Dobrava-Belgrade virus: Phylogeny, epidemiology, disease

doi:10.1016/j.antiviral.2012.05.011

Antiviral Research

Volume 95, Issue 2, August 2012, Pages 104-117

https://doi.org/10.1016/j.antiviral.2012.05.011 Get rights and content

Abstract

Dobrava-Belgrade virus (DOBV) is an Old World hantavirus that causes hemorrhagic fever with renal syndrome in humans. With a case fatality rate up to 12%, DOBV infection is the most life-threatening hantavirus disease in Europe. The virus was initially identified in the Balkans, but the discovery of new endemic foci have expanded its recognized geographic range. The recent description of novel genetic variants with different degrees of pathogenicity have complicated its taxonomic analysis. The original rodent host of DOBV is Apodemus flavicollis, however additional Apodemus species, such Apodemus agrarius and Apodemus ponticus, have been found to serve as hosts of the various DOBV genotypes. The complex evolution and genetic diversity of the virus are still under investigation. The present review aims to provide an update on the phylogeny of DOBV and the epidemiology of infection in rodents and humans; to describe the clinical characteristics of the disease; to present current knowledge about laboratory diagnosis, treatment and prevention; discuss the current state of the art in antiviral drug and vaccine development.

Highlights

► Dobrava-Belgrade virus (DOBV) is the principal cause of hemorrhagic fever with renal syndrome in southeastern Europe. ► The epidemiology of DOBV and phylogenetic relationships among DOBV strains are described. ► Different DOBV genotypes present different levels of pathogenicity for humans. ► Approaches used for drug development and vaccine design are summarized.

Section snippets

Introduction historical perspective

Hantaviruses (genus Hantavirus, family Bunyaviridae) cause two clinical syndromes in humans: hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe, and hantavirus pulmonary (or cardiopulmonary) syndrome (HPS) in the Americas, with fatality rates of up to 12% and 60%, respectively (Jonsson et al., 2010). They are transmitted to humans through inhalation of the aerosolized excreta of persistently, but asymptomatically infected rodents, belonging to the Murinae, Arvicolinae and

Virion structure and genome

The hantavirus virion is spherical, with an average diameter of 80–120 nm, and a surface structure composed of a grid-like pattern due to glycoprotein projections anchored in the lipid bilayer envelope (Battisti et al., 2011, Huiskonen et al., 2010). It contains a single-stranded, negative-sense RNA genome consisting of three segments, the small (S), medium (M) and large (L), all of which are required for infectivity. The 5′and 3′ terminal sequences of each segment are highly conserved and

Classification and phylogenetics

Hantavirology began in 1978, when Ho Wang Lee and his co-workers isolated Hantaan virus (HTNV), the etiological agent of HFRS in Asia (Korean hemorrhagic fever) from the lungs of A. agrarius (Lee et al., 1978). At present, over 20 different hantavirus species are recognized by the ICTV. Most are proven human pathogens, while the rest have been isolated only from rodents or insectivores. HFRS is caused by HTNV, DOBV, Seoul virus (SEOV), and PUUV, while Sin Nombre virus, Andes virus and other

Epidemiology

Rodent species of the genus Apodemus have been present in Europe for at least 3 million years (Michaux and Pasquier, 1974). A. flavicollis, the reservoir host of DOBV-Af, is found in large forest areas, mainly with trees with heavy seeds, such as oak and hazel, while A. agrarius, the host of DoBV-Aa and SAAV in Europe, lives in uncultivated land, gullies, ravines and field edges. DOBV infections in the Balkans, where DOBV-Af predominates, display a strong seasonal distribution, with most cases

Clinical course

The clinical manifestations of HFRS caused by DOBV range from a mild or moderate febrile illness to fulminant hemorrhagic fever and death. The severity depends on the causative genotype. The most severe disease is seen in DOBV-Af infections, with an 8–12% fatality rate among hospitalized patients (Avsic-Zupanc et al., 1999, Papa and Antoniadis, 2001). The illness caused by DOBV-Ap is moderate to severe, with a fatality rate that was first estimated to be 6% (Klempa et al., 2008), but proved

Pathogenesis

The principal pathophysiologic mechanism of HFRS and HPS is a vascular leak syndrome. Pathogenesis is a multifactorial process, which appears to include immune cell-mediated injury, cytokine-mediated damage and enhanced vascular endothelial growth factor (VEGF) responses from endothelial junctions, resulting from highly specific virus–integrin interactions (Koster and Mackow, 2012). Although studies specifically of DOBV pathogenesis are limited, it is generally known that hantaviruses

Animal models

Research on the pathogenesis of HFRS has been hampered by the lack of suitable animal models. In their rodent reservoirs, hantaviruses cause a persistent infection with no apparent pathology, potentially limiting the role of rodents as models of human disease. Humans and rodents clearly differ in immune responses and the outcome of infection. It has been suggested that the reservoir species are characterized by reduced proinflammatory and antiviral responses and elevated regulatory responses at

Laboratory diagnosis

Depending on the time elapsed since the onset of illness, the diagnosis of acute DOBV infection relies on molecular or serologic assays. As in most viral infections, serologic testing of paired samples and the application of more than one method are the most reliable approaches. Isolation of DOBV is a tedious and rarely successful process, which typically requires several blind cell culture passages under BSL-3 containment. It is not used for routine diagnostic purposes.

Treatment

There are currently no FDA-approved drugs for the prevention or treatment of HFRS (Maes et al., 2004). Treatment of DOBV patients is symptomatic, and consists of management of electrolytes, hydration, blood pressure, oxygenation support and dialysis, if required (Sargianou et al., 2012). Vasoactive agents should be used in cases of shock, after correcting the volume deficit. Blood transfusion and H₂-receptor antagonists are indicated in cases of gastrointestinal bleeding.

Rodent control measures

Because DOBV is carried by rodents, preventing exposure is the most important task. People are recommended to minimize contact with rodents during outdoor activities, and to maintain a clean house, keeping food and water in protected areas, so as not to attract rodents.

Vaccines

Despite efforts to develop vaccines for hantavirus infections, there is currently no WHO-approved vaccine with widespread acceptance. Mouse-brain and cell-culture-derived inactivated vaccines (HTNV, SEOV, or SEOV/HTNV) have been

Concluding remarks

A great deal of knowledge of the epidemiology, genetic variability and pathogenicity of DOBV has been gained in recent years. Further studies of viral evolution and its relationship to rodent migration routes will be enhanced by the collection of additional viral sequences from endemic areas. Future environmental and demographic changes may affect the geographic distribution and dynamics of rodent populations, which in turn may influence the epidemiology of hantaviruses, including DOBV.

Acknowledgments

I thank the three reviewers of the manuscript for their helpful suggestions.

References (171)

M. Aitichou et al.
Identification of Dobrava, Hantaan, Seoul, and Puumala viruses by one-step real-time RT–PCR
J. Virol. Methods
(2005)
K. Araki et al.
A new model of Hantaan virus persistence in mice. the balance between HTNV infection and CD8(+) T-cell responses
Virology
(2004)
T. Buranda et al.
Recognition of decay accelerating factor and alpha(v)beta(3) by inactivated hantaviruses: toward the development of high-throughput screening flow cytometry assays
Anal. Biochem.
(2010)
D.H. Chung et al.
Synthesis of 1-beta-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole and its in vitro and in vivo efficacy against Hantavirus
Antiviral Res.
(2008)
E. Eltari et al.
Haemorrhagic fever with renal syndrome in a case in northern Albania
Lancet
(1987)
A. Geldmacher et al.
A hantavirus nucleocapsid protein segment exposed on hepatitis B virus core particles is highly immunogenic in mice when applied without adjuvants or in the presence of pre-existing anti-core antibodies
Vaccine
(2005)
P.R. Hall et al.
Small molecule inhibitors of hantavirus infection
Bioorg. Med. Chem. Lett.
(2010)
J.W. Hooper et al.
A lethal disease model for hantavirus pulmonary syndrome
Virology
(2001)
H. Hujakka et al.
Diagnostic rapid tests for acute hantavirus infections: specific tests for Hantaan, Dobrava and Puumala viruses versus a hantavirus combination test
J. Virol. Methods
(2003)
M. Hukic et al.
Haemorrhagic fever with renal syndrome in north-east Bosnia
Lancet
(1996)

J. Klingstrom et al.

Vaccination of C57/BL6 mice with Dobrava hantavirus nucleocapsid protein in Freund’s adjuvant induced partial protection against challenge

Vaccine

(2004)

J. Klingstrom et al.

Dobrava, but not Saaremaa, hantavirus is lethal and induces nitric oxide production in suckling mice

Microbes Infect.

(2006)

M. Korva et al.

The hantaviral load in tissues of naturally infected rodents

Microbes Infect.

(2009)

D.H. Kruger et al.

Hantavirus infections and their prevention

Microbes Infect.

(2001)

A. Lundkvist et al.

Dobrava hantavirus outbreak in Russia

Lancet

(1997)

A. Lundkvist et al.

Human Dobrava hantavirus infections in Estonia

Lancet

(1998)

P. Maes et al.

A proposal for new criteria for the classification of hantaviruses, based on S and M segment protein sequences

Infect. Genet. Evol.

(2009)

A. Antoniades et al.

Isolation of a hantavirus from a severely ill patient with hemorrhagic fever with renal syndrome in Greece

J. Infect. Dis.

(1987)

A. Antoniadis et al.

Two cases of hemorrhagic fever with renal syndrome in northern Greece

J. Infect. Dis.

(1984)

A. Antoniadis et al.

Clinical and epidemiological aspects of hemorrhagic fever with renal syndrome (HFRS) in Greece

Eur. J. Epidemiol.

(1987)

A. Antoniadis et al.

Direct genetic detection of Dobrava virus in Greek and Albanian patients with hemorrhagic fever with renal syndrome

J. Infect. Dis.

(1996)

K. Araki et al.

Truncated hantavirus nucleocapsid proteins for serotyping Hantaan, Seoul, and Dobrava hantavirus infections

J. Clin. Microbiol.

(2001)

T. Avsic-Zupanc et al.

Evidence for Hantavirus disease in Slovenia, Yugoslavia

Acta Virol.

(1989)

T. Avsic-Zupanc et al.

Characterization of Dobrava virus: a Hantavirus from Slovenia, Yugoslavia

J. Med. Virol.

(1992)

T. Avsic-Zupanc et al.

Isolation of a strain of a Hantaan virus from a fatal case of hemorrhagic fever with renal syndrome in Slovenia

Am. J. Trop. Med. Hyg.

(1994)

T. Avsic-Zupanc et al.

Genetic and antigenic properties of Dobrava virus: a unique member of the Hantavirus genus, family Bunyaviridae

J. Gen. Virol.

(1995)

T. Avsic-Zupanc et al.

Hemorrhagic fever with renal syndrome in the Dolenjska region of Slovenia -a 10-year survey

Clin. Infect. Dis.

(1999)

T. Avsic-Zupanc et al.

Genetic analysis of wild-type Dobrava hantavirus in Slovenia: co-existence of two distinct genetic lineages within the same natural focus

J. Gen. Virol.

(2000)

C.V. Badger et al.

Development and application of a flow cytometric potency assay for DNA vaccines

(2011)

A.J. Battisti et al.

Structural studies of Hantaan virus

J. Virol.

(2011)

R. Bogdanovic et al.

Belgrade and Hantaan hantaviruses–the causative agents of haemorrhagic fever with renal syndrome in children in Serbia

Srp. Arh. Celok. Lek.

(1995)

L. Cebalo et al.

Grading the severity of disease in patients with Puumala or Dobrava virus infections from 1995 to 2000 in Croatia

Acta Med. Croatica

(2003)

M. Chumakov et al.

Seroepidemiology of haemorrhagic fever with renal syndrome in Bulgaria

Acta Virol.

(1988)

J. Clement et al.

A unifying hypothesis and a single name for a complex globally emerging infection: hantavirus disease

Eur. J. Clin. Microbiol. Infect. Dis.

(2012)

T.K. Dzagurova et al.

Molecular diagnostics of hemorrhagic fever with renal syndrome during a Dobrava virus infection outbreak in the European part of Russia

J. Clin. Microbiol.

(2009)

T.K. Dzagurova et al.

Isolation of Sochi virus from a fatal case of hantavirus disease with fulminant clinical course

Clin. Infect. Dis.

(2012)

J.D. Easterbrook et al.

Immunological mechanisms mediating hantavirus persistence in rodent reservoirs

PLoS Pathog.

(2008)

M. Eboriadou et al.

Hantavirus nephropathy in a child

Nephrol. Dial. Transplant.

(1999)

F. Elgh et al.

Serological diagnosis of hantavirus infections by an enzyme-linked immunosorbent assay based on detection of immunoglobulin G and M responses to recombinant nucleocapsid proteins of five viral serotypes

J. Clin. Microbiol.

(1997)

M. Elisaf et al.

Mild human infections of HFRS in northwestern Greece

J. Virol. Dis.

(1993)

M. Elisaf et al.

Chronic renal dysfunction in hemorrhagic fever with renal syndrome patients

Ren. Fail.

(1993)

M. Elisaf et al.

Liver involvement in hemorrhagic fever with renal syndrome

J. Clin. Gastroenterol.

(1993)

Ertek, M. and Buzgan, T., 2009. An outbreak caused by hantavirus in the Black Sea region of Turkey, January–May 2009....

C.M. Fauquet et al.

Virus Taxonomy

(2005)

S.B. Garanina et al.

Genetic diversity and geographic distribution of hantaviruses in Russia

Zoonoses Public Health

(2009)

I.N. Gavrilovskaya et al.

Hemorrhagic fever with renal sydrome in Bulgaria: spreading and serologic proof

Epidemiol. Microbiol. Infekt Bol.

(1984)

I.N. Gavrilovskaya et al.

Hantaviruses direct endothelial cell permeability by sensitizing cells to the vascular permeability factor VEGF, while angiopoietin 1 and sphingosine 1-phosphate inhibit hantavirus-directed permeability

J. Virol.

(2008)

A. Geldmacher et al.

Yeast-expressed hantavirus Dobrava nucleocapsid protein induces a strong, long-lasting, and highly cross-reactive immune response in mice

Viral Immunol.

(2004)

Z.B. Gledovic et al.

Hemorrhagic fever with renal syndrome in Montenegro

Jpn. J. Infect. Dis.

(2008)

A. Gligic et al.

Hemorrhagic fever with renal syndrome in Yugoslavia: detection of hantaviral antigen and antibody in wild rodents and serological diagnosis of human disease

Scand. J. Infect. Dis.

(1988)

Cited by (53)

Hybrid capture-based next-generation sequencing of new and old world Orthohantavirus strains and wild-type Puumala isolates from humans and bank voles
2024, Journal of Clinical Virology
Orthohantaviruses, transmitted primarily by rodents, cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome in the Americas. These viruses, with documented human-to-human transmission, exhibit a wide case-fatality rate, 0.5–40 %, depending on the virus species, and no vaccine or effective treatment for severe Orthohantavirus infections exists. In Europe, the Puumala virus (PUUV), carried by the bank vole Myodes glareolus, causes a milder form of HFRS. Despite the reliance on serology and PCR for diagnosis, the three genomic segments of Swedish wild-type PUUV have yet to be completely sequenced.
We have developed a targeted hybrid-capture method aimed at comprehensive genomic sequencing of wild-type PUUV isolates and the identification of other Orthohantaviruses. Our custom-designed panel includes >11,200 probes covering the entire Orthohantavirus genus. Using this panel, we sequenced complete viral genomes from bank vole lung tissue, human plasma samples, and cell-cultured reference strains. Analysis revealed that Swedish PUUV isolates belong to the Northern Scandinavian lineage, with nucleotide diversity ranging from 2.8 % to 3.7 % among them. Notably, no significant genotypic differences were observed between the viral sequences from reservoirs and human cases except in the nonstructural protein.
Despite the high endemicity of PUUV in Northern Sweden, these are the first complete Swedish wild-type PUUV genomes and substantially increase our understanding of PUUV evolution and epidemiology. The panel's sensitivity enables genomic sequencing of human samples with viral RNA levels reflecting the natural progression of infection and underscores our panel's diagnostic value, and could help to uncover novel Orthohantavirus transmission routes.
Hantavirus in humans: a review of clinical aspects and management
2023, The Lancet Infectious Diseases
Hantavirus infections are part of the broad group of viral haemorrhagic fevers. They are also recognised as a distinct model of an emergent zoonotic infection with a global distribution. Many factors influence their epidemiology and transmission, such as climate, environment, social development, ecology of rodent hosts, and human behaviour in endemic regions. Transmission to humans occurs by exposure to infected rodents in endemic areas; however, Andes hantavirus is unique in that it can be transmitted from person to person. As hantaviruses target endothelial cells, they can affect diverse organ systems; increased vascular permeability is central to pathogenesis. The main clinical syndromes associated with hantaviruses are haemorrhagic fever with renal syndrome (HFRS), which is endemic in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), which is endemic in the Americas. HCPS and HFRS are separate clinical entities, but they share several features and have many overlapping symptoms, signs, and pathogenic alterations. For HCPS in particular, clinical outcomes are highly associated with early clinical suspicion, access to rapid diagnostic testing or algorithms for presumptive diagnosis, and prompt transfer to a facility with critical care units. No specific effective antiviral treatment is available.
A comprehensive screening of the whole proteome of hantavirus and designing a multi-epitope subunit vaccine for cross-protection against hantavirus: Structural vaccinology and immunoinformatics study
2021, Microbial Pathogenesis
Hantaviruses are an emerging zoonotic group of rodent-borne viruses that are having serious implications on global public health due to the increase in outbreaks. Since there is no permanent cure, there is increasing interest in developing a vaccine against the hantavirus. This research aimed to design a robust cross-protective subunit vaccine using a novel immunoinformatics approach. After careful evaluation, the best predicted cytotoxic & helper T-cell and B-cell epitopes from nucleocapsid proteins, glycoproteins, RdRp proteins, and non-structural proteins were considered as potential vaccine candidates. Among the four generated vaccine models with different adjuvant, the model with toll-like receptor-4 (TLR-4) agonist adjuvant was selected because of its high antigenicity, non-allergenicity, and structural quality. The selected model was 654 amino acids long and had a molecular weight of 70.5 kDa, which characterizes the construct as a good antigenic vaccine candidate. The prediction of the conformational B-lymphocyte (CBL) epitope secured its ability to induce the humoral response. Thereafter, disulfide engineering improved vaccine stability. Afterwards, the molecular docking confirmed a good binding affinity of −1292 kj/mol with considered immune receptor TLR-4 and the dynamics simulation showed high stability of the vaccine-receptor complex. Later, the in silico cloning confirmed the better expression of the constructed vaccine protein in E. coli K12. Finally, in in silico immune simulation, significantly high levels of immunoglobulin M (IgM), immunoglobulin G1 (IgG1), cytotoxic & helper T lymphocyte (CTL & HTL) populations, and numerous cytokines such as interferon-γ (IFN-γ), interleukin-2 (IL-2) etc. were found as coherence with actual immune response and also showed faster antigen clearance for repeated exposures. Nonetheless, experimental validation can demonstrate the safety and cross-protective ability of the proposed vaccine to fight against hantavirus infection.
Molecular epidemiology of Dobrava-Belgrade virus in Greece
2018, Infection, Genetics and Evolution
Citation Excerpt :
The most severe form of HFRS is caused by Dobrava and Sochi genotypes. The disease is characterized by fever, myalgia, thrombocytopenia, and acute renal insufficiency; the case fatality rate is 9–15% (Papa, 2012; Kruger et al., 2015). Greece is located in the southernmost region of the Balkan peninsula in the southwestern Europe.
In order to gain an insight into the genetic relatedness of the Dobrava-Belgrade virus (DOBV) in Greece, a phylogenetic analysis was performed based on all currently available DOBV sequences obtained from hospitalized cases with hemorrhagic fever with renal syndrome (HFRS). Most cases occurred in northwestern and north central part of the country. Two sequence datasets consisted of 41 S and 12 M partial DOBV RNA segment sequences were analyzed. All DOBV strains belong to Dobrava genotype which is associated with the rodent Apodemus flavicollis. In both phylogenetic trees (S and M segments), two main clusters of Greek strains could be distinguished. Phylogenetic analysis showed a spatial rather than temporal relation of the strains, since their genetic clustering was highly associated with the geographic distribution of the cases. Besides previous characterized endemic foci, novel ones have been identified, expanding our knowledge on the epidemiology of HFRS in Greece.
Molecular characterization of Dobrava-Belgrade hantavirus in Serbia, 2007–2011
2019, Journal of Infection and Public Health
Citation Excerpt :
HFRS is known to be present in Serbia since mid-20th century, whereas hantavirus isolates from human cases in Serbia, dating from 1988, were the very first ones from the Balkan region [5]. However, up to now very few molecular genetic studies of hantavirus isolates from Serbia, have been reported, in particular from cases of human infection [1]. Serum samples of HFRS cases, previously determined seropositive for hantaviruses at the Serbian National Reference Laboratory for Arboviruses from January 2007 to October 2011, were included in the study.
Hantaviruses are etiological agents of emerging zoonotic diseases worldwide, including hemorrhagic fever with renal syndrome (HFRS). A number of hantavirus species is known to be present in Europe. In Serbia, existing data on hantavirus presence and prevalence rely in serological findings. In this study, molecular analysis was performed in order to characterize HFRS causing hantaviruses in Serbia.
Sixty four serum samples of HFRS cases, previously found seropositive to anti-hantaviral antibodies, were included in the study. Partial hantaviral L and S segments were PCR amplified producing 390nt and 598nt amplicons, respectively, in parallel with human beta-actin mRNA as external reverse transcription positive control. Hantavirus specific PCR products were DNA sequenced in both direction and the obtained sequences phylogenetically confirmed and analyzed.
PCR detection of hantavirus L and S genome segments was positive in 18/64 and 11/64 tested samples, respectively. Positive PCR results involved samples obtained from different locations, mostly from central and southern parts of Serbia. All the obtained sequences were identified as Dobrava-Belgrade virus (DOBV). In the phylogenetic analysis sequences from Serbia tended to cluster in distinctive, geographically related clusters.
Our findings indicate DOBV as the main HFRS causing hantavirus in Serbia, the site of its initial isolation.
Two cases of imported hemorrhagic fever with renal syndrome and systematic review of literature
2019, Travel Medicine and Infectious Disease
Citation Excerpt :
Increasing numbers of journeys imply an increased potential for travelers to receive and then import these exotic, infectious diseases to their countries of origin, especially those who travel to subtropical and tropical areas [31]. HFRS is an infectious disease known for worldwide spread, including to the Balkan Peninsula [5,6,34,35]. Factors responsible for its spread involve the host, transmission chain, and ecological system.
Many factors are involved in the epidemiology of hemorrhagic fever with renal syndrome (HFRS). Imported cases, as well as those by emigrants, have been reported in literature worldwide. Our goal is to document two cases of HFRS, imported by two immigrants from two countries, and to make a review of the imported HFRS literature data. We performed a systematic literature review (PRISMA guidelines) of imported cases of HFRS and herein describe our two clinical cases. We found 20 published papers, with 16 of them in English and 4 in other languages. Twenty-three patients with travel- or immigration-associated HFRS, including our two cases, were identified. We included only papers that were in English. The average age of the patients was 35.9 ± 15.13 years, and the ratio of male to female was 8:1. Imported disease from Europe to Europe occurred in seven cases, America to Europe occurred in four cases, Europe to America occurred in two cases, America to America occurred in two cases, Asia to Asia in one case, Asia to Europe in one case, and Europe to Asia in one case. The results of the two cited cases are based on the clinical–laboratory, anamnestic, and serologic data for both the patients who tested positive for HFRS. Our systematic analysis shows that international travelers are important sources of infectious diseases. HFRS related to travel and immigration is a rare event. Principal risk factors for travelers and immigrants are camping outside recommended areas or under unsuitable conditions. In recent years, various publications have shown that international travelers and immigrants have expanded the spectrum of imported infectious diseases. The literature data show that the actual reported numbers of imported case of HFRS are limited.

View all citing articles on Scopus

View full text

Dobrava-Belgrade virus: Phylogeny, epidemiology, disease

Abstract

Highlights

Section snippets

Introduction historical perspective

Virion structure and genome

Classification and phylogenetics

Epidemiology

Clinical course

Pathogenesis

Animal models

Laboratory diagnosis

Treatment

Rodent control measures

Vaccines

Concluding remarks

Acknowledgments

J. Virol. Methods

Virology

Anal. Biochem.

Antiviral Res.

Lancet

Vaccine

Bioorg. Med. Chem. Lett.

Virology

J. Virol. Methods

Lancet

Vaccine

Microbes Infect.

Microbes Infect.

Microbes Infect.

Lancet

Lancet

Infect. Genet. Evol.

Isolation of a hantavirus from a severely ill patient with hemorrhagic fever with renal syndrome in Greece

J. Infect. Dis.

Two cases of hemorrhagic fever with renal syndrome in northern Greece

J. Infect. Dis.

Clinical and epidemiological aspects of hemorrhagic fever with renal syndrome (HFRS) in Greece

Eur. J. Epidemiol.

Direct genetic detection of Dobrava virus in Greek and Albanian patients with hemorrhagic fever with renal syndrome

J. Infect. Dis.

Truncated hantavirus nucleocapsid proteins for serotyping Hantaan, Seoul, and Dobrava hantavirus infections

J. Clin. Microbiol.

Evidence for Hantavirus disease in Slovenia, Yugoslavia

Acta Virol.

Characterization of Dobrava virus: a Hantavirus from Slovenia, Yugoslavia

J. Med. Virol.

Isolation of a strain of a Hantaan virus from a fatal case of hemorrhagic fever with renal syndrome in Slovenia

Am. J. Trop. Med. Hyg.

Genetic and antigenic properties of Dobrava virus: a unique member of the Hantavirus genus, family Bunyaviridae

J. Gen. Virol.

Hemorrhagic fever with renal syndrome in the Dolenjska region of Slovenia -a 10-year survey

Clin. Infect. Dis.

Genetic analysis of wild-type Dobrava hantavirus in Slovenia: co-existence of two distinct genetic lineages within the same natural focus

J. Gen. Virol.

Development and application of a flow cytometric potency assay for DNA vaccines

Structural studies of Hantaan virus

J. Virol.

Belgrade and Hantaan hantaviruses–the causative agents of haemorrhagic fever with renal syndrome in children in Serbia

Srp. Arh. Celok. Lek.

Grading the severity of disease in patients with Puumala or Dobrava virus infections from 1995 to 2000 in Croatia

Acta Med. Croatica

Seroepidemiology of haemorrhagic fever with renal syndrome in Bulgaria

Acta Virol.

A unifying hypothesis and a single name for a complex globally emerging infection: hantavirus disease

Eur. J. Clin. Microbiol. Infect. Dis.

Molecular diagnostics of hemorrhagic fever with renal syndrome during a Dobrava virus infection outbreak in the European part of Russia

J. Clin. Microbiol.

Isolation of Sochi virus from a fatal case of hantavirus disease with fulminant clinical course

Clin. Infect. Dis.

Immunological mechanisms mediating hantavirus persistence in rodent reservoirs

PLoS Pathog.

Hantavirus nephropathy in a child

Nephrol. Dial. Transplant.

Serological diagnosis of hantavirus infections by an enzyme-linked immunosorbent assay based on detection of immunoglobulin G and M responses to recombinant nucleocapsid proteins of five viral serotypes

J. Clin. Microbiol.

Mild human infections of HFRS in northwestern Greece

J. Virol. Dis.

Chronic renal dysfunction in hemorrhagic fever with renal syndrome patients