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Global Virus Network (GVN) Center of Excellence TSRI Investigation Reveals First-Ever Image of Elusive Viral Protein

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Global Virus Network (GVN) Center of Excellence TSRI Investigation Reveals First-Ever Image of Elusive Viral Protein

 New Direction for Lifesaving Vaccine

LA JOLLA, CA – June 2, 2017 – Before Ebola virus ever struck West Africa, locals were already on the lookout for a deadly pathogen: Lassa virus. With thousands dying from Lassa every year—and the potential for the virus to cause even larger outbreaks—researchers are committed to designing a vaccine to stop it.

Now a team led by Staff Scientist Kathryn Hastie and Professor Erica Ollmann Saphire at The Scripps Research Institute (TSRI) has solved the structure of the viral machinery that Lassa virus uses to enter human cells. Their study, published June 2, 2017 in the journal Science, is the first to show a key piece of the viral structure, called the surface glycoprotein, for any member of the deadly arenavirus family.
Importantly, the new structure provides a guide for designing a Lassa virus vaccine.

“Studying Lassa is critically important. Hundreds of thousands of people are infected with the virus every year, and it is the viral hemorrhagic fever that most frequently comes to the United States and Europe,” said Ollmann Saphire, senior author of the new study and co-director of the TSRI Global Virus Network (GVN) Center of Excellence. “This structure gives you the blueprints to make a vaccine that would deliver antibody protection.”

Like Ebola virus, Lassa fever starts with flu-like symptoms and can lead to debilitating vomiting, neurological problems and even hemorrhaging from the eyes, gums and nose. The disease is 50 to 70 percent fatal—and up to 90 percent fatal in pregnant women.

Success in Solving the Structure

The researchers solved this structure of the Lassa virus glycoprotein using a technique called x-ray crystallography, in which researchers prompt protein molecules from a virus to align and form a crystal. When x-rays hit the electrons in the crystal, they create a diffraction pattern that reveals the organization of the crystal and the molecular structure of the protein that formed it.

The researchers quickly found that Lassa virus posed a challenge for x-ray crystallography. The technique depends on having a stable protein, yet all the Lassa virus glycoprotein wanted to do was fall apart.
The problem was that glycoproteins are made up of smaller subunits. Other viruses have bonds that hold the subunits together, “like a staple,” Hastie said. Arenaviruses don’t have that staple; instead, the subunits float away from each other. Another challenge was to recreate part of the viral lifecycle in the lab—a stage when Lassa’s glycoprotein gets clipped into two subunits. “We had to figure out how to get the subunits to be sufficiently clipped and where to put the staple to make sure they stayed together,” Hastie said.

To overcome these obstacles, Hastie created mutant versions of important parts of the molecule and engineered a version of the Lassa virus surface glycoprotein that didn’t fall apart. She then used this model glycoprotein as a sort of magnet to find antibodies in patient samples that could bind with the glycoprotein to neutralize the virus.The molecular structure of the Lassa virus glycoprotein trimer provides the blueprints for vaccine design.

The molecular structure of the Lassa virus glycoprotein trimer provides the blueprints for vaccine design.
Image credit Christina Corbaci TSRI

At last, she solved the structure of the Lassa virus glycoprotein, bound to a neutralizing antibody from a human survivor.

Hastie’s structure showed that the glycoprotein has two parts. She compared the shape to an ice cream cone and a scoop of ice cream. A subunit called GP2 forms the cone, and the GP1 subunit sits on top. They work together when they encounter a host cell. GP1 binds to a host cell receptor, and GP2 starts the fusion process to enter that cell.

The new structure also showed a long structure hanging off the side of GP1—like a drip of melting ice cream running down the cone. This “drip” holds the two subunits together in their pre-fusion state.

Zooming in even closer, Hastie discovered that three of the GP1-GP2 pairs come together like a tripod. This arrangement appears to be unique to Lassa virus. Other viruses, such as influenza and HIV, also have three-part proteins (called trimers) at this site, but their subunits come together to form a pole, not a tripod.

“It was great to see exactly how Lassa was different from other viruses,” said Hastie, 10 years after starting the project. “It was a tremendous relief to finally have the structure.”

This tripod arrangement offers a path for vaccine design. The scientists found that 90 percent of the effective antibodies in Lassa patients targeted the spot where the three GP subunits came together. These antibodies locked the subunits together, preventing the virus from gearing up to enter a host cell.

A future vaccine would likely have the greatest chance of success if it could trigger the body to produce antibodies to target the same site.

 

 

Antibody from a human survivor (turquoise) is shown inactivating the Lassa virus surface protein. The work shows how to engineer vaccine strategies to elicit protective immune responses. Image credit Christina Corbaci TSRI

 

Moving Forward with a Lassa Vaccine

The next step is to test a vaccine that will prompt the immune system to target Lassa’s glycoprotein. As director of the Viral Hemorrhagic Fever Immunotherapeutic Consortium, Ollmann Saphire is already coordinating with her partners at Tulane and Kenema to bring a vaccine to patients.

The Coalition for Epidemic Preparedness Innovations (CEPI), an international collaboration that includes the Wellcome Trust and the World Health Organization as partners has recently named a vaccine for Lassa virus as one of its three top priorities. “The community is keenly interested in making a Lassa vaccine, and we think we have the best template to do that,” said Ollmann Saphire.

She added that with Hastie’s techniques for solving arenavirus structures, researchers can now get a closer look at other hemorrhagic fever viruses, which cause death, neurological diseases and even birth defects around the world.

In addition to Ollmann Saphire and Hastie, authors of the study, “Structural basis for antibody-mediated neutralization of Lassa virus,” were Michelle A. Zandonatti of TSRI; James E. Robinson and Robert F. Garry of Tulane University and Director of Tulane’s GVN Center of Excellence; Lara M. Kleinfelter and Kartik Chandran of the Albert Einstein College of Medicine; and Megan L. Heinrich, Megan M. Rowland and Luis M. Branco of Zalgen Labs.

The study was supported by the National Institutes of Health (grants 1U19AI109762-01, R21 AI116112 and contract HHSC272200900049C) and an Investigators in Pathogenesis of Infectious Diseases Award from the Burroughs Wellcome Fund.

TSRI and Tulane University are Centers of Excellence in the Global Virus Network (GVN), which represents 38 Centers of Excellence and six affiliates in 24 countries and comprises foremost experts in every class of virus causing disease in humans.   The GVN is a global authority and resource for the identification and investigation, interpretation and explanation, control and suppression, of viral diseases posing threats to mankind.  It enhances the international capacity for reactive, proactive and interactive activities that address mankind-threatening viruses and addresses a global need for coordinated virology training through scholarly exchange programs for recruiting and training young scientists in medical virology.  The GVN also serves as a resource to governments and international organizations seeking advice about viral disease threats, prevention or response strategies, and GVN advocates for research and training on virus infections and their many disease manifestations.

Pioneers in Infectious Agents and Cancer Meeting in Naples March 22-23, 2017

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The Institute Naz. – Tumori Fondazione Pascale, in partnership with GVN and the online journal Infectious Agents and Cancer, hosted the “Pioneers in Infectious Agents and Cancer Meeting” in Naples March 22-23, 2017  to honor GVN’s Co-Founder & Scientific Director, Robert Gallo, MD, in celebration of his 80th Birthday.

https://sites.google.com/site/infectagentscancer1/iac/pioneers-in-infectious-agents-and-cancer

Global Virus Network (GVN) Announces Seven Distinguished International Appointments to Board of Directors

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Global Virus Network (GVN) Announces Seven Distinguished  International Appointments to Board of Directors

World leaders in business & science are committed to supporting the GVN

Baltimore, MD (March 22, 2017) – The Global Virus Network (GVN), a coalition of the world’s leading medical virology research centers working together to prevent illness and death from viral disease, today announced the addition of seven distinguished global leaders to its Board of Directors, including Lawrence Blatt, PhD, Global Head of Infectious Diseases, Jansen Pharmaceuticals and President and CEO, Alios Biopharma; Peter Palese, PhD, Horace W. Goldsmith Professor and Chair Department of Microbiology, Professor, Department of Medicine Icahn School of Medicine at Mount Sinai; Pierluigi Petrone, CEO, Petrone Group; Guangqi Tian, President, Sino Invest Group Limited; Guy Vernet, PhD, Scientific Director, Fondation Mérieux; Danny Wong, Founder and Chairman, Medisun and Chairman, Beijing Financial Group Limited; and, Koichi Yamanishi, MD, Director General, Research Foundation for Microbial Diseases of Osaka University (Biken). The announcement was made today by Robert Gallo, MD, Co-founder and Director, Global Virus Network (GVN) and Homer & Martha Gudelsky Distinguished Professor in Medicine, Director, Institute of Human Virology at the University of Maryland School of Medicine, a GVN Center of Excellence.

“GVN will benefit greatly with each new Board members’ expertise and tremendous success in leading prosperous organizations and ventures around the globe,” said Robert Gallo, MD, who is world renowned for his co-discovery of HIV as the cause of AIDS and development of the HIV blood test. “We look forward to working with our new and current board members as we expand GVN’s collaborations with government entities, the public and private sectors, and most recently with the pharmaceutical industry to advance biomedical research and train the next generation of medical virologists while addressing the world’s most pressing viral threats, such as Zika, Ebola, influenza, and HIV to name a few.”

“I am pleased and honored to be joining the GVN Board, whose mission to address global public health threats relating to established and emerging viruses, is well aligned to my personal goals and aspirations,” said Lawrence Blatt, PhD, Global Head of Infectious Diseases, Jansen Pharmaceuticals and President and CEO, Alios Biopharma both in San Francisco, CA, USA.  “Viral infections account for significant morbidity and mortality throughout the world and the GVN is establishing a worldwide community to facilitate cooperation among physicians, scientists and healthcare workers.” Dr. Blatt has spent the last 30 years working in drug research and development with a specific focus on biology of the immune system, antiviral therapies and relevant therapeutic interventions including among other discoveries the development of Danoprevir®, an HCV protease inhibitor, in partnership with Roche.

“The question regarding novel emerging viral pathogens is not if – but when,” said Peter Palese, PhD, Horace W. Goldsmith Professor and Chair, Department of Microbiology, Professor, Department of Medicine, Icahn School of Medicine at Mount Sinai in New York, NY, USA.  Dr. Palese’s groundbreaking research includes designing the next-generation of flu vaccines that provoke a more robust and durable immune response to a wide variety of influenza viruses – a feat that aims to produce a broadly protective universal vaccine that not only saves lives but eliminates the need for annual revaccination and associated costs.  Dr. Palese is also Director of the GVN Center of Excellence at the Icahn School of Medicine at Mount Sinai and a Member of the National Academy of Sciences and the National Academy of Medicine (IOM).

 

“I am proud and happy to join this interesting and motivating Board of Directors,” said Pierluigi Petrone, CEO, Petrone Group, a Naples, Italy holding company of approximately 30 firms operating in the pharmaceutical and health sectors.  “I will try to liaise scientific evidences with manufacturing processes, allowing pharmaceutical companies to approach new useful products to move forward against dangerous and undiscovered infections worldwide.”  Mr. Petrone is also Chairman of STM Group Logistica Integrata and a Business Relation Officer of Pierrel S.p.A which collectively encompass the life science, biopharma and pharmaceutical industries.

“As basic biomedical and behavioral research make it possible to more accurately characterize the causes of viral disease onset and progression,  I am honored to serve the GVN with all my knowledge and energy to accelerate the process of scientific discovery and research to development and optimization of therapeutics to test in human trials, ultimately, to the application of the approved therapy, device, or diagnostic in the real world,” said Guangqi Tian, President, Sino Invest Group Limited.  Mr. Tian founded multiple companies in cities in China including Harbin, Tianjin, and Beijing since 2005 and owns businesses in Beijing, Tianjin, Hong Kong, U.S., Panama, and Dubai which include international trade and investment.

“I am convinced that it is only by gathering experts and leaders from different disciplines, from the public and private sectors, in networks like the GVN that we will defeat deadly viral diseases,” said Guy Vernet, PhD, Fondation Mérieux, USA.  “Laboratories and diagnostics are key components of public health response to epidemic infectious diseases, especially in resource-limited, tropical countries and I am honored to have a chance to contribute, with my experience in this domain, to the objectives of the GVN.” Dr. Vernet has been Director General of the Pasteur Institute in Yaoundé, Cameroon and Scientific Director of Fondation Mérieux in Lyon, France. He previously held several positions within the R&D Department of bioMérieux, and led many research projects with the goal to improve the diagnosis of major human pathologies, particularly HIV infection, hepatitis and tuberculosis.

“Today’s rapid spread of viral diseases in the world endangers human health, and it is critical to pull together all the resources we have to reduce and eliminate the threat by conducting more cutting edge R&D and translational medicine,” said Danny Wong, Founder and Chairman, Medisun and Chairman, Beijing Financial Group Limited.  “I am thrilled to join the GVN alongside others to tackle this issue.”  Mr. Wong has over 20 years of experience in investment including successfully launching dozens of high-tech companies in Hong Kong and founding the first venture capital company in China.

“I am pleased to join the GVN Board of Directors and advance the mission of the GVN in its efforts to combat viral threats,” said Koichi Yamanishi, MD, Director General, Research Foundation for Microbial Diseases of Osaka University (Biken) in Osaka, Japan. “I look forward to working with my colleagues in Japan and Asia to expand collaborative efforts established during GVN’s annual meeting held in Sapporo last fall.”  Dr. Yamanishi’s laboratory studies includes novel advances in both human herpes virus (HHV) research, especially HHV-6, and varicella zoster virus.

 

While new Board members will advise the GVN on many issues, they will also lead efforts in their areas of expertise.  Dr. Lawrence Blatt will garner business, financial and scientific support for viral therapies; Dr. Peter Palese will garner business, financial and scientific support in influenza initiatives, in addition to his responsibilities as a GVN Center of Excellence Director; Mr. Pierluigi Petrone will garner business and financial support from manufacturers globally; Mr. Guangqi Tian will garner business, financial and scientific support in China; Dr. Guy Vernet will garner business, financial and scientific support for diagnosis of viral diseases globally and especially resource-limited countries; Mr. Danny Wong will garner business, financial and scientific support in Asia; and, Dr. Koichi Yamanishi will cultivate business, financial and scientific relationships in Japan and Asia.

Gilead Sciences Awards $148K to the Global Virus Network (GVN) to Combat Hepatitis C Virus (HCV) in Remote Regions of India The pilot study will build specific training models to test, link and treat specialized HCV patient populations in high prevalence regions of India

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Gilead Sciences Awards $148K to the Global Virus Network (GVN) to Combat Hepatitis C Virus (HCV) in Remote Regions of India

The pilot study will build specific training models to test, link and treat specialized HCV patient populations in high prevalence regions of India

Baltimore, Maryland, USA, March 1, 2017: The Global Virus Network (GVN), representing 38 Centers of Excellence and six affiliates in 25 countries and comprising foremost experts in every class of virus causing disease in humans, was awarded $148,000 by Gilead Sciences, Inc. to develop and implement a sustainable program for testing, treating and linking to care hard to reach patient populations in India. The announcement was made today by Robert C. Gallo, MD, Co-Founder, Scientific Director, GVN, The Homer and Martha Gudelsky Distinguished Professor in Medicine, Director, Institute of Human Virology (IHV) at the University of Maryland School of Medicine, a GVN Center of Excellence, and Shyamasundaran Kottilil, MBBS, PhD, who will lead this study and is Professor of Medicine, Co-Director, Clinical Research Unit, Associate Director for Clinical Research, IHV.

“We are grateful to Gilead for their continued leadership in, among other efforts, making medication and affordable healthcare a priority around the world, and in this particular case with escalation of novel hepatitis C virus treatment in India,” said Dr. Robert Gallo, who is renowned for his co-discovery of HIV as the cause of AIDS and development of the HIV blood test. “Dr. Kottilil is a leader in the field who can take on challenging variables and successfully bring effective, sustainable healthcare and treatment models to low resource communities around the globe.”

The proposed study utilizes a model of building local capacity through high-level clinical mentoring to 80 physicians who are then responsible for mentoring more than 500 healthcare workers throughout the country to significantly decrease HCV prevalence. The project focuses on building specific training for specialized populations including patients with injection drug use and community clinic patients as well as considerations in varying settings such as urban versus rural.

“The purpose of this program is to develop an HCV training model for medical providers in India that can be duplicated and applied to other areas within South Asia,” said Dr. Kottilil. “Generic medications for the treatment of hepatitis C are already available and approved to use in India.”

“We are pleased to support the Global Virus Network, an organization that shares our goal of addressing the world’s biggest health challenges,” said Gregg Alton, Executive Vice President, Corporate and Medical Affairs.  “In India, the majority of the population lives in rural areas where hepatitis screening is limited. This initiative will support education efforts that will help increase routine hepatitis C screening, which is essential to slowing and ultimately ending the epidemic in India.”

In the past couple of years, oral, interferon-free, directing agents (DAAs) have emerged resulting in an effective HCV cure.  At this time, only a few providers worldwide have experience in the management of HCV with interferon/ribavirin, and there are no infectious disease specialists in India with experience using the DAAs.

“Despite high HCV disease burden in many parts of Asia, no studies exist, to date documenting diagnostic and treatment outcomes of DAAs such as sofosbuvir in a real-world context in this region said Dr. Kottilil. “We are pleased to partner with our colleagues in India to accelerate HCV care continuum. On paper, we can rid the world of HCV but to do so, we must innovate proven, effective community driven outreach models that educate, test, treat and link to care the most vulnerable populations like those we are reaching through this grant.”

Global Virus Network Inspires New Collaborations to Combat Viral Threats During Meeting of Top Medical Researchers

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Dr. Ab Osterhaus Presented with The GVN Robert C. Gallo Award for Scientific Excellence and Leadership

Baltimore, MD, November 17, 2016: The Global Virus Network (GVN), a coalition of the world’s leading medical virology research centers working together to prevent illness and death from viral disease, held its 8th meeting in Sapporo, Japan late last month in partnership with the Japanese Society of Virology, the National Institute of Infectious Diseases (NIID) in Tokyo, Japan and the Research Center for Zoonosis Control (CZC) at Hokkaido University in Sapporo, Japan. At a time when new pandemics caused by viruses such as Zika and virulent reemerging threats such as Ebola are on the rise, top international researchers shared compelling data to inspire new collaborations and address public health crises. Viruses dominating discussions also included, among others, human papilloma virus (HPV), influenza, Lassa virus, dengue virus, human immunodeficiency virus (HIV), hepatitis viruses, chikungunya virus, and human T cell leukemia virus (HTLV).

“This year’s program included some of the most interesting and robust research data that I have seen since GVN’s inception,” said Robert Gallo, MD, Co-Founder and Scientific Director of the GVN and Director of the Institute of Human Virology at the University of Maryland School of Medicine, a GVN Center of Excellence, in Baltimore, Maryland, USA. “I was equally impressed with the enthusiasm and creative ideas put forth by our members that will strengthen GVN’s reach both scientifically and regionally. Their commitment to advancing GVN’s mission is inspiring.” He continued, “Further, I want to extend my gratitude to our GVN colleagues Hideki Hasegawa, MD, PhD, Director of the Department of Pathology of Japan’s National Institute of Infectious Diseases and Hirofumi Sawa, MD, PhD, Deputy Director and Professor of Molecular Pathobiology at the Research Center for Zoonosis Control (CZC) at Hokkaido University for their gracious hospitality and for co-hosting a profoundly productive meeting.”

“We were pleased that the Japanese Society of Virology partnered with the GVN to host this year’s meeting in Sapporo,” said Drs. Hasegawa and Sawa. “We heard from many Japanese researchers who benefited from the exposure to GVN’s elite virus researchers, and we hope that those contacts facilitated through this meeting are utilized as Japanese virologists advance their own laboratory research.”

During the meeting, the GVN presented Ab Osterhaus, DVM, PhD, Director of the University of Veterinary Medicine Hannover in Hannover, Germany, a GVN Center of Excellence, with The GVN Robert C. Gallo Award for Scientific Excellence and Leadership for his pioneering contributions in influenza and coronavirus research as well as his contributions to advancing the GVN mission.

“Dr. Osterhaus is most deserving of this honor with his decades long career including, among many other important contributions, discovering more than 50 new viruses in humans and animals and helping the World Health Organization to effectively combat outbreaks including SARS and pandemic influenza,” said William Hall, MD, PhD, Co-founder of the GVN and Professor of Microbiology at the University College Dublin, a GVN Center of Excellence in Dublin, Ireland. “Dr. Osterhaus has also been a leader in the GVN by actively participating in our international meetings and short course programs, and providing ongoing scientific analyses and updates on viral threats.”

Dr. Gallo continued, “I respect Dr. Osterhaus for his important basic science contributions in medical virology and his ability to translate those contributions into broad public health initiatives. He is a true leader and the GVN values both his intellect and his friendship.”

In addition to honoring Dr. Osterhaus, GVN Centers of Excellence reviewed strategies propelling the GVN forward, including engaging new scientific communities, the launch of a new GVN Task Force, and the exchange of ideas on training programs that address new and existing viral threats.

“Since many GVN Centers of Excellence are working with animal pathogens, I believe the GVN will benefit from increased partnerships with veterinary research institutes working on epizootic animal diseases,” said Joaquim Segalés, DVM, PhD, Director of the Centre de Recerca en Sanitat Animal (CReSA-IRTA) located at the Universitat Autònoma de Barcelona (UAB) in Barcelona, Spain. “I will help lead the GVN in cultivating these important collaborations with organizations that can provide a number of new possibilities in better preventing future animal to man outbreaks.”

The GVN Zika Task Force Chair Scott Weaver, MS, PhD, who is also Director of the University of Texas Medical Branch’s Institute for Human Infections and Immunity and Scientific Director of the Galveston National Laboratory, a GVN Center of Excellence in Galveston, Texas, USA, introduced GVN members to the Task Force’s latest Zika serum bank initiative. The Task Force, comprising 28 top Zika experts from around the world, serves as a catalyst for driving communication and information flow between fellow GVN colleagues researching and responding to the Zika epidemic gripping the world.

“As many of you know, a major obstacle to understanding and controlling the Zika epidemic is affordable, accurate diagnostics,” said Dr. Weaver. “The Zika serum bank will help alleviate this obstacle. We hope to assemble a collection of at least 25 sera, each in quantities to supply 25 or more investigators, and we will ensure that these precious samples are made available to the worthiest requestors worldwide,” said Dr. Weaver.

Peter Palese, PhD, Chair of the Department of Microbiology at Icahn School of Medicine at Mount Sinai, a GVN Center of Excellence in New York, New York, USA, facilitated discussions on fostering international partnerships among GVN members to address the worldwide problem of influenza. “My colleagues and I are working to design the next-generation of flu vaccines that provoke a more robust and durable immune response to a wide variety of influenza viruses,” said Dr. Palese. “I believe we can achieve this feat. A broadly protective universal vaccine will not only save lives, but it will eliminate the need for annual revaccination while saving enormous amounts of money in associated costs.”

Sharon Lewin, FRACP, PhD, Director of the GVN Center of Excellence, The Peter Doherty Institute for Infection & Immunity at The University of Melbourne & Royal Melbourne Hospital, announced that GVN’s 9th international meeting will be held next year in Melbourne, Australia. “Australia is looking forward to welcoming GVN members to Australia in the Fall of 2017,” said Dr. Lewin. “We will boost GVN’s annual meeting program and design next year’s agenda to include a day dedicated to the next generation of medical virologists. It is incumbent upon us, the members of the GVN, to look for new ways to mentor rising medical virologists so that the world is better prepared against viral threats in the years to come.”