News

New insights into the anti HIV-1 restriction factor SERINC5

The gene-edited Jurkat clone P1E8, labelled with Cell TrackerTM Red CMTPX Dye and immunostained with anti-HA (red fluorescence, shows endogenous SERINC5). PFA-fixed were analyzed by confocal microscopy.

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

Hepatitis B: Unusual virus discovered in shrews

Scientists discovered an unusual Hepatitis B virus in shrews, that offers new opportunities of better understanding the disease. © Ulrike Rosenfeld

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 CharitéUniversitätsmedizin 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 - University Medicine 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 – University Medicine 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

CharitéUniversitätsmedizin Berlin                  

t: +49 30 450 525 461

E-Mail: felix.drexler@charite.de

 

 

 

Early Dengue Virus Infection could “defuse” Zika Virus

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 CharitéUniversitätsmedizin 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

CharitéUniversitätsmedizin 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

Novel virus discovered in Kenya

Study site in Kenya. Red: place where the virus was found. Blue: places where blood samples were taken.

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

 

Comment on Zika virus diagnostics

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

New research project on hepatitis E virus started

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.

 

Professor Christine Goffinet joins the institute

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 CharitéUniversitätsmedizin 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

Three „Highly Cited Researchers“ at our institute

The US companyClarivate 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

Identification of a novel hepatitis B virus in capuchin monkeys

Researchers from CharitéUniversitätsmedizin 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

Charité Institute of Virology contributes to historical findings on genetic evidence of Hepatitis B virus in ancient DNA from 4,500 year-old skeletons

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

Institue of Virology: Location