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Blomberg, J., Rizwan, M., Böhlin-Wiener, A., Elfaitouri, A., Julin, P., Zachrisson, O., . . . Gottfries, C.-G. (2019). Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Frontiers in Immunology, 10, Article ID 1946.
Open this publication in new window or tab >>Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1946Article in journal (Refereed) Published
Abstract [en]

Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection. The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed. Among the human herpesviruses (HHV-1 -8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS. It was therefore logical to search for serological evidence of past herpesvirus infection/reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria). Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG). The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls. ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens. We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
anti-herpesviral antibodies, human herpesviruses, HHV, Epstein-Barr virus, EBV, myalgic encephalomyelitis, ME/CFS, suspension multiplex immunoassay
National Category
Immunology in the medical area Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-393658 (URN)10.3389/fimmu.2019.01946 (DOI)000480721700004 ()31475007 (PubMedID)
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved
Pisano, M. P., Grandi, N., Cadeddu, M., Blomberg, J. & Tramontano, E. (2019). Comprehensive Characterization of the Human Endogenous Retrovirus HERV-K(HML-6) Group: Overview of Structure, Phylogeny, and Contribution to the Human Genome. Journal of Virology, 93(16), Article ID e00110-19.
Open this publication in new window or tab >>Comprehensive Characterization of the Human Endogenous Retrovirus HERV-K(HML-6) Group: Overview of Structure, Phylogeny, and Contribution to the Human Genome
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2019 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 93, no 16, article id e00110-19Article in journal (Refereed) Published
Abstract [en]

Eight percent of the human genome is composed of human endogenous retroviruses (HERVs), remnants of ancestral germ line infections by exogenous retroviruses, which have been vertically transmitted as Mendelian characters. The HML-6 group, a member of the class II betaretrovirus-like viruses, includes several proviral loci with an increased transcriptional activity in cancer and at least two elements that are known for retaining an intact open reading frame and for encoding small proteins such as ERVK3-1, which is expressed in various healthy tissues, and HERV-K-MEL, a small Env peptide expressed in samples of cutaneous and ocular melanoma but not in normal tissues. IMPORTANCE We reported the distribution and genetic composition of 66 HML-6 elements. We analyzed the phylogeny of the HML-6 sequences and identified two main clusters. We provided the first description of a Rec domain within the env sequence of 23 HML-6 elements. A Rec domain was also predicted within the ERVK3-1 transcript sequence, revealing its expression in various healthy tissues. Evidence about the context of insertion and colocalization of 19 HML-6 elements with functional human genes are also reported, including the sequence 16p11.2, whose 5' long terminal repeat overlapped the exon of one transcript variant of a cellular zinc finger upregulated and involved in hepatocellular carcinoma. The present work provides the first complete overview of the HML-6 elements in GRCh37(hg19), describing the structure, phylogeny, and genomic context of insertion of each locus. This information allows a better understanding of the genetics of one of the most expressed HERV groups in the human genome.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY, 2019
Keywords
endogenous retrovirus, HERV, HERV-K-MEL, HML-6, RetroTector, bioinformatics
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-393620 (URN)10.1128/JVI.00110-19 (DOI)000480711400002 ()31167914 (PubMedID)
Available from: 2019-09-26 Created: 2019-09-26 Last updated: 2019-09-26Bibliographically approved
Chang, T.-C., Goud, S., Torcivia-Rodriguez, J., Hu, Y., Pan, Q., Kahsay, R., . . . Mazumder, R. (2019). Investigation of somatic single nucleotide variations in human endogenous retrovirus elements and their potential association with cancer. PLoS ONE, 14(4), Article ID e0213770.
Open this publication in new window or tab >>Investigation of somatic single nucleotide variations in human endogenous retrovirus elements and their potential association with cancer
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4, article id e0213770Article in journal (Refereed) Published
Abstract [en]

Human endogenous retroviruses (HERVs) have been investigated for potential links with human cancer. However, the distribution of somatic nucleotide variations in HERV elements has not been explored in detail. This study aims to identify HERV elements with an over-representation of somatic mutations (hot spots) in cancer patients. Four HERV elements with mutation hotspots were identified that overlap with exons of four human protein coding genes. These hotspots were identified based on the significant over-representation (p<8.62e-4) of non-synonymous single-nucleotide variations (nsSNVs). These genes are TNN (HERV-9/LTR12), OR4K15 (HERV-IP10F/LTR10F), ZNF99 (HERV-W/HERV17/LTR17), and KIR2DL1 (MST/MaLR). In an effort to identify mutations that effect survival, all nsSNVs were further evaluated and it was found that kidney cancer patients with mutation C2270G in ZNF99 have a significantly lower survival rate (hazard ratio = 2.6) compared to those without it. Among HERV elements in the human non-protein coding regions, we found 788 HERVs with significantly elevated numbers of somatic single-nucleotide variations (SNVs) (p<1.60e-5). From this category the top three HERV elements with significantly over-represented SNVs are HERV-H/LTR7, HERV-9/LTR12 and HERV-L/MLT2. Majority of the SNVs in these 788 HERV elements are located in three DNA functional groups: long non-coding RNAs (lncRNAs) (60%), introns (22.2%) and transcriptional factor binding sites (TFBS) (14.8%). This study provides a list of mutational hotspots in HERVs, which could potentially be used as biomarkers and therapeutic targets.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2019
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-382521 (URN)10.1371/journal.pone.0213770 (DOI)000462867000006 ()30934003 (PubMedID)
Available from: 2019-04-30 Created: 2019-04-30 Last updated: 2019-04-30Bibliographically approved
Albinsson, B., Vene, S., Rombo, L., Blomberg, J., Lundkvist, Å. & Rönnberg, B. (2018). Distinction between serological responses following tick-borne encephalitis virus (TBEV) infection vs vaccination, Sweden 2017. Eurosurveillance, 23(3), 2-7, Article ID 17-00838.
Open this publication in new window or tab >>Distinction between serological responses following tick-borne encephalitis virus (TBEV) infection vs vaccination, Sweden 2017
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2018 (English)In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 23, no 3, p. 2-7, article id 17-00838Article in journal (Refereed) Published
Abstract [en]

Tick-borne encephalitis virus (TBEV) is an important European vaccine-preventable pathogen. Discrimination of vaccine-induced antibodies from those elicited by infection is important. We studied anti-TBEV IgM/IgG responses, including avidity and neutralisation, by multiplex serology in 50 TBEV patients and 50 TBEV vaccinees. Infection induced antibodies reactive to both whole virus (WV) and non-structural protein 1 (NS1) in 48 clinical cases, whereas 47 TBEV vaccinees had WV, but not NS1 antibodies, enabling efficient discrimination of infection/vaccination.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-343857 (URN)10.2807/1560-7917.ES.2018.23.3.17-00838 (DOI)000423449200001 ()
Available from: 2018-03-02 Created: 2018-03-02 Last updated: 2018-03-02Bibliographically approved
Grandi, N., Cadeddu, M., Blomberg, J., Mayer, J. & Tramontano, E. (2018). HERV-W group evolutionary history in non-human primates: characterization of ERV-W orthologs in Catarrhini and related ERV groups in Platyrrhini. BMC Evolutionary Biology, 18, Article ID 6.
Open this publication in new window or tab >>HERV-W group evolutionary history in non-human primates: characterization of ERV-W orthologs in Catarrhini and related ERV groups in Platyrrhini
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2018 (English)In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 18, article id 6Article in journal (Refereed) Published
Abstract [en]

Background: The genomes of all vertebrates harbor remnants of ancient retroviral infections, having affected the germ line cells during the last 100 million years. These sequences, named Endogenous Retroviruses (ERVs), have been transmitted to the offspring in a Mendelian way, being relatively stable components of the host genome even long after their exogenous counterparts went extinct. Among human ERVs (HERVs), the HERV-W group is of particular interest for our physiology and pathology. A HERV-W provirus in locus 7q21.2 has been coopted during evolution to exert an essential role in placenta, and the group expression has been tentatively linked to Multiple Sclerosis and other diseases. Following up on a detailed analysis of 213 HERV-W insertions in the human genome, we now investigated the ERV-W group genomic spread within primate lineages.

Results: We analyzed HERV-W orthologous loci in the genome sequences of 12 non-human primate species belonging to Simiiformes (parvorders Catarrhini and Platyrrhini), Tarsiiformes and to the most primitive Prosimians. Analysis of HERV-W orthologous loci in non-human Catarrhini primates revealed species-specific insertions in the genomes of Chimpanzee (3), Gorilla (4), Orangutan (6), Gibbon (2) and especially Rhesus Macaque (66). Such sequences were acquired in a retroviral fashion and, in the majority of cases, by L1-mediated formation of processed pseudogenes. There were also a number of LTR-LTR homologous recombination events that occurred subsequent to separation of Catarrhini sub-lineages. Moreover, we retrieved 130 sequences in Marmoset and Squirrel Monkeys (family Cebidae, Platyrrhini parvorder), identified as ERV1–1_CJa based on RepBase annotations, which appear closely related to the ERV-W group. Such sequences were also identified in Atelidae and Pitheciidae, representative of the other Platyrrhini families. In contrast, no ERV-W-related sequences were found in genome sequence assemblies of Tarsiiformes and Prosimians.

Conclusions: Overall, our analysis now provides a detailed picture of the ERV-W sequences colonization of the primate lineages genomes, revealing the exact dynamics of ERV-W locus formations as well as novel insights into the evolution and origin of the group.

Keywords
Comparative genomics, Endogenous retroviruses, HERV-W, Syncytin, ERV1-1, Viral evolution, Monkey and ape retroviruses
National Category
Evolutionary Biology Genetics
Identifiers
urn:nbn:se:uu:diva-343855 (URN)10.1186/s12862-018-1125-1 (DOI)000423128100003 ()29351742 (PubMedID)
Available from: 2018-03-02 Created: 2018-03-02 Last updated: 2018-03-02Bibliographically approved
Blomberg, J., Gottfries, C.-G., Elfaitouri, A., Rizwan, M. & Rosén, A. (2018). Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Frontiers in Immunology, 9, Article ID 229.
Open this publication in new window or tab >>Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 229Article in journal (Refereed) Published
Abstract [en]

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
chronic fatigue syndrome, myalgic encephalomyelitis, irritable bowel syndrome, postexertional malaise, autoimmunity
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-348102 (URN)10.3389/fimmu.2018.00229 (DOI)000425152100001 ()29497420 (PubMedID)
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-04-11Bibliographically approved
Gifford, R. J., Blomberg, J., Coffin, J. M., Fan, H., Heidmann, T., Mayer, J., . . . Johnson, W. E. (2018). Nomenclature for endogenous retrovirus (ERV) loci. Retrovirology, 15, Article ID 59.
Open this publication in new window or tab >>Nomenclature for endogenous retrovirus (ERV) loci
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2018 (English)In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 15, article id 59Article, review/survey (Refereed) Published
Abstract [en]

Retroviral integration into germline DNA can result in the formation of a vertically inherited proviral sequence called an endogenous retrovirus (ERV). Over the course of their evolution, vertebrate genomes have accumulated many thousands of ERV loci. These sequences provide useful retrospective information about ancient retroviruses, and have also played an important role in shaping the evolution of vertebrate genomes. There is an immediate need for a unified system of nomenclature for ERV loci, not only to assist genome annotation, but also to facilitate research on ERVs and their impact on genome biology and evolution. In this review, we examine how ERV nomenclatures have developed, and consider the possibilities for the implementation of a systematic approach for naming ERV loci. We propose that such a nomenclature should not only provide unique identifiers for individual loci, but also denote orthologous relationships between ERVs in different species. In addition, we propose that-where possible-mnemonic links to previous, well-established names for ERV loci and groups should be retained. We show how this approach can be applied and integrated into existing taxonomic and nomenclature schemes for retroviruses, ERVs and transposable elements.

Place, publisher, year, edition, pages
BMC, 2018
Keywords
Retrovirus, Nomenclature, Endogenous, Taxonomy, Classification
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-364730 (URN)10.1186/s12977-018-0442-1 (DOI)000443648700001 ()30153831 (PubMedID)
Available from: 2018-11-01 Created: 2018-11-01 Last updated: 2018-11-01Bibliographically approved
Krupovic, M., Blomberg, J., Coffin, J. M., Dasgupta, I., Fan, H., Geering, A. D., . . . Kuhn, J. H. (2018). Ortervirales: New Virus Order Unifying Five Families of Reverse-Transcribing Viruses [Letter to the editor]. Journal of Virology, 92(12), Article ID e00515-18.
Open this publication in new window or tab >>Ortervirales: New Virus Order Unifying Five Families of Reverse-Transcribing Viruses
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2018 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 12, article id e00515-18Article in journal, Letter (Other academic) Published
Keywords
Belpaoviridae, Caulimoviridae, Hepadnaviridae, International Committee on Taxonomy of Viruses (ICTV), Metaviridae, Pseudoviridae, Retroviridae, retroviruses, Ty3/Gypsy and Ty1/Copia LTR retrotransposons, virus classification, virus evolution
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-361422 (URN)10.1128/JVI.00515-18 (DOI)000433416900021 ()29618642 (PubMedID)
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved
Rönnberg, B., Gustafsson, Å., Vapalahti, O., Emmerich, P., Lundkvist, Å., Schmidt-Chanasit, J. & Blomberg, J. (2017). Compensating for cross-reactions using avidity and computation in a suspension multiplex immunoassay for serotyping of Zika versus other flavivirus infections. Medical Microbiology and Immmunology, 206(5), 383-401
Open this publication in new window or tab >>Compensating for cross-reactions using avidity and computation in a suspension multiplex immunoassay for serotyping of Zika versus other flavivirus infections
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2017 (English)In: Medical Microbiology and Immmunology, ISSN 0300-8584, E-ISSN 1432-1831, Vol. 206, no 5, p. 383-401Article in journal (Refereed) Published
Abstract [en]

The recent spread of Zika virus (ZIKV) in the Americas and Asia necessitates an increased preparedness for improved maternal and perinatal health and blood safety. However, serological cross-reactions, especially to Dengue virus (DENV), complicate ZIKV antibody serodiagnosis. A novel "pan-Flavi" suspension multiplex immunoassay (PFSMIA) using 25 antigens, whole virus (WV), non-structural protein 1 (NS1), and envelope (E) proteins, from 7 zoonotic flaviviruses for specific detection of ZIKV and DENV IgM and IgG was developed. Patterns of antibody cross-reactivity, avidity, and kinetics were established in 104 sera from returning travelers with known ZIKV and DENV infections. PFSMIA gave IgM- and IgG-sensitivities for both viruses of 96-100%, compared to an immunofluorescence assay. Main IgM cross-reactions were to NS1, for IgG to the E and WV antigens. Infecting virus yielded reactivity to several antigens of the homologous virus, while cross-reactions tended to occur only to a single antigen from heterologous virus(es). A specificity-enhancing computer procedure took into account antibody isotype, number of antibody-reactive antigens per virus, avidity, average degree of cross-reactivity to heterologous flavivirus antigens, and reactivity changes in serial sera. It classified all 50 cases correctly. Applied to sera from 200 pregnant women and 173 blood donors from Sweden, one blood donor was found ZIKV NS1 IgM positive, and another as ZIKV NS1 IgG positive. These samples did not react with other ZIKV antigens and were thereby judged as false-positives. PFSMIA provided sensitive and specific ZIKV and DENV serology, warranting high-throughput serological surveillance and a minimized need for laborious and expensive virus neutralization assays.

Place, publisher, year, edition, pages
SPRINGER, 2017
Keywords
Zika virus, Dengue virus, Flavivirus, Suspension multiplex immunoassay, Serological crossreaction, Pathogen surveillance
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-335127 (URN)10.1007/s00430-017-0517-y (DOI)000410805500006 ()28852878 (PubMedID)
Available from: 2017-12-04 Created: 2017-12-04 Last updated: 2017-12-04Bibliographically approved
Westman, G., Blomberg, J., Yun, Z., Lannfelt, L., Ingelsson, M. & Eriksson, B.-M. (2017). Decreased HHV-6 IgG in Alzheimer's Disease. Frontiers in Neurology, 8, Article ID 40.
Open this publication in new window or tab >>Decreased HHV-6 IgG in Alzheimer's Disease
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2017 (English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 8, article id 40Article in journal (Refereed) Published
Abstract [en]

Human herpesviruses have previously been implicated in the pathogenesis of Alzheimer's disease (AD) but whether they are causal, facilitating, or confounding factors is yet to be established. A total of 50 AD subjects and 52 non-demented (ND) controls were analyzed in a multiplex assay for IgG reactivity toward herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6). The HHV-6 IgG reactivity was significantly lower in AD subjects compared to ND controls, whereas there were no differences in HSV, VZV, or CMV antibody levels between the groups. Analysis of peripheral blood mononuclear cells with a subtype-specific HHV-6 PCR revealed no signs of reactivation, as AD and ND subjects presented with comparable HHV-6 DNA levels in PBMCs, and all positive samples were of subtype B. Whether HHV-6 is a factor in AD remains to be elucidated in future studies.

Keywords
Alzheimer's disease, herpesvirus, HHV-6, multiplex, immunoassay, IgG
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317581 (URN)10.3389/fneur.2017.00040 (DOI)000394338300001 ()28265256 (PubMedID)
Available from: 2017-03-22 Created: 2017-03-22 Last updated: 2017-11-29Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-6492-2491

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