ROBERT GALLO OF THE UM SCHOOL OF MEDICINE INSTITUTE OF HUMAN VIROLOGY AND GLOBAL VIRUS NETWORK AWARDED TOP LIFE SCIENCES AND MEDICINE PRIZE FROM CHINA

Baltimore, Maryland, USA, December 21, 2020: Robert C. Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor in Medicine, co-founder and director of the Institute Human Virology at the University of Maryland School of Medicine and co-founder and international scientific advisor of the Global Virus Network, was awarded the “VCANBIO Award for Biosciences and Medicine,” a significant and authoritative award in the life sciences and medicine field of China.  The elite Prize is jointly presented by the University of Chinese Academy of Sciences and the VCANBIO CELL & GENE ENGINEERING CORP, LTD to push forward scientific research, technological innovation and continuous development in the life sciences and medicine field of China.

“The Prize also serves to facilitate the industrial development and application of innovative life science achievements,” said George F. Gao, DVM, DPHIL (OXON), Director General of the Chinese Center for Disease Control and Prevention (China CDC), Director, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Professor, Institute of Microbiology, Dean of the Medical School of the Chinese Academy of Sciences and Director of China’s Global Virus Network Center of Excellence.  “Dr. Gallo is a pioneer in virus research and most worthy of this Prize.  We are pleased to see him recognized by many members of the Chinese Academy of Sciences.”

“Hosted by the Medical School of the University of Chinese Academy of Sciences, this award commends outstanding and innovative Chinese and foreign scientists, who have accomplished innovation achievements and breakthroughs in the life sciences and medicine field,” said Yiming Shao, MD, the Chief Expert on AIDS, China CDC, Director of the Division of Research on Virology and Immunology, National Center for AIDS/STD Control and Prevention, China and Member of the GVN SARS-CoV-2 Task Force and China GVN.  “I have worked with Dr. Gallo through the decades and admire his intellect and leadership, which have led to discoveries that have broad implications in protecting mankind from viral threats.  I am delighted that my Chinese colleagues are recognizing him with this significant honor.”

“Prof. Gallo has made a great deal of contribution to promote the Sino-American friendship and collaboration, especially for medical talent training and public health in China,” said Prof. Guanhua Xu, Chairman of the selection committee of the VCANBIO Award for Biosciences and Medicine.

“This is a tremendous and well-deserved honor for Dr. Gallo,” said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, the John Z. and Akiko K. Bowers Distinguished Professor, and Dean, University of Maryland School of Medicine.  “Dr. Gallo has dedicated his career to building international collaborations that have produced major scientific discoveries in human virology, including with leading scientists and academic colleagues in China. As a result, the Institute of Human Virology continues to be recognized as the global leader in the fight against chronic viral diseases.

“I am humbled and honored to receive this esteemed Prize from my colleagues in China,” said Dr. Robert Gallo“I take this opportunity to stress that it is imperative that government and politics not interfere with science, and that my Chinese and American colleagues, who have a long history of collaborating together and contributing scientific breakthroughs to protect humanity from global health threats, continue to have the freedom to do so and to grow these collaborations.”

A Distinguished Scientific Career Advancing Global Health

Dr. Robert Gallo has long believed in the necessity of international cooperation and collaboration in medical sciences in general, and infectious diseases in particular, in part to build global friendships and advance humanitarian principles. Though entertainment and sports facilitate such connections he believes the “knots” are tied best through medical sciences. Throughout his 30 years at the National Institutes of Health (NIH) and more recently his nearly 25 years at Baltimore’s Institute of Human Virology (IHV) at the University of Maryland School of Medicine, he has fostered these connections.  First, through his pioneering scientific discoveries including his discovery in 1976 of Interleukin-2, the first cytokine, a growth regulating substance now used as immune therapy in some cancers and in autoimmune diseases when suppressive T cells are needed.  Then in 1980, the first human retrovirus, HTLV-1, a cause of human leukemia and paralytic neurological diseases as well as severe inflammatory disorders, which is endemic in some regions such as parts of Africa, the Caribbean Islands, Japan, Aboriginal Australians, Iran and South America. Dr. Gallo and his team developed a blood test for HTLV-1 applicable to all countries which protects people receiving blood transfusions that would be contaminated with this virus. Similarly, in 1984, when he and his team co-discovered HIV as the cause of AIDS they also developed the HIV blood test for the world and made their reagents available to all.  Dr. Gallo and his team established collaborations in HIV/AIDS research, education, therapy and care for many African countries, particularly in Nigeria and some Caribbean nations. During the current pandemic he quickly became involved in initiating preventive measures against SARS-CoV-2 and COVID-19 disease through the idea of stimulating innate immunity with “live” virus vaccines such as the oral polio vaccine. Dr. Gallo, abetted by his collaborator, Konstantin Chumakov, PhD, Associate Director for Research for the U.S. Food and Drug Administration’s (FDA) Office of Vaccines Research and Review and a GVN Center Director and his clinical colleague, Shyam Kottilil, MBBS, PhD, professor of medicine and director of the Clinical Care and Research Division of the Institute of Human Virology at the University of Maryland School of Medicine and senior advisor at the GVN, are advising on trials in India and in discussion about trials in Mexico, Brazil, Uzbekistan and China. He has also fostered the international nature of his research by hosting students beyond the U.S., including post-doctoral senior scientists from Asia, Middle East, Europe, the Americas and many African nations.

However, nothing demonstrates his concern for medical science cooperation more than when he established the idea for the Global Virus Network (GVN), which he co-founded in 2011 with the late Prof. Reinhard Kurth, MD, formerly Director of the Robert Koch Institute in Berlin, and Prof. William Hall, BSc, PhD, MD, DTMH, of University College Dublin. Now, GVN is headed by its President Christian Bréchot, MD, PhD.  The GVN was formed to advance medical and zoological science without any government influence, giving members of the GVN maximum freedom to speak freely while encouraging all nations to be involved. China, among several dozen other countries, has an active Center of Excellence within the GVN and was the site of the 7th meeting of the GVN in May 2015 held in Beijing and hosted by the late GVN Center Director, Zeng Yi of Beijing University of Technology. Experts shared information on varying viral threats, including those causing hemorrhagic fevers, hepatitis, HIV, measles, influenza, dengue and chikungunya, to name a few. GVN members also reviewed strategies at the center of the organization including the creation of specialized task forces and the launch of training programs to address growing viral threats.

A History with Chinese-American Collaborations

Dr. Gallo had a deep friendship with Dr. Robert Ting who came to the U.S. as a child refugee from Shanghai during the Japanese invasion. As a student, Dr. Ting worked with the famous Italian molecular biologist, Dr. Salvatore Luria at MIT, who won a Nobel Prize. Dr. Ting then went to Caltech to work with another Italian Nobel Prize winner, Dr. Renato Dulbecco and they were joined by two others who were soon to be Nobel Prize winners, Drs. Howard Temin and David Baltimore. Dr. Ting was not just Dr. Gallo’s friend but also his teacher by introducing him to Chinese culture and food, tennis, and the field of virology. Soon after meeting Dr. Ting, another Chinese-born and educated young man, Dr. Alan Wu, came to Dr. Gallo’s lab from Toronto bringing with him the knowledge and skills of blood stem cells. There were then several other Chinese post-doctoral fellows culminating with Dr. Flossie Wong-Staal from Canton Province and who played a very major role in advancing molecular biology on Dr. Gallo’s team for about 15 years. Dr. Nancy Chang, also Chinese, came as a visiting scientist on a few occasions. On one such time she was key to the development of the second-generation HIV blood test used around the world.

In 2009, with the help of a University of Maryland School of Medicine colleague, Dr. Richard Zhao, born in China and educated in the U.S., the Shandong Academy of Medical Sciences (SAMS) announced the establishment of the Shandong Gallo Institute of Virology (SGIV). The announcement was made simultaneously with a ceremony to establish China’s first Molecular Diagnostic Center for Personalized Healthcare (MDCPH), which was a joint venture among the University of Maryland, Baltimore, Roche Diagnostics Asia Pacific and SGIV at the Shandong Academy of Medical Sciences. The mission of the SGIV is to promote the basic science of virology especially in the area of HIV/AIDS and other important and emerging viral diseases and to facilitate translational research and clinical trials for related diseases. SGIV also aims to provide molecular-based testing for disease diagnosis, prognosis and treatment in the area of individualized molecular testing for personalized medicine.

Since the founding of the Institute of Human Virology (IHV), Dr. Gallo notes that several of his key science leaders at the Institute of Human Virology came from China, including: Dr. Wuyuan Lu (recent Director of the Division of Infectious Agents and Cancer), Dr. Yang Liu (recent Director of the Division of Immunotherapy), Dr. Pan Zheng (Division of Immunotherapy), Dr. Lishan Su (current Director of the Division of Virology, Pathogenesis and Cancer), Dr. Man Charurat (current Director of the Division of Epidemiology and Prevention and Ciheb) and Dr. Lai-Xi Wang (formerly at IHV and now at University of Maryland, College Park).  With each of these leaders also came labs full of Chinese colleagues, who Dr. Gallo states contributed greatly to advancing America’s biomedical research.  Further, over the past six decades, Dr. Gallo visited China countless times to discuss potential collaborations with public and private sector entities, mentored rising Chinese scientists and facilitated open scientific discussions to advance the field of human virology, among other important things.

About the Institute of Human Virology

Formed in 1996 as a partnership between the State of Maryland, the City of Baltimore, the University System of Maryland, and the University of Maryland Medical System, the IHV is an institute of the University of Maryland School of Medicine and is home to some of the most globally-recognized and world-renowned experts in all of virology. The IHV combines the disciplines of basic research, epidemiology, and clinical research in a concerted effort to speed the discovery of diagnostics and therapeutics for a wide variety of chronic and deadly viral and immune disorders – most notably, HIV the virus that causes AIDS. For more information, visit www.ihv.org and follow us on Twitter @IHVmaryland.

About the Global Virus Network (GVN)

The Global Virus Network (GVN) is essential and critical in the preparedness, defense and first research response to emerging, exiting and unidentified viruses that pose a clear and present threat to public health, working in close coordination with established national and international institutions. It is a coalition comprised of eminent human and animal virologists from 57 Centers of Excellence and 11 Affiliates in 33 countries worldwide, working collaboratively to train the next generation, advance knowledge about how to identify and diagnose pandemic viruses, mitigate and control how such viruses spread and make us sick, as well as develop drugs, vaccines and treatments to combat them. No single institution in the world has expertise in all viral areas other than the GVN, which brings together the finest medical virologists to leverage their individual expertise and coalesce global teams of specialists on the scientific challenges, issues and problems posed by pandemic viruses. The GVN is a non-profit 501(c)(3) organization. For more information, please visit www.gvn.org. Follow us on Twitter @GlobalVirusNews

Media Contact:
Nora Samaranayake
443-823-0613
[email protected]

 

GLOBAL VIRUS NETWORK COMMENDS THE PHARMACEUTICAL INDUSTRY FOR UNPRECEDENTED COVID-19 VACCINE ADVANCES

Recommends Large-scale Vaccination To Thwart The Pandemic

Baltimore, Maryland, USA, December 16, 2020:  The Global Virus Network (GVN), a coalition comprised of the world’s preeminent human and animal virologists from 59 Centers of Excellence and 10 Affiliates in 33 countries, working collaboratively in the preparedness, defense and first research response to emerging, exiting and unidentified viruses that cause illness and death, commends the pharmaceutical industry for its unprecedented efforts and advances in developing vaccines to thwart the COVID-19 pandemic.

“The wait for a vaccine is over,” said Dr. Christian Bréchot, President of GVN and Professor at the University of South Florida’s Morsani College of Medicine. “We applaud the latest developments in the vaccine rollout and implementation, and we commend the various governmental regulatory agencies around the world that have worked round-the-clock with scientists and pharmaceutical companies in the development and distribution of COVID-19 vaccines. We are particularly gratified that those on the frontlines and the most vulnerable among us will receive first access to the COVID-19 vaccines,” Dr. Bréchot added.

GVN also emphasizes the need to monitor ongoing vaccination programs regarding side effects, duration of protection, potential impact of viral genome mutations and actual impact on transmission of the virus as important findings in the coming days and months. Also GVN emphasizes the need to provide vaccine availability to all countries.

In this context, while news of the vaccine rollout is an uplifting one, the scientists and virologists of the GVN are concerned about anti-vaccination sentiments in the global population. Recent polls in the U.S. suggest that around 25% of respondents claim they will not obtain the vaccines while another 25% indicate that they are only “considering” doing so. These figures are even higher in some parts of Europe.

Though the highly infectious SARS-CoV-2 that induces COVID-19 has an overall low mortality rate, more than 75 million people have been affected by this pandemic so far, with 1.6 million deaths globally and over 300,000 deaths in the US[1]. The COVID-19 pandemic has overwhelmed the world’s healthcare, economic, sociological, and political infrastructures, and its long-term consequences will be extremely hard to manage, if the general public refrain from getting vaccinated.

Moreover, approximately 30-40% of patients who have recovered from COVID-19 show respiratory problems three months after apparent recovery, and the same holds true for symptoms such as anosmia (loss of smell) or agueusia (loss of taste). Additionally, the mortality rates are significantly higher in older individuals as well as in those with chronic diseases such as diabetes, obesity, cardiovascular and pulmonary disorders, among other co-morbidities. In addition to mortality, COVID-19 induces a still underappreciated high rate of pulmonary and vascular disorders which can have long term effects.

In this context, the recent unprecedented progress on vaccines against COVID-19 has provided some initial sense of insight and hope as to how we can contain the pandemic now and in the future. Championed by GVN leadership since the beginning of the pandemic, the concept of innate immunity and non-specific effects of vaccines such as Oral Polio Virus (OPV), measles and BCG vaccines are existing tools that can help bridge gaps until classical vaccines are developed and distributed and can serve to prevent the spread of future viral threats.

“Many of my GVN colleagues and I believe that innate immunity plays an important role in protection against COVID-19, and as such we have taken the live attenuated vaccine of measles, mumps, rubella (MMR) to stimulate protection until an effective, long-lasting vaccine is available,” said Dr. Robert Gallo, The Homer & Martha Gudelsky Distinguished Professor in Medicine, Co-Founder and Director, Institute of Human Virology (IHV) at the University of Maryland School of Medicine and Co-Founder and International Scientific Advisor of the Global Virus Network (GVN). “We would have taken the oral polio vaccine, but it was not widely available. We need to change this.  As soon as this new COVID-19 vaccine is available, I will be taking it alongside not just my colleagues but all my family members as well.”

Finally, GVN, including centers in Africa, Asia, Europe, Latin America and the Caribbean and North America emphasized that curbing the pandemic will take time and that vaccination should not exclude the importance of wearing masks, maintaining social distance, avoiding gatherings and frequent hand washing.

[1] Johns Hopkins Coronavirus Resource Center, coronavirus.jhu.edu., https://coronavirus.jhu.edu/map.html

#          #          #          #

About the Global Virus Network (GVN)
The Global Virus Network (GVN) is essential and critical in the preparedness, defense and first research response to emerging, exiting and unidentified viruses that pose a clear and present threat to public health, working in close coordination with established national and international institutions. It is a coalition comprised of eminent human and animal virologists from 57 Centers of Excellence and 11 Affiliates in 33 countries worldwide, working collaboratively to train the next generation, advance knowledge about how to identify and diagnose pandemic viruses, mitigate and control how such viruses spread and make us sick, as well as develop drugs, vaccines and treatments to combat them. No single institution in the world has expertise in all viral areas other than the GVN, which brings together the finest medical virologists to leverage their individual expertise and coalesce global teams of specialists on the scientific challenges, issues and problems posed by pandemic viruses. The GVN is a non-profit 501(c)(3) organization. For more information, please visit www.gvn.org. Follow us on Twitter @GlobalVirusNews

GVN MEDIA CONTACTS:
Chandrani Raysarkar
Phone: 240-535-1574; Email: [email protected]
Nora Samaranayake
Phone: 410-706-1966; Email: [email protected]

Interferon Antagonism of SARS-CoV-2

It has become clear that the type 1 interferon responses to SARS-CoV-2 have a great deal to do with the outcome of infection. Patients with benign courses of infection yield high levels of expression of interferon-α (IFNα), while critical cases of COVID-19 show low levels of its expression. Paradoxically, in severe disease, expression of INF receptors is elevated, while expression of INF sensitive genes is depressed, suggesting that things are awry downstream from the receptors. It is not clear if this is because of the activity of virally encoded gene products or the lack of adequate INF-α or both. Variants of genes involved in INF activity have been identified in severe cases of Covid-19 patients. And the virus seems to have multiple proteins that are able to antagonize aspects of INF signaling. We will consider these points separately.

Coronavirus infections in general appear to involve perturbations in INF activities. A good overview of the role of INF in coronavirus infections shows some of the involved signaling pathways(1). Innate immunity is abnormal in severe disease. Early expression of INF-α appears to correlate with a favorable outcome in controlling SARS-CoV-2 infection, whereas INF-β expression appears to be negligible(2). While mild infections are correlated with continued high levels of expression of INF-α, severe disease is marked by low levels of INF-α expression(2). In contrast, inflammatory cytokine expression, as evidenced by IL-6 and TNFα, is high. Although INF-α and inflammatory cytokines are both part of innate immunity, the former is regulated by the transcription factors IRF3 and 7, while the latter are regulated by NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), a protein complex controlling transcription of DNA, cytokine production and cell survival. This suggests that NF-κB signaling is relatively unperturbed by the virus. Thus, its IFN perturbation could be important for antagonizing host defense system.

Some clues as to which factors involved in regulating INF activities may be affected in Covid-19 have been learned by whole exome sequencing of patients with severe disease genomes, particularly those that lack obvious risk factors. In light of this, it is instructive to look at a study of two pairs of young adult brothers, one pair from the Netherlands and the other from West Africa, who had severe Covid-19 (one died)(3). The pairs each had different loss-of-function mutations in TLR7, an intracellular receptor for viral RNA. Primary mononuclear cells showed downregulation of downstream INF signaling, including that of IRF7. The genes are X-linked; this means that men who inherit the defective gene are at greater risk than females, who would need to be homozygous for risk. While loss of function mutations in TLR7 are rare, so is severe Covid-19 in young people, and the congruency of these two rare phenomena is telling. Another study showed loss of function variants in 3.5% (out of 659) of severely ill patients of 13 genes involved in TLR3 and IRF7-dependent INF activities(4). Cells with IRF7 variants produced no type 1 IFN when infected in vitro with SARS-CoV-2.

There is also a report that some patients with severe Covid-19 have neutralizing autoantibodies to IFN-α, -ω, or both(5). These were present in 101 of 987 patients with life threatening disease but in none of the 663 patients with mild or asymptomatic infection. The autoantibodies existed prior to infection.  Oddly, most of the patients with autoantibodies were male, whereas generally women have a higher incidence of autoimmunity. This suggests an X-linked genetic basis.

The above studies (and others for which space constraints preclude detailed consideration) point to a failure of INF-related activities as a critical risk factor for the development of severe Covid-19 and suggest that INF represents a potentially serious block to replication of SARS-CoV-2. We might then ask how the virus deals with this problem.

It appears that the virus encodes a number proteins that potentially antagonize cellular signaling pathways involved in INF activity. As a convenient reference to the proteins encoded by SARS-CoV2, we commend you to a website maintained by the Zhang lab at the University of Michigan (https://zhanglab.ccmb.med.umich.edu/COVID-19/).  Several studies have shown an effect on IFN activity in vitro(6-10), but these should be interpreted with caution as they use artificially high levels of viral gene expression. In fact, it is not clear at what levels these proteins are expressed in vivo. Moreover, these studies do not completely agree on which are the most relevant viral proteins.

Yuen et al.(10) transfected expression constructs for 27 different genes for their ability to inhibit RIG-I-dependent induction of an IFN-β promoter. RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) responsible for the type 1 interferon (IFN1) response. They found that four viral proteins (nsp13, 14 and 15 and orf6) were strongly inhibitory. However,  the papain-like protease (PLpro) of SARS-CoV-2 was not an inhibitor, even though the SARS-CoV-1 PLpro is known to inhibit type I IFN by inhibiting IRF3 phosphorylation, thus blocking downstream Interferon induction. This suggests interference with activities downstream from RIG-I. Orf6 also inhibited IFN α-2, β, and λ secretion induced by Sendai virus infection. Using similar methodology, Lei et al.(7) found similar activities with nsp1, 3, 12, 13 and 14, ORFs 3 and 6, and the membrane (M) protein leading to RIG I or MDA5 activation. In contrast, ORF6 overexpression inhibited nuclear translocation of STAT1, which is required for IFN-stimulated gene expression. Li et al.(8) looked at the ability of selected viral proteins to inhibit Sendai virus-induced IFN activity. ORF 6 strongly inhibited the activity of IFN-β, interferon-sensitive response element (ISRE), and NF-κB promoters, as assessed by reporter gene activity. ORF8 and the nucleocapsid protein (N) showed less dramatic inhibitory activity. ISRE related activity was inhibited less markedly by ORF6 when cells were stimulated by IFN-β. From the above studies, there appears to be general agreement that ORF6 is a critical component of IFN antagonism by SARS-CoV-2 infection, with the caveat that the studies all involve overexpression.

Liu et al.(9) show that PLpro has IFN antagonistic activity, but by a different mechanism than those reported above. ISG15 is a multi-function protein that serves as a cytokine but also as a ubiquitin-like intracellular protein conjugate. ISGylation activates the viral RNA sensor MDA5, which is involved in IFN activity. MDA5 activity is antagonized by removal of ISG moieties by PLpro, thus inhibiting IFN expression.

Konno et al.(6) reported that ORF3b, a 22 amino acid protein that is truncated by introduction of a stop codon, antagonizes IFN activity. This is contradictory to SARS-COV-1 homolog. In spite of its small size, ORF3b suppressed Sendai virus-mediated stimulation of the IFNβ1 promoter more strongly than did the larger size of SARS-CoV-1 protein. Interestingly, there are naturally occurring SARS-CoV2 variants in which the full length ORF3b is restored; these are even more strongly inhibitory than is the truncated version.

The above presents a complicated picture that nonetheless points to the importance of type 1 INF in the outcome of Covid-19. A wide variety of data point to defects in the host IFN response that are correlative with severe disease. According to in vitro studies of the viral proteins (with the caveats inherent from the use of overexpression systems), the virus mounts multifactorial defenses against IFN antiviral activities, with ORF6 and PLpro (and perhaps ORF3b) being prime candidates. Hopefully, future in vivo studies will bring more clarity. Overall these studies point to type 1 IFN-signaling as a potential important therapeutic target.

 

References

 

  1. A. Park, A. Iwasaki, Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe 27, 870-878 (2020).
  2. J. Hadjadj et al., Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369, 718-724 (2020).
  3. C. I. van der Made et al., Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA 324, 663-673 (2020).
  4. Q. Zhang et al., Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science, (2020).
  5. P. Bastard et al., Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science, (2020).
  6. Y. Konno et al., SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant. Cell Rep 32, 108185 (2020).
  7. X. Lei et al., Activation and evasion of type I interferon responses by SARS-CoV-2. Nat Commun 11, 3810 (2020).
  8. J. Y. Li et al., The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus Res 286, 198074 (2020).
  9. G. Liu et al., ISG15-dependent Activation of the RNA Sensor MDA5 and its Antagonism by the SARS-CoV-2 papain-like protease. bioRxiv, (2020).
  10. C. K. Yuen et al., SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg Microbes Infect 9, 1418-1428 (2020).