Memorial plaque celebrating the discovery of viruses unveiled

The Minister of Health of Bolivia, Jeyson Auza, thanks for the rapid development of monkeypox diagnostics in his country. This was possible due to the established cooperation with the Institute of Virology of the Charité (Prof. Dr. Felix Drexler).

Comparable support is currently provided by the Charité in Benin and Madagascar.

Link to the video (in Spanish).

Interferons normally protect against viral infections. These cytokines are produced by several cell types as an early response to a viral infection and induce an antiviral program that supports the cells to impede the spread of the infection. Patients with APS-1 (autoimmune polyendocrine syndrome type 1) develop various autoimmune diseases during their lifetime due to an inherited disorder of the immune system. For poorly understood reasons, these patients typically also display high levels of auto-antibodies against interferons in the blood, which neutralize the effect of the interferons. It is therefore anticipated that patients with APS-1 are particularly prone to a severe course of SARS-CoV-2 infection. This hypothesis is also supported by the fact that, according to a current study, up to 14% of intensive care patients, especially male, elderly COVID-19 patients, have high quantities of IFN autoantibodies.

An interdisciplinary team at Charité, including Prof. Christine Goffinet, Institute for Virology, Dr. Christian Meisel, Institute for Medical Immunology and Labor Berlin, and Prof. Horst von Bernuth, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, however show that neutralizing anti-IFN-autoantibodies, as present in patients with APS-1, do not necessarily lead to a severe course of the COVID-19 disease in the case of a SARS-CoV-2 infection. In this prospective study, six patients with APS-1 were followed, four of whom were infected with SARS-CoV-2. "Analyses of sera collected before and after SARS-CoV-2 infection showed that anti-IFN autoantibodies were pre-existing and displayed potent neutralizing activity in a cell culture-based function test," says Bengisu Akbil, co-first author of the study. Nevertheless, all four individuals developed mild disease only. Interestingly, these were all young, female persons. "Our study shows that the presence of type I IFN autoantibodies per se is not sufficient for the development of a severe course of COVID-19," says Dr. Christian Meisel, first author of the study. The next step is to clarify why autoantibodies against IFN are benign in young female patients, but are associated with severe COVID-19 in the elderly male population. Potential reasons might include X-linked and/or age-related factors.

Mild COVID-19 despite autoantibodies to type I IFNs in Autoimmune-Polyendocrine-Syndrome Type 1 (APS-1)

Christian Meisel*, Bengisu Akbil*, Tim Meyer, Erwin Lankes, Victor M. Corman, Olga Staudacher, Nadine Unterwalder, Uwe Kölsch, Christian Drosten, Marcus A. Mall, Tilmann Kallinich, Dirk Schnabel, Christine Goffinet# and Horst von Bernuth#

Journal of Clinical Investigation, 2021. Link to freely accessible article: www.jci.org/articles/view/150867

This study was co-financed by the Innovationsfond of Labor Berlin, by the German Research Foundation and by BIH.

Every other week, Prof Felix Drexler answers questions of Latin American readers regarding the Covid-19 pandemic on the Spanish website of Deutsche Welle (DW). The topics broached are not limited to the origin and spread of the pandemic, but also include strategies for its confinement. The page has gained widespread popularity among an audience that values the factual perspective of the proficient virologist. Particularly in times of insecurity and widespread misinformation, the sober and objective analysis of Prof Drexler is much appreciated.

Prof Drexler’s column is a component of a project that Charité is implementing with funding provided by the German Ministry of Foreign Affairs.

Sandflies are tiny blood-feeding insects that transmit sandfly fever in the Mediterranean. Infections are associated with fever, headache and gastrointestinal symptoms. Severe infections can involve neurological symptoms such as impaired vision, acute hearing loss, meningitis or encephalitis. Three viruses belonging to the group of phleboviruses are responsible for these infections. The group of Sandra Junglen together with partners from the International Centre of Insect Physiology and Ecology (icipe) has discovered four previously unknown phleboviruses in sandflies from Kenya. The newly identified viruses show different serologic characteristics. While one virus reacts with the Toscana serocomplex, the other three do not react with the related Sicilian serocomplex and establish a new serogroup. The novel viruses may also cause similar symptoms of disease as their relatives from the Mediterranean. The international team has established methods that can now help to study the geographic distribution of the novel viruses and examine infection-related symptoms of disease. The genetic diversity of the detected viruses and their phylogenetic positions imply that the Mediterranean phleboviruses originate from sub-Saharan Africa.

Link to the original publication: https://msphere.asm.org/content/5/5/e00598-20

A joint press release by Charité, the University of Bonn and the DZIF

Researchers from the German Center for Infection Research (DZIF) at Charité – Universitätsmedizin Berlin and the University of Bonn have examined the way in which SARS-CoV-2 reprograms the metabolism of the host cell in order to gain an overall advantage. According to their report in Nature Communications*, the researchers were able to identify four substances which inhibit SARS-CoV-2 replication in the host cell: spermine and spermidine, substances naturally found in the body; MK-2206, an experimental cancer drug; and niclosamide, a tapeworm drug. Charité is currently conducting a trial to determine whether niclosamide is also effective against COVID-19 in humans.

Link to the original publication

To the press release

Contact:

PD Dr. Marcel A. Müller

Email: marcel.mueller@charite.de

Phone: 030-450-625097

The MERS virus is a zoonotic agent acquired from camels. It undergoes limited onward transmission from human to human if introduced into a favorable environment, e.g., in hospitals. As transmission occurs via the airborne route, further adaptation to humans involves pandemic risks.

Researchers from our institute, together with colleagues from Saudi Arabia, have now conducted a large surveillance study of imported camels in the harbor of Jeddah.

Jeddah is by far the largest import harbor for camels on the Arabian Peninsula. More than 140,000 animals are imported from Africa each year. The present study shows that African viruses cannot establish themselves in Saudi Arabia in spite of their steady import.

Moreover, it becomes obvious that a novel recombinant lineage of the virus that was first detected in 2014 is now the only lineage circulating in the Peninsula. All other cocirculating virus lineages have disappeared. This suggest that the novel lineage may have increased its fitness relative to earlier-detected lineages. This is a surprising and novel finding that requires further investigation to understand the associated pandemic risks.

18.12.2019

Link to the original publication: https://www.thelancet.com/journals/lanplh/article/PIIS2542-5196(19)30243-8/fulltext

A major transcriptome study of insects has revealed a unique glimpse into the biodiversity of viruses.

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008224

Researchers from Charité´s institute of virology, in collaboration with colleagues from the Research Museum Alexander König in Bonn, have scanned the most comprehensive collection of insect transcriptomes for viral genomes. The present publication focuses on only a part of the overall findings and describes novel insect-associated RNA viruses with a negative strand genome. The detected viruses will require the definition of at least 20 novel genera and one novel family of viruses.

Based on the knowledge of these novel viruses, researchers hope to discover new agents of disease in animals including humans. Because virus discovery is based on sequence comparison, computer algorithms used in virus discovery pipelines can only recognize new viruses if these are not too different from known viruses. Discoveries of fundamentally new viruses, such as in the present study, may therefore extend our general capabilities to discover new causes and etiologies of diseases previously unexplained. Also, emerging viruses from insects may be recognized early on.

In addition, the study enables important conclusions regarding the evolution of viruses. For the first time, it becomes obvious that major lineages of viruses were shaped by coevolution with their insect hosts. These data enable a better understanding of sources of infection for humans and animals. Knowledge of insect-associated viruses is also relevant for a major upcoming challenge in human nutrition: the utility of insects as a protein source for a growing human population.

Licensed drugs effective in cells

Joint press release by Charité and the DZIF

First identified in 2012, the MERS-coronavirus is capable of causing severe and often fatal pneumonia. There are no effective treatments for MERS. Researchers from the German Center for Infection Research (DZIF) at Charité – Universitätsmedizin Berlin recently identified a cellular recycling process known as autophagy as a potential target in the fight against MERS. Autophagy-inducing substances – including certain licensed drugs – were shown to be capable of drastically reducing the rate at which the virus replicates. Results from this research have been published in Nature Communications*.

Link to the original publication

Full press release

Kontakt:

Marcel Müller

marcel.mueller@charite.de

HCMV is a member of the herpesvirus family and represents a major human pathogen causing severe disease in newborns and immunocompromised patients for which the development of new non-nucleosidic antiviral agents are highly important. This manuscript focuses on DNA packaging, which is a target for development of new antivirals. The terminase subunit pUL89 is involved in this process. The paper presents the identification of DNA binding and nuclease motifs with invariant amino acids and highlights its first 3-D surface structure at approx. 3 nm resolution. At this resolution, the calculated 3-D Surface structure matches well with the predicted structure. In conjunction with earlier studies it was possible to define structure-function relationships for the HCMV terminase subunit pUL89.

Full-length human cytomegalovirus terminase pUL89 adopts a two-domain structure required for DNA packaging; Theiß, J, M.W. Sun, A. Holzenburg and E. Bogner. 2019. PLOS Path. 15(12): e1008175. doi:10.1371/journal.ppat.1008175. 

Christine Goffinet contributes to the World Health Summit 2019 by speaking about the role of academic science in fighting against HIV-1/AIDS

The World Health Summit is one of the most important international conferences for global health issues with more than 2,500 participants from 100 nations. Science, politics, the private sector and civil society come together here to discuss the challenges of global health: from climate change to antibiotic resistance and digitization.

Prof. Christine Goffinet, BIH Professor of Virology, discussed the topic "Securing Political Leadership for Global Health to Accelerate the Elimination of Communicable Diseases" with politicians and civil society.

“The existence of an excellent antiretroviral therapy against HIV-1/AIDS is a tremendous scientific achievement. However, it is unlikely that it will suffice to eradicate HIV-1/AIDS globally. A reinforcement of academic science is crucial in order to develop a protective vaccine and a cure”. She also stressed the need for interdisciplinary implementation science in order to translate clinical evidence and protective strategies more effectively to the real world. Finally, she advocated for a reinforcement of universities directly in affected countries, allowing a better implementation of research findings in the most affected and vulnerable populations. These goals can only be reached if global health-associated science obtains more dedicated support and recognition by funding agencies and politics.

Co-speakers were Ricardo Baptista Leite, Portuguese parliamentarian, Founder and president of UNITE; Gunilla Carlsson, executive director UNAIDS; Jaak Peeters, Head of Global Public Health, Johnson & Johnson; Esther Passaris, Kenian parliamentarian; and Alan Donelly, convener of G20 Health and Development Partnership Initiative.

More information can be found on the World Health Summit 2019 website: https://www.worldhealthsummit.org

The research group of Christine Goffinet established new properties of the antiviral restriction factor SERINC5. Restriction factors are proteins of the cell-intrinsic innate immune system that interfere with virus replication. However, several viruses have evolved strategies to evade or counteract these cellular defenses. The transmembrane protein SERINC5 incorporates into and reduces the infectivity of HIV-1 particles and is antagonized by the HIV-1 accessory protein Nef. Because antibodies of sufficient sensitivity and specificity against SERINC5 do not exist, studies addressing the subcellular localization and properties as anti-HIV-1 restriction factors were largely restricted to heterologously expressed protein. Here, an HA epitope tag was inserted into the SERINC5 gene alleles of a T-cell line via CRISP/Cas9-assisted gene editing. This modification allowed, for the first time, the detection of endogenously expressed SERINC5 protein. This unique tool allowed deciphering an unexpected modulation of subcellular localization of SERINC5 protein through type I interferons and identifying Nef-mediated antagonism modes that go beyond the so far suggested Nef-mediated virion exclusion of SERINC5. CRISPR/Cas9-mediated gene editing paves avenues towards understanding of the impact of single nucleotide polymorphisms in genes encoding antiviral factors, an important step towards personalized medicine. This project is funded by the Collaborative Research Centre 900 (Sonderforschungsbereich 900) “Microbial Persistence and its Control” of the German Research Foundation.

Characterization of Endogenous SERINC5 Protein as anti-HIV-1 Factor, Vânia Passos, Thomas Zillinger, Nicoletta Casartelli, Amelie S. Wachs, Shuting Xu, Angelina Malassa, Katja Steppich, Hildegard Schilling, Sergej Franz, Daniel Todt, Eike Steinmann, Kathrin Sutter, Ulf Dittmer, Jens Bohne, Olivier Schwartz, Winfried Barchet, and Christine Goffinet, Journal of Virology 2019, Epub ahead of print

Link to the open access article: https://jvi.asm.org/content/early/2019/10/03/JVI.01221-19

The discovery of an unusual hepatitis B virus from shrews offers new opportunities of better understanding the chronic progression of the disease. International research teams were able to demonstrate that an important protein which is essential for the development of a chronic course of infection is not present in this virus. DZIF scientists at the Charité – Universitätsmedizin Berlin and the University of Gießen are leading the research.

Infection with the hepatitis B virus (HBV) is one of the major global health problems. The high number of chronic cases is particularly problematic: More than 240 million people around the world are chronically infected with this virus and over 887,000 of those infected die each year of the long-term consequences such as liver cirrhosis and liver cancer. The chronification of HBV infection that often goes undetected for decades is one of the fundamental characteristics of this virus. “Discovering this unusual HBV in shrews gives us an opportunity to better understand the pathogenesis of this chronic illness,” explains lead author of the study Andrea Rasche, scientist at the Charité - Universitätsmedizin Berlin and DZIF scholarship holder of the “Maternity Leave” programme.

An important protein that is required for the chronification of the infection is not present in the virus in shrews. “Without this immunomodulator, HBeAg, the disease could not become chronic,” emphasises Prof. Dr. Jan Felix Drexler, DZIF scientist at the Charité – Universitätsmedizin Berlin and DZIF researcher in the research field “Emerging Infections”. And this applies to all known HBVs in mammals. They form this protein during the infection. This immunomodulator suppresses the body’s specific immune response to HBV so that the infection cannot heal and becomes chronic – often with very high viral concentrations in the blood. When this viral protein is not present, the body’s immune system can successfully fight the infection.

This is not the case with the newly discovered HBV in shrews. The researchers examined almost 700 shrew samples from Europe and Africa and despite the absence of HBeAg, those animals that were infected still showed high concentrations of HBV in the blood. “This indicates a very successful but unusual characteristic of the infection and the transmission of shrew HBV in its host,” explains Prof. Dr. Dieter Glebe, head of the National Reference Centre for Hepatitis B and D viruses at the Justus Liebig University of Gießen (JLU) and DZIF scientist in the research field “Hepatitis”. “Since the virus cannot infect human liver cells, it is highly unlikely that the virus can infect people.” Therefore, it can be reasonably concluded that there is no risk for humans if they come into contact with shrews infected with HBV.

Another characteristic of the newly discovered virus is that it does not use the liver bile acid transporter to enter the liver cells as is the case with HBV in humans and apes, but takes an unknown path into the cell. “This shows that we still do not know all HBV receptor molecules,” explains Prof. Drexler. In addition to these important findings about the HBV infection, the shrew virus gives us new insight into the genealogy of HBV. “Our evolutionary studies show that HBV exists in mammals for millions of years, probably around 80 million years,” says Prof. Drexler. 

The scientists now want to further examine the unusual infection pattern of shrew HBV that develops without the central immunomodulator HBeAg. Despite intensive international efforts, an effective treatment for chronic hepatitis B has yet to be developed. One reason for this is that there are no suitable animal models that can be used to examine the complex interactions of the virus infection with the host’s immune system. “Shrews could be a promising animal model for HBV research. The virus discovered here is particularly suitable for examining the mechanisms of chronic HBV infections,” says Prof. Drexler.

International collaboration

Together with the teams led by Prof. Dr. Dieter Glebe and Prof. Dr. Jan Felix Drexler, many national and international research teams are involved in the study. The work was primarily funded by the German Research Foundation (DFG) and as part of the German Centre for Infection Research (DZIF). JLU, the Charité - Universitätsmedizin Berlin, the Bernhard Nocht Institute for Tropical Medicine in Hamburg, the Friedrich Loeffler Institute in Greifswald/Riems as well as universities and institutes in Brazil, the Netherlands, Sierra Leone, Nigeria, the Ivory Coast, Latvia, Lithuania and Russia are involved in the study.

Kontakt:

Prof. Dr. Jan Felix Drexler

Institut für Virologie

Charité – Universitätsmedizin Berlin                  

t: +49 30 450 525 461

E-Mail: felix.drexler@charite.de

The Zika virus outbreak in Latin America has affected over 60 million people up to now. The infection can have potentially fatal consequences for pregnant women and their unborn children: many children have subsequently been born with malformations of the head, or so-called microcephaly. A particularly high incidence of these Zika-associated malformations exists in northeastern Brazil. DZIF scientists from Charité – Universitätsmedizin Berlin tried to find out the reasons for this regional cluster and discovered a surprising protective factor.

“We now know for sure that Zika virus infection during pregnancy can affect the unborn foetus in such a way that the child develops microcephaly and other severe symptoms,” explains Prof Felix Drexler, a virologist at the Charité who has been developing diagnostic tests for Zika and other viruses at the DZIF. Just a few years ago, pictures of affected new-borns were cause for worldwide dismay and perplexity. “However, what we did not understand then was that high incidence of microcephaly seemed to occur particularly in northeastern Brazil,” says Drexler. Why are expecting mothers in these regions at a higher risk of developing severe Zika-associated disease than in other regions? The scientists consequently began to search for cofactors that have an influence on whether a Zika infection during pregnancy will develop fatal consequences or not.

Contact:

Prof. Dr. Jan Felix Drexler

Institut für Virologie

Charité – Universitätsmedizin Berlin                  

phone: +49 30 450 525 461

mail: felix.drexler@charite.de

Links und Downloads:

Institut für Virologie: https://virologie-ccm.charite.de/

Deutsches Zentrum für Infektionsforschung (DZIF): https://www.dzif.de/de

The group of Sandra Junglen has discovered a novel virus during work on a project by the Germany Research Council (Deutsche Forschungsgemeinschaft, DFG). The virus belongs to the so-called phleboviruses which are transmitted by sandflies. The German-Kenyan team found the virus in these tiny blood-feeding insects and isolated it in the laboratory. Blood tests showed that humans can be infected. The finding may provide a novel explanation for unknown disease causes, such as in patients with fever or meningoencephalitis. The investigation of unknown causes of human disease is among the main goals of the institute of virology. 

Here is a link to the open-access article:

https://wwwnc.cdc.gov/eid/article/25/4/18-0750_article

In a recent commentary published in The Lancet Infectious Diseases, Charité virologists highlight the difficulties of obtaining reliable Zika virus diagnostics during the catastrophic outbreak that has struck Latin America since 2015. Prof. Jan Felix Drexler works on Zika virus animal reservoirs and diagnostics in the EU-funded project ZIKAlliance.

More information about the project ZIKAlliance.

The Lancet infectious diseases.

07.03.2019

Hepatitis E virus is among the most relevant courses of acute hepatitis. Only in the past few years it has become wider knowledge that the virus is also endemic in Germany. Immunocompromised patients can have prolonged courses that can complicate the outcome of organ transplantations and sometimes may even lead to death. Together with the Robert Koch Institute, our institute is coordinating a novel reserach consortium dedicated to the aspect of chronic hepatitis E in Germany. The Ministry of Health is funding the project with the amount of 671.000 Euro since February 2019.

Since the beginning of February this year, Christine Goffinet has been the BIH Professor of Virology at the Berlin Institute of Health (BIH) and the Institute of Virology at Charité – Universitätsmedizin Berlin. She is conducting research into the human immunodeficiency virus (HIV) and the chikungunya virus, an emerging virus that has also spread to Europe as a result of global warming. Goffinet, who is a biologist, has a particular interest in the communication between the virus and the host and its immune system, exploring questions like: How does the host cell defend itself from infection, and how does the virus elude this defense mechanism?

“The HIV infection can be successfully treated, but it can’t be cured,” is how Goffinet, a native of France, describes the situation of people who are HIV positive. In fact, people infected with HIV have to take medication their whole lives because the virus reappears if medication is stopped. The virus hides in dormant HIV cells by smuggling its genetic information into the chromosomes of these cells. Goffinet now wants to reawaken the dormant virus-carrying cells so that they start producing the virus again. “We will then try to kill these reactivated cells – either with the help of the body’s own immune system or through a novel treatment that uses the communication between the virus and the immune system,” is how she sums up her ambitious goal. “And it must be successful 100 percent of the time, because a single remaining HIV-positive cell is probably enough to allow the virus to start replicating itself again.

Researchers have known about the chikungunya virus for some time now as a result of disease outbreaks in Africa and Southeast Asia. It is considered an emerging virus because the infection rate is growing around the world. Like the dengue virus, it is transmitted by the Aedes mosquito, which is slowly making its way from southern to northern Europe. Those infected suffer from painful joint inflammation and bouts of fever. Normally, the immune system of the host defends itself against the virus and the symptoms abate within one to two weeks. But the infection may become chronic in some cases, with patients experiencing repeated bouts of joint inflammation. This frequently leads to persistent joint pain, which causes those affected to walk hunched over and limits their ability to move about, often leaving them unable to work. “We want to find out why some people fully recover from the virus and why the infection turns chronic in other people. Little is still known about the virus’s infection cycle; there is neither a vaccine nor special medicines,” explains Goffinet. “We know so much about HIV in comparison: There are not only established laboratory methods and laboratory systems, but also reagents and an effective treatment regimen. In the case of chikungunya, we’re largely starting from scratch. That’s what appeals to me!”

Christine Goffinet was born in France but at the age of eleven moved to Hamburg, where she completed her Abitur and studied biology at the city’s university. For her PhD she went to Heidelberg University, specifically Department of Virology, where she developed a small animal model for HIV infection. That proved difficult because the virus does not multiply in rats or mice, which meant that the model inadequately described the progression of the disease, especially the massive loss of immune cells. The rodents also do not contract AIDS in the model created by Goffinet, but their genetically modified immune cells do become infected with the virus, enabling researchers to test drugs that aim to prevent exactly that from happening. She then established her first research group at Ulm University, which also focused on HIV research. Three years later came the call from the Hannover Medical School, where she was appointed junior professor. It was during this period that Goffinet began to study the chikungunya virus in addition to the HIV virus. Christine Goffinet is married and has a daughter.

01.02.2019

The US company Clarivate Analyticdetermines the top 1% most cited scientists in 22 disciplines.

For 2006 to 2016, three members of our institute ranked among the top 1% in their field

Christian Drosten

Victor M. Corman

Marcel A. Müller

The publications that the evaluation is based on were from the university of Bonn, where all three persons were employed until 2016. Christian Drosten was among the „Highly Cited Researchers“ already during 2005-2015.

07.12.2018

Researchers from Charité – Universitätsmedizin Berlin and Justus-Liebig-Universität (JLU) Gießen have identified a new hepatitis B virus in Brazilian capuchin monkeys. Their research, which offers insights into the evolution of hepatitis B viruses in primates, suggests that the virus originated in African monkeys and was introduced to South America millions of years ago. Findings from this study have been published in the "Journal of Hepatology"*.

Hepatitis B is a viral disease that targets the liver and affects approximately 257 million people worldwide. It is caused by the hepatitis B virus (HBV), which is passed from person to person through blood or other body fluids. In a recent discovery, an international team of researchers from Germany, Brazil and Belgium found that HBV originated in nonhuman primates; more precisely, they discovered that the virus originally emerged in the African ancestors of South American monkeys. Until now, there had been no clear evidence of its evolutionary origin. As hepatitis B is not an airborne disease, it must have emerged in African monkeys, who then traveled to South America via islands in the Atlantic Ocean at a time when the coast of West Africa was much closer to South America than it is today. This conclusion is in line with previous research findings which suggest that the monkeys now found in South America have African ancestry.

"The precise details of HBV’s transmission to hominids – such as when, where and how it was transmitted – remain a mystery, though it was likely transmitted by a monkey infected with the virus," says the study’s lead researcher, Prof. Dr. Jan Felix Drexler, who heads the Virus Epidemiology Group at Charité's Institute of Virology. "What is certain, however, is that the virus we isolated in Brazilian capuchin monkeys is similar to human HBV and that it uses the same surface proteins to infect human liver cells," explains Prof. Drexler. The new virus, which the researchers named capuchin monkey hepatitis B virus (CMHBV), is only the second HBV species to have been isolated in nonhuman primates; the first one was discovered in woolly monkeys in 1998.

"So far, effective treatments for chronic hepatitis B have been few and far between," says Prof. Dr. Dieter Glebe, Director of the JLU’s National Reference Center for Hepatitis B and D Viruses. He adds: "We would like to use our insights into the CMHBV to develop new models for use in preclinical drug development research."

* de Carvalho Dominguez Souza BF et al. A novel hepatitis B virus species discovered in capuchin monkeys sheds new light on the evolution of primate hepadnaviruses. J Hepatol. 2018 Jun;68(6):1114-1122. doi: 10.1016/j.jhep.2018.01.029.

Links

Institute of Virology / Virus epidemiology Research Group

An extinct strain of the human Hepatitis B virus (HBV) has been discovered in Bronze Age human skeletons found in burial sites across Europe and Asia.

A pioneering study has identified the one of the oldest evidence of HBV in the ancient remains and proved that viruses can become extinct. The scientific significance of the research has been described as 'truly remarkable' and compared to the discovery of the first fossils.

Today the Hepatitis B virus affects millions of people worldwide. In 2015 it was estimated that approximately 257 million people were chronically infected with HBV and 887,000 died due to associated complications such as liver cancer.

The new research, led by a group of academics at the Center for Pathogen Evolution in the Department of Zoology at the University of Cambridge and the Centre for GeoGenetics at the University of Copenhagen, took genetic samples from skeletons across Europe and Asia from the Bronze Age to the Medieval period, and found 25 HBV-positive skeletons amongst the remains. In 12 of these skeletons, they found enough of the HBV genome to perform detailed analyses – the oldest of which was 4,500 years old.

From this data they were able to extract the genetic sequences of HBV that infected the individuals thousands of years ago.

The findings, published in the journal "Nature", present new insights into the origins and evolution of HBV. The genetic makeup of this strain could have implications for improving vaccines for HBV.

Before this study, the oldest human viruses to be discovered were approximately 450 years old but most are no more than 50 years old. The research now forms the oldest and largest datasets scientists have of ancient human viruses.

Barbara Mühlemann, joint first author on the research paper and a graduate student at the University of Cambridge, said: "People have tried to unravel the history of HBV for decades – this study transforms our understanding of the virus and proves it affected people as far back as the Bronze Age. We have also shown that it is possible to recover viral sequences from samples of this age which will have much wider scientific implications."

Although HBV is a global health issue, little is known about its origin and evolution. As with many human viruses, this is largely due to a lack of historical evidence which has been difficult to locate and identify.

Dr Terry Jones, joint first author who is based at the University of Cambridge's Department of Zoology, explained: "Scientists mostly study modern virus strains and we have mainly been in the dark regarding ancient sequences – until now. It was like trying to study evolution without fossils. If we only studied the animals living today it would give us a very inaccurate picture of their evolution – it is the same with viruses."

Understanding more about HBV may now be possible. Showing that the virus has been circulating in humans since at least the Bronze Age is a big scientific advancement, as previous attempts to estimate how long the virus has infected humans have ranged from 400 years to 34,000 years.

The study was led by Professor Eske Willerslev, who holds positions both at St John's College, University of Cambridge, and the University of Copenhagen.

He said: "This data gives us an idea of how this virus behaves, and it provides us with a better idea of what is biologically possible in the future. Analysis of other ancient DNA samples may reveal further discoveries and this pioneering study could have huge implications for how the virus affects humans today."

The research also shows the existence of ancient HBV genotypes in locations incompatible with their present-day distribution, contradicting previously-suggested geographical origins of the virus.

Professor Willerslev initially suspected that it might be possible to find viruses in human remains based on previous research during his role at the University of Copenhagen. He approached Mühlemann and Jones who have specialised in identifying and studying the evolution of viruses. Included in the interpretation of the results were, among others, the virologists Christian Drosten from the Institute for Virology, at Charité, Berlin, and Dieter Glebe from the National Reference Centre for Hepatitis B and D Viruses at the Institute of Medical Virology at Justus-Liebig University in Giessen.

The research approach the group used in the study, called 'shotgun sequencing', looks at all genetic material present in a sample, as opposed to 'genome bio-capture' which focuses only on the human genome.

Professor Willerslev said: "This study is just the start. We're talking about one virus here, but there are a lot of other viruses we could look for."

This text is a translation of the original news release "Oldest genetic evidence of hepatitis B virus found in ancient DNA from 4,500 year-old skeletons" of the University of Cambridge with some text changes. Text license: CC BY 4.0, photo: Alexey A. Kovalev

Links

Link to the original publication in the journal "Nature: a weekly journal of science"

Link to the original news release