DNA within genes UL29 and UL30, respectively, have reached near fixation, with a minority of strains retaining sequences we posit as ancestral HSV-2. Our data add to previous in vitro and animal work, implying that in vivo cellular co-infection with HSV-1 and HSV-2 yields viable interspecies recombinants in the natural human host.
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http://dx.doi.org/10.1038/srep44084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347006PMC
March 2017

Revisiting Recombination Signal in the Tick-Borne Encephalitis Virus: A Simulation Approach.

PLoS One 2016 19;11(10):e0164435. Epub 2016 Oct 19.

Department of Clinical Microbiology, Sahlgrenska University, Gothenburg, Sweden.

The hypothesis of wide spread reticulate evolution in Tick-Borne Encephalitis virus (TBEV) has recently gained momentum with several publications describing past recombination events involving various TBEV clades. Despite a large body of work, no consensus has yet emerged on TBEV evolutionary dynamics. Understanding the occurrence and frequency of recombination in TBEV bears significant impact on epidemiology, evolution, and vaccination with live vaccines. In this study, we investigated the possibility of detecting recombination events in TBEV by simulating recombinations at several locations on the virus' phylogenetic tree and for different lengths of recombining fragments. We derived estimations of rates of true and false positive for the detection of past recombination events for seven recombination detection algorithms. Our analytical framework can be applied to any investigation dealing with the difficult task of distinguishing genuine recombination signal from background noise. Our results suggest that the problem of false positives associated with low detection P-values in TBEV, is more insidious than generally acknowledged. We reappraised the recombination signals present in the empirical data, and showed that reliable signals could only be obtained in a few cases when highly genetically divergent strains were involved, whereas false positives were common among genetically similar strains. We thus conclude that recombination among wild-type TBEV strains may occur, which has potential implications for vaccination with live vaccines, but that these events are surprisingly rare.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164435PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070875PMC
June 2017

Human Tick-Borne Encephalitis and Characterization of Virus from Biting Tick.

Emerg Infect Dis 2016 08;22(8):1485-7

We report a case of human tick-borne encephalitis (TBE) in which the TBE virus was isolated from the biting tick. Viral growth and sequence were characterized and compared with those of a reference strain. Virus isolation from ticks from patients with TBE may offer a new approach for studies of epidemiology and pathogenicity.
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http://dx.doi.org/10.3201/eid2208.151962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982194PMC
August 2016

Recombination of Globally Circulating Varicella-Zoster Virus.

J Virol 2015 Jul;89(14):7133-46

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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http://dx.doi.org/10.1128/JVI.00437-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473579PMC
July 2015

Published sequences do not support transfer of oseltamivir resistance mutations from avian to human influenza A virus strains.

BMC Infect Dis 2015 Mar 28;15:162. Epub 2015 Mar 28.

Department of Infectious Diseases and Virology, Sahlgrenska Academy, University of Göteborg, Guldhedsgatan 10 B, S-413 46, Gothenburg, Sweden.

Background: Tamiflu (oseltamivir phosphate ester, OE) is a widely used antiviral active against influenza A virus. Its active metabolite, oseltamivir carboxylate (OC), is chemically stable and secreted into wastewater treatment plants. OC contamination of natural habitats of waterfowl might induce OC resistance in influenza viruses persistently infecting waterfowl, and lead to transfer of OC-resistance from avian to human influenza. The aim of this study was to evaluate whether such has occurred.

Methods: A genomics approach including phylogenetic analysis and probability calculations for homologous recombination was applied on altogether 19,755 neuraminidase (N1 and N2) genes from virus sampled in humans and birds, with and without resistance mutations.

Results: No evidence for transfer of OE resistance mutations from avian to human N genes was obtained, and events suggesting recombination between human and avian influenza virus variants could not be traced in the sequence material studied.

Conclusions: The results indicate that resistance in influenza viruses infecting humans is due to the selection pressure posed by the global OE administration in humans rather than transfer from avian influenza A virus strains carrying mutations induced by environmental exposure to OC.
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http://dx.doi.org/10.1186/s12879-015-0860-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387679PMC
March 2015

Rad51 and Rad52 are involved in homologous recombination of replicating herpes simplex virus DNA.

PLoS One 2014 3;9(11):e111584. Epub 2014 Nov 3.

Department of Infectious Diseases, Section of Virology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

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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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111584PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218770PMC
August 2015

Detection of tick-borne encephalitis virus RNA in urine.

J Clin Microbiol 2014 Nov 27;52(11):4111-2. Epub 2014 Aug 27.

Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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http://dx.doi.org/10.1128/JCM.02428-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313253PMC
November 2014

Complete nucleotide sequence and analysis of two conjugative broad host range plasmids from a marine microbial biofilm.

PLoS One 2014 19;9(3):e92321. Epub 2014 Mar 19.

Department of Chemistry and Molecular Biology, Microbiology, University of Gothenburg, Göteborg, Sweden.

The complete nucleotide sequence of plasmids pMCBF1 and pMCBF6 was determined and analyzed. pMCBF1 and pMCBF6 form a novel clade within the IncP-1 plasmid family designated IncP-1 ς. The plasmids were exogenously isolated earlier from a marine biofilm. pMCBF1 (62 689 base pairs; bp) and pMCBF6 (66 729 bp) have identical backbones, but differ in their mercury resistance transposons. pMCBF1 carries Tn5053 and pMCBF6 carries Tn5058. Both are flanked by 5 bp direct repeats, typical of replicative transposition. Both insertions are in the vicinity of a resolvase gene in the backbone, supporting the idea that both transposons are "res-site hunters" that preferably insert close to and use external resolvase functions. The similarity of the backbones indicates recent insertion of the two transposons and the ongoing dynamics of plasmid evolution in marine biofilms. Both plasmids also carry the insertion sequence ISPst1, albeit without flanking repeats. ISPs1is located in an unusual site within the control region of the plasmid. In contrast to most known IncP-1 plasmids the pMCBF1/pMCBF6 backbone has no insert between the replication initiation gene (trfA) and the vegetative replication origin (oriV). One pMCBF1/pMCBF6 block of about 2.5 kilo bases (kb) has no similarity with known sequences in the databases. Furthermore, insertion of three genes with similarity to the multidrug efflux pump operon mexEF and a gene from the NodT family of the tripartite multi-drug resistance-nodulation-division (RND) system in Pseudomonas aeruginosa was found. They do not seem to confer antibiotic resistance to the hosts of pMCBF1/pMCBF6, but the presence of RND on promiscuous plasmids may have serious implications for the spread of antibiotic multi-resistance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960245PMC
November 2014

Genetic recombination of tick-borne flaviviruses among wild-type strains.

Virology 2013 Jun 17;440(2):105-16. Epub 2013 Mar 17.

Department of Infectious Diseases, Section for Clinical Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

Genetic recombination has been suggested to occur in mosquito-borne flaviviruses. In contrast, tick-borne flaviviruses have been thought to evolve in a clonal manner, although recent studies suggest that recombination occurs also for these viruses. We re-analyzed the data and found that previous conclusions on wild type recombination were probably falsely drawn due to misalignments of nucleotide sequences, ambiguities in GenBank sequences, or different laboratory culture histories suggestive of recombination events in laboratory. To evaluate if reliable predictions of wild type recombination of tick-borne flaviviruses can be made, we analyzed viral strains sequenced exclusively for this study, and other flavivirus sequences retrieved from GenBank. We detected genetic signals supporting recombination between viruses within the three clades of TBEV-Eu, TBEV-Sib and TBEV-Fe, respectively. Our results suggest that the tick-borne encephalitis viruses may undergo recombination under natural conditions, but that geographic barriers restrict most recombination events to involve only closely genetically related viruses.
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http://dx.doi.org/10.1016/j.virol.2013.02.017DOI Listing
June 2013

The evolution of infectious agents in relation to sex in animals and humans: brief discussions of some individual organisms.

Ann N Y Acad Sci 2011 Aug;1230:74-107

Florida Museum of Natural History, University of Florida, Gainesville, Florida, USA.

The following series of concise summaries addresses the evolution of infectious agents in relation to sex in animals and humans from the perspective of three specific questions: (1) what have we learned about the likely origin and phylogeny, up to the establishment of the infectious agent in the genital econiche, including the relative frequency of its sexual transmission; (2) what further research is needed to provide additional knowledge on some of these evolutionary aspects; and (3) what evolutionary considerations might aid in providing novel approaches to the more practical clinical and public health issues facing us currently and in the future?
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http://dx.doi.org/10.1111/j.1749-6632.2011.06133.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694397PMC
August 2011

A genome-wide comparative evolutionary analysis of herpes simplex virus type 1 and varicella zoster virus.

PLoS One 2011 25;6(7):e22527. Epub 2011 Jul 25.

Department of Virology, University of Gothenburg, Gothenburg, Sweden.

Herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) are closely related viruses causing lifelong infections. They are typically associated with mucocutaneous or skin lesions, but may also cause severe neurological or ophthalmic diseases, possibly due to viral- and/or host-genetic factors. Although these viruses are well characterized, genome-wide evolutionary studies have hitherto only been presented for VZV. Here, we present a genome-wide study on HSV-1. We also compared the evolutionary characteristics of HSV-1 with those for VZV. We demonstrate that, in contrast to VZV for which only a few ancient recombination events have been suggested, all HSV-1 genomes contain mosaic patterns of segments with different evolutionary origins. Thus, recombination seems to occur extremely frequent for HSV-1. We conclude by proposing a timescale for HSV-1 evolution, and by discussing putative underlying mechanisms for why these otherwise biologically similar viruses have such striking evolutionary differences.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022527PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143153PMC
December 2011

The IncP-1 plasmid backbone adapts to different host bacterial species and evolves through homologous recombination.

Nat Commun 2011 5;2:268. Epub 2011 Apr 5.

Department of Cell and Molecular Biology, Microbiology, University of Gothenburg, Box 462, SE 413 46, Gothenburg, Sweden.

Plasmids are important members of the bacterial mobile gene pool, and are among the most important contributors to horizontal gene transfer between bacteria. They typically harbour a wide spectrum of host beneficial traits, such as antibiotic resistance, inserted into their backbones. Although these inserted elements have drawn considerable interest, evolutionary information about the plasmid backbones, which encode plasmid related traits, is sparse. Here we analyse 25 complete backbone genomes from the broad-host-range IncP-1 plasmid family. Phylogenetic analysis reveals seven clades, in which two plasmids that we isolated from a marine biofilm represent a novel clade. We also found that homologous recombination is a prominent feature of the plasmid backbone evolution. Analysis of genomic signatures indicates that the plasmids have adapted to different host bacterial species. Globally circulating IncP-1 plasmids hence contain mosaic structures of segments derived from several parental plasmids that have evolved in, and adapted to, different, phylogenetically very distant host bacterial species.
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http://dx.doi.org/10.1038/ncomms1267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104523PMC
July 2011

A proposal for a common nomenclature for viral clades that form the species varicella-zoster virus: summary of VZV Nomenclature Meeting 2008, Barts and the London School of Medicine and Dentistry, 24-25 July 2008.

J Gen Virol 2010 Apr 13;91(Pt 4):821-8. Epub 2010 Jan 13.

Division of Infection and Immunity, University College London, Windeyer Institute, 46 Cleveland Street, London WC1 4JF, UK.

Varicella-zoster virus (VZV), the cause of chickenpox and zoster, was the first human herpesvirus to be sequenced fully and the first for which vaccines have been licensed and widely used. Three groups have published genotyping schemes based on single nucleotide polymorphisms (SNPs) and, between them, have identified five distinct phylogenetic clades, with an additional two putative clades. Sequencing of over 23 whole VZV genomes from around the world further refined the phylogenetic distinctions between SNP genotypes. Widespread surveillance in countries in which the varicella vaccine is now in use and the difficulties posed by three unique genotyping approaches prompted an international meeting, at which a common nomenclature based on phylogenetic clades was agreed upon. In this paper, we review the original genotyping schemes and discuss the basis for a novel common nomenclature for VZV strains. We propose a minimum set of SNPs that we recommend should be used to genotype these viruses. Finally, we suggest criteria by which novel clades can be recognized.
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http://dx.doi.org/10.1099/vir.0.017814-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888159PMC
April 2010

Divergence and genotyping of human alpha-herpesviruses: an overview.

Authors:
Peter Norberg

Infect Genet Evol 2010 Jan 20;10(1):14-25. Epub 2009 Sep 20.

Dept. of Cell and Molecular Biology, Microbiology, University of Gothenburg, Box 462, 405 30 Gothenburg, Sweden.

Herpesviruses are large DNA viruses that are highly disseminated among animals. Of the eight herpesviruses identified in humans, three are classified into the alpha-herpesvirus subfamily: herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), which are typically associated with mucocutaneous lesions, and varicella-zoster virus (VZV), which is the cause of chicken pox and herpes zoster. All three viruses establish lifelong infections and may also induce more severe symptoms, such as neurological manifestations and fatal neonatal infections. Despite thorough investigation of the genetic variability among circulating strains of each virus in recent decades, little is known about possible associations between the genetic setups of the viruses and clinical manifestations in human hosts. This review focuses mainly on evolutionary studies of and genotyping strategies for these three human alpha-herpesviruses, emphasizing the ambiguities induced by a high frequency of circulating recombinant strains. It also aims to shed light on the challenges of establishing a uniform genotyping strategy for all three viruses.
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http://dx.doi.org/10.1016/j.meegid.2009.09.004DOI Listing
January 2010

Asymptomatically shed recombinant herpes simplex virus type 1 strains detected in saliva.

J Gen Virol 2009 Mar;90(Pt 3):559-566

Department of Clinical Virology, Göteborg University, Guldhedsgatan 10B, S-413 46 Göteborg, Sweden.

Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen infecting most individuals worldwide. The majority of HSV-1-infected individuals have no clinical symptoms but shed HSV-1 asymptomatically in saliva. Recent phylogenetic analyses of HSV-1 have defined three genetic clades (A-C) and recombinants thereof. These data have all been based on clinical HSV-1 isolates and do not cover genetic variation of asymptomatically shed HSV-1. The primary goal of this study was to investigate such variation. A total of 648 consecutive saliva samples from five HSV-1-infected volunteers was collected. Asymptomatic shedding was detected on 7.6 % of the days from four subjects. The HSV-1 genome loads were quantified with real-time PCR and varied from 1x10(2) to 2.8x10(6) copies of virus DNA (ml saliva)(-1). Phylogenetic network analyses and bootscanning were performed on asymptomatically shed HSV-1. The analyses were based on DNA sequencing of the glycoprotein I gene, and also of the glycoprotein E gene for putative recombinants. For two individuals with clinical HSV-1 infection, the same HSV-1 strain was shed asymptomatically as induced clinical lesions, and sequence analyses revealed that these strains clustered distinctly to clades A and B, respectively. For one of the subjects with no clinical HSV-1 infection, a recombinant strain was identified. The other truly asymptomatic individual shed evolutionarily distinct HSV-1 strains on two occasions. The first strain was classified as a recombinant and the other strain clustered in clade A. High replication rates of different strains in the same person may facilitate the creation of recombinant clinical HSV-1 strains.
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http://dx.doi.org/10.1099/vir.0.007070-0DOI Listing
March 2009

Divergence and recombination of clinical herpes simplex virus type 2 isolates.

J Virol 2007 Dec 19;81(23):13158-67. Epub 2007 Sep 19.

Department of Virology, University of Göteborg, Guldhedsgatan 10 B, S-413 46 Göteborg, Sweden.

Herpes simplex virus type 2 (HSV-2) infects the genital mucosa and is one of the most common sexually transmitted viruses. Here we sequenced a segment comprising 3.5% of the HSV-2 genome, including genes coding for glycoproteins G, I, and E, from 27 clinical isolates from Tanzania, 10 isolates from Norway, and 10 isolates from Sweden. The sequence variation was low compared to that described for clinical HSV-1 isolates, with an overall similarity of 99.6% between the two most distant HSV-2 isolates. Phylogenetic analysis revealed a divergence into at least two genogroups arbitrarily designated A and B, supported by high bootstrap values and evolutionarily separated at the root. Genogroup A contained isolates collected in Tanzania, and genogroup B contained isolates collected in Tanzania and Scandinavia, implying that the genetic variability of HSV-2 is higher in Tanzania than in Scandinavia. Recombination network analysis and bootscan analysis revealed a complex pattern of phylogenetically conflicting informative sites in the sequence alignments. These signals were present in synonymous and nonsynonymous sites in all three genes and were not accumulated in specific regions, observations arguing against positive selection. Since the PHI test applied solely to synonymous sites revealed a high statistical probability of recombination, we suggest as a novel finding that homologous recombination is, as reported earlier for HSV-1 and varicella-zoster virus, a prominent feature in the evolution of HSV-2.
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http://dx.doi.org/10.1128/JVI.01310-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2169075PMC
December 2007

Glycoprotein I of herpes simplex virus type 1 contains a unique polymorphic tandem-repeated mucin region.

J Gen Virol 2007 Jun;88(Pt 6):1683-1688

Department of Virology, University of Göteborg, Guldhedsgatan 10B, S-413 46 Göteborg, Sweden.

Glycoprotein I (gI) of herpes simplex virus type 1 (HSV-1) contains a tandem repeat (TR) region including the amino acids serine and threonine, residues that can be utilized for O-glycosylation. The length of this TR region was determined for 82 clinical HSV-1 isolates and the results revealed a polymorphic distribution of two to six or eight repeated blocks with a majority harbouring between two and four repeats. Assessment of the O-glycosylation capacity of an acceptor peptide (STPSTTTSTPSTTT), representing two of the gI blocks, showed that the peptide was a universal substrate for O-glycosylation not only for the two most commonly expressed N-acetyl-d-galactosamine (GalNAc)-T1 and -T2 transferases, but also for the GalNAc-T3, -T4 and -T11 transferases. Immunoblotting of virus-infected cells showed that gI was exclusively O-glycosylated with GalNAc monosaccharides (Tn antigen). A polymorphic mucin region has not been described previously for HSV-1 and is a unique finding, as repeated blocks within gI homologues are lacking in other alphaherpesviruses.
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http://dx.doi.org/10.1099/vir.0.82500-0DOI Listing
June 2007

Genotyping of clinical herpes simplex virus type 1 isolates by use of restriction enzymes.

J Clin Microbiol 2006 Dec 11;44(12):4511-4. Epub 2006 Oct 11.

Department of Clinical Virology, Göteborg University, Guldhedsgatan 10 B, S-413 46 Göteborg, Sweden.

Recently, three distinct genotypes of clinical herpes simplex virus type 1 (HSV-1) isolates were identified based on DNA sequence information and phylogenetic analysis of clinical isolates and laboratory strains. We utilized single-nucleotide polymorphism within the genes coding for glycoproteins G and I for rapid genotype classification by PCR and restriction enzyme cleavage. The method is suitable for high-scale genotyping of clinical HSV-1 isolates and for the detection of recombinants.
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http://dx.doi.org/10.1128/JCM.00421-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1698414PMC
December 2006

Complete-genome phylogenetic approach to varicella-zoster virus evolution: genetic divergence and evidence for recombination.

J Virol 2006 Oct;80(19):9569-76

Department of Clinical Virology, Göteborg University, Guldhedsgatan 10b, 413 46 Göteborg, Sweden.

Recent studies of varicella-zoster virus (VZV) DNA sequence variation, involving large numbers of globally distributed clinical isolates, suggest that this virus has diverged into at least three distinct genotypes designated European (E), Japanese (J), and mosaic (M). In the present study, we determined and analyzed the complete genomic sequences of two M VZV strains and compared them to the sequences of three E strains and two J strains retrieved from GenBank (including the Oka vaccine preparation, V-Oka). Except for a few polymorphic tandem repeat regions, the whole genome, representing approximately 125,000 nucleotides, is highly conserved, presenting a genetic similarity between the E and J genotypes of approximately 99.85%. These analyses revealed that VZV strains distinctly segregate into at least four genotypes (E, J, M1, and M2) in phylogenetic trees supported by high bootstrap values. Separate analyses of informative sites revealed that the tree topology was dependent on the region of the VZV genome used to determine the phylogeny; collectively, these results indicate the observed strain variation is likely to have resulted, at least in part, from interstrain recombination. Recombination analyses suggest that strains belonging to the M1 and M2 genotypes are mosaic recombinant strains that originated from ancestral isolates belonging to the E and J genotypes through recombination on multiple occasions. Furthermore, evidence of more recent recombination events between M1 and M2 strains is present in six segments of the VZV genome. As such, interstrain recombination in dually infected cells seems to figure prominently in the evolutionary history of VZV, a feature it has in common with other herpesviruses. In addition, we report here six novel genomic targets located in open reading frames 51 to 58 suitable for genotyping of clinical VZV isolates.
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http://dx.doi.org/10.1128/JVI.00835-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1617251PMC
October 2006

Phylogenetic analysis of clinical herpes simplex virus type 1 isolates identified three genetic groups and recombinant viruses.

J Virol 2004 Oct;78(19):10755-64

Department of Virology, University of Göteborg, Guldhedsgatan 10 B, S-413 46 Göteborg, Sweden.

Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen which establishes lifelong infections. In the present study, we determined the sequence diversity of the complete genes coding for glycoproteins G (gG), I (gI), and E (gE), comprising 2.3% of the HSV-1 genome and located within the unique short (US) region, for 28 clinical HSV-1 isolates inducing oral lesions, genital lesions, or encephalitis. Laboratory strains F and KOS321 were sequenced in parallel. Phylogenetic analysis, including analysis of laboratory strain 17 (GenBank), revealed that the sequences were separated into three genetic groups. The identification of different genogroups facilitated the detection of recombinant viruses by using specific nucleotide substitutions as recombination markers. Seven of the isolates and strain 17 displayed sequences consistent with intergenic recombination, and at least four isolates were intragenic recombinants. The observed frequency of recombination based on an analysis of a short stretch of the US region suggests that most full-length HSV-1 genomes consist of a mosaic of segments from different genetic groups. Polymorphic tandem repeat regions, consisting of two to eight blocks of 21 nucleotides in the gI gene and seven to eight repeats of 3 nucleotides in the gG gene, were also detected. Laboratory strain KOS321 displayed a frameshift mutation in the gI gene with a subsequent alteration of the deduced intracellular portion of the protein. The presence of polymorphic tandem repeat regions and the different genogroup identities can be used for molecular epidemiology studies and for further detection of recombination in the HSV-1 genome.
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http://dx.doi.org/10.1128/JVI.78.19.10755-10764.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC516408PMC
October 2004