Francis V. Chisari, M.D. is Emeritus Professor of Virology and Immunology at
The Scripps Research Institute in La Jolla, CA where he has studied the hostvirus interactions that determine the outcome of hepatitis B (HBV) and hepatitis C
(HCV) virus infections for the past 42 years.
In a ground-breaking series of studies beginning in the 1970s, Dr. Chisari and his
colleagues defined the specificity, magnitude and kinetics of the CD4+ and CD8+
T cell response to the hepatitis B virus (HBV) in patients and chimpanzees; and
later, in tempo with the laboratories of Bruce Walker and Christopher Walker, to
the hepatitis C virus (HCV). Comparison of these immune parameters with the
course and outcome of infection revealed that viral clearance and self-limited
infection by these viruses is heralded by a vigorous, polyclonal and multispecific
T cell response that is both attenuated and narrowly focused in chronically
infected patients. They also discovered that, contrary to prevailing thought, HBVinfected cells can persist in the liver for decades after resolution of acute hepatitis
and that infectious virus circulates in immune complexes with neutralizing
antibodies that likely restrain viral spread. Collectively, these results established
the immunological paradigm for these infections and provided the rationale for
immunotherapeutic approaches to cure them when they persist.
To confirm and extend these results required interventional studies in tractable
animal models. By depleting CD4+ and CD8+ T cells in chimpanzees at varying
times relative to the onset of experimental HBV infection, the Chisari lab, in
collaboration with Bob Purcell’s group at the NIH, proved that both subsets of T
cells are required for viral clearance and for disease pathogenesis during HBV
infection. In HBV dose-titration experiments, they made the surprising discovery
that the duration of HBV infection is inversely related to the size of the viral
inoculum, and they demonstrated that the clearance of HBV requires the
development of an early CD4+ T cell response and that it is ultimately mediated
by CD8+ T cells. In related chimpanzee experiments, they showed that HCV
induces a strong intrahepatic innate response while HBV does not, consistent
with evidence that the HBV genome is sequestered from the innate sensing
machinery of infected cells while the HCV genome is readily detectable. Perhaps
most importantly, they discovered that T cell-mediated clearance of the HBV
covalently closed circular DNA transcriptional template from the liver begins
before the onset of liver cell injury in acutely infected chimpanzees. These
exciting results suggested that noncytolytic antiviral T cell functions may
contribute to viral clearance during acute HBV infection, and they raised the
possibility that therapeutic activation or mimicry of these functions might
terminate chronic HBV infection as well.
To explore these immunobiological hypotheses, Dr. Chisari developed the first
transgenic mouse model of any human viral pathogen, using an HBV isolate that
was cloned and sequenced in Pierre Tiollais’ laboratory at the Pasteur Institute.
Later, in collaboration with Heinz Schaller in Heidelberg and with critical
contributions by Luca Guidotti, his postdoctoral fellow at the time, Dr. Chisari
produced transgenic mice containing the entire HBV genome whose hepatocytes
produce fully infectious virus. When these animals were used as recipients of
HBV specific CD8+ CTLs they developed a transient necroinflammatory liver
disease, histologically identical to acute viral hepatitis, proving the immunological
basis of viral hepatitis and identifying the molecular and cellular events required
for it to occur. In the course of these studies, they discovered that hepatocellular
HBV replication was abolished by antiviral cytokines, especially interferon
gamma, that were secreted by CTLs following antigen recognition, suggesting
that viral clearance during HBV-infection may reflect noncytolytic antiviral
functions of CD8+ CTLs. Collectively, these results demonstrated that the
immune response can mediate viral clearance by curing as well as by killing
infected cells. This represented a major paradigm shift in viral immunology.
In related experiments Chisari and colleagues discovered that hepatocellular
antigen presentation triggers abortive activation of antigen-specific CD8+ T cells
by failing to deliver positive costimulatory signals to the T cells while efficiently
delivering strongly negative costimulatory signals, potentially explaining why
hepatotropic virus infections often persist. They also discovered that the negative
impact of hepatocellular antigen presentation can be reversed by dendritic cell
activation, offering a new and exciting therapeutic option for the treatment of
chronic HBV infection.
In another series of experiments, they established an HBV transgenic mouse
model of immune-mediated chronic hepatitis that was characterized by CD8+
CTL-induced liver cell death, regeneration, inflammation, macrophage activation,
oxygen radical production and DNA damage, that ultimately progressed to
hepatocellular carcinoma. By demonstrating that hepatocellular carcinoma can
have an immune pathogenesis, these exciting results established a general
model for carcinogenesis that extends to chronic inflammatory liver diseases of
any etiology, and perhaps to other forms of cancer as well.
In addition to his in vivo experiments in humans, chimpanzees and mice, Dr.
Chisari and his colleagues used an in vitro cell culture infection system that was
pioneered by the laboratories of Takaji Wakita in Tokyo and Charles Rice in New
York to elucidate many of the biochemical and ultrastructural characteristics of
infectious HCV particles, the dependence of the HCV life cycle on the cholesterol
and fatty acid biosynthetic pathways of the cell, and mechanisms whereby HCV
can defeat the innate host response in infected cells. In a recent series of
experiments, the Chisari lab discovered a novel cell-cell communication system
by which nonpermissive cells of the innate immune system can sense HCVinfected cells and secrete interferon, and by which replication-competent RNA
can be transmitted to uninfected permissive cells by extracellular vesicles,
thereby enabling the virus to spread while avoiding the antibody response.
In recognition of these contributions, Dr. Chisari has received many honors and
awards, including the Ernst Jung Prize in Medicine, the Rous-Whipple Award
from the American Society of Investigative Pathology, the First Distinguished
Scientific Achievement Award from the American Liver Foundation, and election
to membership in the Association of American Physicians, the American
Academy of Microbiology, the National Academy of Sciences, and the Institute of
Medicine of the National Academy of Sciences.