What causes the varicella-zoster virus (which
remains dormant after causing chickenpox) to reactivate, thereby
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
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.
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
Expanding Fellowship Program
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
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
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
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
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,
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
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,
- 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
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. Fickenschers 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
"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. Maresovas 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."
Fellowship Program Supporters
The Achelis and Bodman Foundations
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