Fostering Research: The VZVRF Post-Doctoral
Research Fellowship Program

What causes the varicella-zoster virus (which remains dormant after causing chickenpox) to reactivate, thereby causing shingles?

How can shingles be prevented?

What is the most effective means of treating the pain associated with post-herpetic neuralgia?

The answers to these and many other questions involving the varicella-zoster virus (VZV) and VZV infections remain a mystery. Although scientific research can potentially provide the answers, too little funding has traditionally been allocated to the study of VZV by the public and private sectors.

In 1993, two years after its founding, the VZV Research Foundation established its Post-Doctoral Research Fellowship Program, an international competition designed to encourage research into the pathogenesis, treatment and prevention of VZV infections by promising, young investigators. As of March 2001, twelve, two-year grants totaling $1.25 million have been awarded. This summary of the first six studies is followed by descriptions of the six fellowships awarded since 1999.

Unraveling the Mysteries of Latency and Reactivation
University of Liège

Two research grants were awarded to scientists in the Laboratory of Fundamental Virology and Immunology at the University of Liège in Liège, Belgium: Catherine Sadzot-Delvaux, Ph.D., in 1993, and Patricia Defechereux, Ph.D., in 1997. Their mentor is Bernard Rentier, Ph.D., D.Sc., vice-rector, professor of Biology and head of the Fundamental Virology Unit at the University's Institute of Pathology.

VZVRF Fellows

The objective of studies conducted by Drs. Sadzot-Delvaux and Defechereux was to more fully understand how the life cycle of the virus is regulated and how the virus remains latent in the peripheral nervous system, only to reactivate after many years of inactivity. A key element of their research was an attempt to unravel some of the complex interactions and mechanisms that control VZV gene expression.

Dr. Defechereux is studying the IE viral proteins, which are expressed in the early stages of the initial VZV infection, in addition to the early stages of VZV reactivation (shingles). She has demonstrated the interaction between these proteins and, specifically, how the IE62 protein helps transport the IE4 protein, a very important control agent of the infection, in different compartments of the infected cells. Dr. Defechereux has also demonstrated that the HIV virus can be reactivated by the IE4 protein.

Dr. Sadzot-Delvaux, using an in vivo rat model of latency set up in the laboratory, found that at least one of the viral IE proteins, IE63, is abundantly expressed during latency. Moreover, this protein elicits a complete immune response in humans.

According to Dr. Rentier, "While the protein IE63 is known as a regulator protein, it is also a component of the varicella-zoster virus that, for a reason yet unknown, elicits an immune response that was previously undetected due to a lack of tools to measure it. It is unknown whether the response is, in fact, protective, but, if it is, then the addition of IE63 to new vaccine preparations could strengthen their efficacy."

The work of both Drs. Defechereux and Sadzot-Delvaux has shown that varicella-zoster virus latency results in mechanisms which are completely different from those leading to latency in other viruses in the same class, the "alphaherpesviruses."

The results of Dr. Sadzot-Delvaux's research have been published in several scientific journals, including the Journal of Virology, Journal of General Virology and the Journal of Immunology. Dr. Defechereux's study has been published in the Journal of Virology and the Journal of Biological Chemistry.

Columbia University College of Physicians and Surgeons

In 1995, Octavian Lungu, M.D., an associate research scientist in the Department of Microbiology at Columbia University College of Physicians and Surgeons, was awarded a VZVRF Fellowship. Dr. Lungu's mentors at Columbia are: Saul J. Silverstein, Ph.D., professor of Microbiology and chairman of the Microbiology Department; and Anne A. Gershon, M.D., professor of Pediatrics and director of the Division of Pediatric Infectious Diseases.

The purpose of Dr. Lungu's study was to determine if VZV proteins are expressed during latency. His findings were published in the Proceedings of the National Academy of Sciences in June 1998.

Dr. Lungu found VZV regulatory proteins in human ganglia with latent virus. These proteins were only in the cytoplasm of neurons with latent virus and in the cytoplasm and nuclei of neurons with reactivated virus. Therefore, during latency, VZV proteins are prevented from encountering the virus genome, located in the nuclei, and, in turn, prevented from causing reactivation of the virus. Dr. Lungu notes that an understanding of the molecular basis for exclusion of latent VZV proteins from the nucleus will provide insight into the maintenance of VZV latency. This may, in turn, provide a possible target for therapeutic intervention to prevent reactivation and the resultant infection (shingles).

National Institute of Allergy and Infectious Diseases

Dongxiang Xia, M.D., Ph.D., was awarded a Foundation fellowship in 1997. Dr. Xia is a post-doctoral fellow in the Laboratory of Clinical Investigation at the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health in Bethesda, Md. His mentor is Stephen E. Straus, M.D., chief of the Laboratory of Clinical Investigation at NIAID.

Dr. Xia studied the basic molecular biology controlling the persistence of the varicella-zoster virus (VZV) in the hope that a more comprehensive understanding of the mechanism that establishes and maintains the latency period could lead to the design of new drugs or vaccines to treat or possibly prevent the disease, especially its recurrence.

Dr. Xia explains that of the 70 genes present in VZV, at least four are active during the persistence period, or latent phase. He chose to study the most novel, VZV gene 21. His research has defined the precise structure and regulation of the RNA encoded by gene 21. Moreover, Dr. Xia found that gene 21 was transactivated by VZV infection, but it did not have a significant ability to regulate the expression of other VZV genes.

Dr. Xia delivered the first major presentation on his VZVRF-sponsored study at the 23rd International Herpesvirus Workshop in York, England in August 1998.

Developing A "Second Generation" VZV Vaccine
Stanford University

Upon receiving her 1995 VZVRF Fellowship, Darlene E. Jenkins, Ph.D. set out to contribute to the eventual development of a "second generation," recombinant VZV vaccine for immunocompromised patients. As a postdoctoral fellow in the Department of Pediatrics at Stanford University, she developed a method to test proteins that could serve as the basis for such a vaccine. Her mentor was Ann M. Arvin, M.D., a professor of Pediatrics, and Microbiology and Immunology, and chief of the Pediatric Infectious Disease Division at Stanford.

According to Dr. Jenkins, the current varicella vaccine consists of a weakened VZV strain that presents little risk to healthy individuals, but could be potentially troublesome for immunocompromised individuals. Her study involved the development of a test, or assay, that would enable her to determine which portions of the varicella-zoster virus could be used for a "subunit" vaccine.

Dr. Jenkins tested portions of a protein (peptides) that is known to produce an immune response, or be immunogenic. She determined that some of those peptides were more immunogenic than others and, therefore, would be likely candidates for the development of a subunit vaccine. Dr. Jenkins also noted that the assay she and her team at Stanford developed could have applications to other viruses and pathogens.

Dr. Jenkins is currently a senior scientist at Xenogen Corporation in Alameda, Calif.

Alleviating PHN Pain
Memorial Sloan-Kettering Cancer Center

As a pain fellow in the Department of Neurology of Memorial Sloan-Kettering Cancer Center in New York, Kathryn J. Elliott, M.D. was one of the first two scientists to receive a two-year research grant from the VZV Research Foundation in 1993. Funding for a third year of study was provided to Dr. Elliott by the Foundation in 1995 due to the generosity of the Henry and Lucy Moses Fund and its late President, Henry Schneider.

Dr. Elliott's fellowship enabled her to expand her longstanding clinical interest in the treatment and mechanisms of neuropathic pain, such as the pain experienced during all stages of VZV infection. According to Dr. Elliott, "Neuropathic pain, acute herpetic pain and post-herpetic neuralgia share many common features suggesting similar underlying mechanisms of pain generation. These include peripheral and central sensitization, and the development of these pain states (sensitization) may be a predominant reason why prolonged PHN pain may be so hard to treat." Her research resulted in the identification of new analgesic agents including the NMDA receptor antagonists dextromethorphan, ketamine and gabapentin.

To date, the results of Dr. Elliott's Foundation-sponsored work in new drug development have been featured in 24 scientific articles in such publications as Pain and Anesthesiology, and in 16 abstracts.

Expanding Fellowship Program


The winners of the 1999-2001 VZVRF Fellowship Program were:

  • Maddie Y. Hao, M.D., Columbia University College of Physicians and Surgeons, New York, N.Y.;
  • Chenjun Mo, Ph.D., Stanford University, Stanford, Calif.;
  • Jorge A. Padilla, Ph.D., University of Iowa Hospital, Iowa City, Iowa; and,
  • Karin Lottrup Petersen, M.D., University of California, San Francisco Pain Clinical Research Center, San Francisco, Calif.
Dr. Hao, formerly a senior resident in pediatrics, NYU Medical Center, New York, N.Y., studied "Envelopment, Intracellular Transport, and Infectivity of Varicella Zoster Virus," essentially finding an easier way to propagate and study VZV in vitro. Among her goals were a better way to make vaccine.

Dr. Hao was trained in China at Beijing University and received her M.D. there in 1990. She came to the United States in 1992, and was employed in Columbia University's Division of Molecular Genetics, Department of Pathology for two years. In 1994, she began research on VZV in the laboratories of Drs. Anne and Michael Gershon at Columbia University. She began her residency at NYU in 1996.

Dr. Mo, a post-doctoral fellow in the Department of Pediatrics, Stanford University, researched VZV glycoproteins, in the hope of providing new information about the pathogenesis of VZV which will be relevant for the design of vaccines and potentially, the development of antiviral drugs.

A native of China, Dr. Mo completed his earlier education there and then earned his doctoral degree at Wayne State University, Detroit, Mich. He joined Dr. Arvin's lab upon graduation.

Jorge A. Padilla, Ph.D. is a post-doctoral research fellow in the Department of Pediatrics and Microbiology at the University of Iowa. His study, "Topography of gE on the varicella-zoster virion," sought to characterize the structural biology of VZV glycoprotein gE, using standard molecular virology procedures, as well as newer imaging methodologies he honed while earning his doctorate in Japan.

Dr. Padilla, a native of Mexico, was educated in Mexico City, and completed his doctoral training at Okayama University, Japan, having won a scholarship from Japan"s Ministry of Science and Culture. He spent one year learning Japanese before beginning the five-year graduate program. Since his arrival in Iowa in August 1997, Dr. Padilla began work immediately in the lab of Charles Grose, M.D.

Dr. Petersen is a post-doctoral fellow in the Neurology Department of the University of California at San Francisco (UCSF) Pain Clinical Research Center. Her VZVRF fellowship grant was applied to two studies. One attempted to add to the understanding of the pain and neural dysfunction of acute herpes zoster and PHN. Another explored opioid sensitivity and underlying pain mechanisms in PHN.

Dr. Petersen was born in Copenhagen, Denmark and graduated from the University of Copenhagen Medical School in 1996. In 1997, after completing her internship, Dr. Petersen received a one-year research fellowship from the Danish Medical Research Council and joined the lab of Dr. Howard Fields and Dr. Michael Rowbotham at UCSF.

The winners of the 2001-2003 VZVRF Fellowship Program were:

  • Helmut Fickenscher, Dr. med. habil., a scientist at the Institut fur Klinische und Molekulare Virologie, based at Friedrich-Alexander-Universitaet Erlangen-Nuernberg in Erlangen, Germany.

  • Lucie Maresova, Ph.D., a research fellow in the Pediatrics Department of the University of Iowa in Iowa City, Iowa.

Born in Altdorf, Germany, Dr. Helmut Fickenscher received his degree from Friedrich-Alexander, where his mentor is Bernhard Fleckenstein, Dr. med.habil, chair of Virology and dean of the Medical Faculty.

Dr. Fickenscher’s study is entitled, "Definition of Neuropathic Functions of a Human Varicella Zoster Wildtype Virus Isolate Using Bacterial Chromosomal Techniques." His research is based on a monkey virus, herpesvirus saimiri, which is capable of transforming human T lymphocytes to stable growth in culture. Together with his colleague, Dr. Michaela Kress, a neurophysicist, he recently developed a tissue culture model for shingles-associated pain. As they reported in the FASEB-Journal in April 2001, varicella-zoster virus-infected sensory neurons from rats became de novo sensitive to adrenegeic stimulation.

"Because this induction of sensitivity to noradrenaline was not observed with the vaccine strain OKA (Varilrix), my VZVRF-sponsored study aims at a definition of the neuropathic virus genes by using recombinant viruses and in vitro mutagenesis," said Dr. Fickenscher. "Thus, the mechanisms will be investigated by which the varicella-zoster virus induces pain during and after its reactivation, when clinical zoster is observed."

Born in Prague, Czech Republic, Dr. Lucie Maresova received her Ph.D. degree from the Department of Experimental Virology of Charles University in Prague. Her mentor is Charles Grose, professor of Pediatrics and Microbiology at the University of Iowa.

Dr. Maresova’s study is entitled, "Roles of VZV gB and gE in Fusion." According to Dr. Maresova, "VZV is a highly fusogenic virus. The virus moves from cell to cell by fusing an infected cell to an adjacent, noninfected cell. Therefore, the overall goal of my study is to investigate the four VZV proteins that are the potential major fusogens of VZV. My first aim is to assess the fusogenic potential of the VZV glycoprotein gB. I will also reassess the fusogenic potential of three other glycoproteins: gH, gL and gE. As part of my study, I will work towards defining a more quantitative assay for VZV induced fusion in the infected cell.

"This study will differ from earlier studies in that the VZV genes of interest will be investigated in expression systems in which two VZV glycoproteins are simultaneously cloned and produced," she added. "Finally, this project will provide insight into the mechanism by which VZV can travel from one cell to another cell without ever entering the extracellular space."

In Appreciation

Fellowship Program Supporters

The Achelis and Bodman Foundations
Commonwealth Fund
The Eppley Foundation for Research
The F.M. Kirby Foundation, Inc.
Charles Henry Leach, II Foundation
The Richard Lounsbery Foundation
Mellen Foundation, Inc.
Henry and Lucy Moses Fund, Inc.
The Reed Foundation, Inc.
St. Giles Foundation
Adolph and Ruth Schnurmacher Foundation, Inc.
The Starr Foundation
Arthur K. Watson Charitable Trust