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Dive into the research topics where Francis V. Chisari is active.

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Featured researches published by Francis V. Chisari.


Immunity | 1996

Intracellular Inactivation of the Hepatitis B Virus by Cytotoxic T Lymphocytes

Luca G. Guidotti; Tetsuya Ishikawa; Monte V. Hobbs; Brent Matzke; Robert D. Schreiber; Francis V. Chisari

It is widely believed that viral clearance is mediated principally by the destruction of infected cells by CTLs. In this report, we use a transgenic mouse model of HBV replication to demonstrate that this assumption may not be true for all viruses. We find that adoptively transferred virus-specific CTLs can abolish HBV gene expression and replication in the liver without killing the hepatocytes. This antiviral function is mediated by IFN gamma and TNF alpha secreted by the CTL or by the antigen-nonspecific macrophages and T cells that they activate following antigen recognition. These cytokines activate two independent virocidal pathways: the first pathway eliminates HBV nucleocapsid particles and their cargo of replicating viral genomes, while the second pathway destabilizes the viral RNA. Intracellular viral inactivation mechanisms such as these could greatly amplify the protective effects of the immune response, while failure of such mechanisms could lead to viral persistence or to the death of the host.


Proceedings of the National Academy of Sciences of the United States of America | 2002

Genomic analysis of the host response to hepatitis C virus infection

Andrew I. Su; John Paul Pezacki; Lisa Wodicka; Amy D. Brideau; Lubica Supekova; Robert Thimme; Stefan Wieland; Jens Bukh; Robert H. Purcell; Peter G. Schultz; Francis V. Chisari

We have examined the progression of hepatitis C virus (HCV) infections by gene expression analysis of liver biopsies in acutely infected chimpanzees that developed persistent infection, transient viral clearance, or sustained clearance. Both common responses and outcome-specific changes in expression were observed. All chimpanzees showed gene expression patterns consistent with an IFN-α response that correlated with the magnitude and duration of infection. Transient and sustained viral clearance were uniquely associated with induction of IFN-γ-induced genes and other genes involved in antigen processing and presentation and the adaptive immune response. During the early stages of infection, host genes involved in lipid metabolism were also differentially regulated. We also show that drugs that affect these biosynthetic pathways can regulate HCV replication in HCV replicon systems. Our results reveal genome-wide transcriptional changes that reflect the establishment, spread, and control of infection, and they reveal potentially unique antiviral programs associated with clearance of HCV infection.


Journal of Virology | 2003

CD8+ T Cells Mediate Viral Clearance and Disease Pathogenesis during Acute Hepatitis B Virus Infection

Robert Thimme; Stefan Wieland; Carola Steiger; John Ghrayeb; Keith A. Reimann; Robert H. Purcell; Francis V. Chisari

ABSTRACT Although the CD4+- and CD8+-T-cell responses to the hepatitis B virus (HBV) are thought to be crucial for the control of HBV infection, the relative contribution of each T-cell subset as an effector of viral clearance is not known. To examine this question, we monitored the course of HBV infection in control, CD4-depleted, and CD8-depleted chimpanzees. Our results demonstrate that CD8+ cells are the main effector cells responsible for viral clearance and disease pathogenesis during acute HBV infection, and they suggest that viral clearance is mediated by both noncytolytic and cytolytic effector functions of the CD8+-T-cell response.


Cell | 1989

Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice

Francis V. Chisari; Kathleen Klopchin; Takashi Moriyama; Claudio Pasquinelli; Harold A. Dunsford; Stewart Sell; Carl A. Pinkert; Ralph L. Brinster; Richard D. Palmiter

Transgenic mice that overproduce the hepatitis B virus large envelope polypeptide and accumulate toxic quantities of hepatitis B surface antigen (HBsAg) within the hepatocyte develop severe, prolonged hepatocellular injury that initiates a programmed response within the liver, characterized by inflammation, regenerative hyperplasia, transcriptional deregulation, and aneuploidy. This response inexorably progresses to neoplasia. The incidence of hepatocellular carcinoma in this model corresponds to the frequency, severity, and age of onset of liver cell injury, which itself corresponds to the intrahepatic concentration of HBsAg and is influenced by genetic background and sex. Thus, the inappropriate expression of a single structural viral gene is sufficient to cause malignant transformation in this model. These results suggest that severe, prolonged cellular injury induces a preneoplastic proliferative response that fosters secondary genetic events that program the cell for unrestrained growth.


Proceedings of the National Academy of Sciences of the United States of America | 2002

Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease.

Robert Thimme; Jens Bukh; Hans Christian Spangenberg; Stefan Wieland; Janell Pemberton; Carola Steiger; Sugantha Govindarajan; Robert H. Purcell; Francis V. Chisari

To define the early events that determine the outcome of acute hepatitis C virus (HCV) infection, we compared the course of viremia with the peripheral and intrahepatic T cell response and intrahepatic cytokine profile in six acutely infected chimpanzees. Three different outcomes were observed after peak viral titers were reached: sustained viral clearance, transient viral clearance followed by chronic infection, and chronic infection that persisted at initial peak titers. The results indicate that HCV spread outpaces the T cell response and that HCV rapidly induces but is not controlled by IFN-α/β; that viral clearance follows the entry and accumulation of HCV-specific IFN-γ-producing T cells in the liver; and that it may not require the destruction of infected cells.


Proceedings of the National Academy of Sciences of the United States of America | 2003

Interference of hepatitis C virus RNA replication by short interfering RNAs

Sharookh B. Kapadia; Amy Brideau-Andersen; Francis V. Chisari

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, which can lead to the development of liver cirrhosis and hepatocellular carcinoma. Current therapy of patients with chronic HCV infection includes treatment with IFNα in combination with ribavirin. Because most treated patients do not resolve the infection, alternative treatment is essential. RNA interference (RNAi) is a recently discovered antiviral mechanism present in plants and animals that induces double-stranded RNA degradation. Using a selectable subgenomic HCV replicon cell culture system, we have shown that RNAi can specifically inhibit HCV RNA replication and protein expression in Huh-7 cells that stably replicate the HCV genome, and that this antiviral effect is independent of IFN. These results suggest that RNAi may represent a new approach for the treatment of persistent HCV infection.


Journal of Virology | 2005

Lambda Interferon Inhibits Hepatitis B and C Virus Replication

Michael D. Robek; Bryan Boyd; Francis V. Chisari

ABSTRACT Lambda interferon (IFN-λ) induces an intracellular IFN-α/β-like antiviral response through a receptor complex distinct from the IFN-α/β receptor. We therefore determined the ability of IFN-λ to inhibit hepatitis B virus (HBV) and hepatitis C virus (HCV) replication. IFN-λ inhibits HBV replication in a differentiated murine hepatocyte cell line with kinetics and efficiency similar to IFN-α/β and does not require the expression of IFN-α/β or IFN-γ. Furthermore, IFN-λ blocked the replication of a subgenomic and a full-length genomic HCV replicon in human hepatocyte Huh7 cells. These results suggest the possibility that IFN-λ may be therapeutically useful in the treatment of chronic HBV or HCV infection.


Journal of Virology | 2008

Cellular Determinants of Hepatitis C Virus Assembly, Maturation, Degradation, and Secretion

Pablo Gastaminza; Guofeng Cheng; Stefan D Wieland; Jin Zhong; Wei Liao; Francis V. Chisari

ABSTRACT Intracellular infectious hepatitis C virus (HCV) particles display a distinctly higher buoyant density than do secreted virus particles, suggesting that the characteristic low density of extracellular HCV particles is acquired during viral egress. We took advantage of this difference to examine the determinants of assembly, maturation, degradation, and egress of infectious HCV particles. The results demonstrate that HCV assembly and maturation occur in the endoplasmic reticulum (ER) and post-ER compartments, respectively, and that both depend on microsomal transfer protein and apolipoprotein B, in a manner that parallels the formation of very-low-density lipoproteins (VLDL). In addition, they illustrate that only low-density particles are efficiently secreted and that immature particles are actively degraded, in a proteasome-independent manner, in a post-ER compartment of the cell. These results suggest that by coopting the VLDL assembly, maturation, degradation, and secretory machinery of the cell, HCV acquires its hepatocyte tropism and, by mimicry, its tendency to persist.


Journal of Clinical Investigation | 1995

Cytotoxic T lymphocyte response to hepatitis C virus-derived peptides containing the HLA A2.1 binding motif.

Andreas Cerny; John G. McHutchison; Claudio Pasquinelli; M E Brown; B Grabscheid; P Fowler; Michael Houghton; Francis V. Chisari

The HLA class I-restricted cytotoxic T lymphocyte (CTL) response is a major defense mechanism in viral infections. It has been suggested that the CTL response may contribute to viral clearance and liver cell injury during hepatitis C virus (HCV) infection. To test this hypothesis requires an understanding of the characteristics of HCV-specific cytotoxic effector cells and identification of the target antigens to which they respond. To begin this process we stimulated peripheral blood mononuclear cells (PBMC) from a group of HLA-A2 positive patients with chronic hepatitis C with a panel of 130 HCV-derived peptides containing the HLA-A2 binding motif. Effector cells were tested for their capacity to lyse HLA-A2-matched target cells that were either sensitized with peptide or infected with a vaccinia virus construct containing HCV sequences. Using this approach we have identified nine immunogenic peptides in HCV, three of which are derived from the putative core protein, three from the nonstructural (NS) 3 domain, two from NS4 and one from NS5. Selected responses were shown to be HLA-A2 restricted, mediated by CD8+ T cells and to recognize endogenously synthesized viral antigen. Unexpectedly, peptide-specific CTL responses could also be induced in sero-negative individuals, suggesting in vitro activation of naive CTL precursors. The precursor frequency of peptide-specific CTL was 10 to 100-fold higher in infected patients compared to uninfected controls, and the responses were greatly diminished by removal of CD45 RO+ (memory) T cells. Further quantitative studies are clearly required to establish whether a correlation exists between the HCV-specific CTL response and the clinical course of this disease. Definition of the molecular targets of the human CTL response to HCV creates this opportunity, and may also contribute to the development of a T cell-based HCV vaccine.


Journal of Clinical Investigation | 1997

Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus.

Kyong-Mi Chang; Barbara Rehermann; John G. McHutchison; Claudio Pasquinelli; Scott Southwood; Alessandro Sette; Francis V. Chisari

This study was performed to test the hypothesis that cytotoxic T lymphocyte (CTL) selection of hepatitis C virus (HCV) escape variants plays a role in HCV persistence. The peripheral blood CTL responsiveness of patients with well-established chronic hepatitis C to a panel of 10 prototype HCV peptides (genotype 1a) was compared with the corresponding sequences encoded by the infecting viruses in each patient. Variant viral peptide sequences were threefold more frequent in the presence of a CTL response than in its absence, and CTL responses were detected nearly twice as often in association with variant rather than with prototype viral peptide sequences. Furthermore, over half of the patients were infected with potential CTL escape variants that contained nonimmunogenic and noncross-reactive variant peptides many of which displayed reduced HLA-binding affinity. Surprisingly, follow up analysis over a period of up to 46 mo revealed that, in contrast to the relatively high frequency of escape variants initially observed, the subsequent emergence rate of CTL escape variants was very low. Interestingly, the one escape variant that was detected proved to be a CTL antagonist. Collectively, these observations suggest that CTL selection of epitope variants may have occurred in these patients before their entrance into the study and that it may have played a role in HCV persistence. The low apparent rate of ongoing CTL selection in chronically infected patients, however, suggests that if CTL escape occurs during HCV infection it is probably an early event.

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Luca G. Guidotti

Scripps Research Institute

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Stefan Wieland

Scripps Research Institute

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P Fowler

Scripps Research Institute

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Alessandro Sette

La Jolla Institute for Allergy and Immunology

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David R. Milich

Scripps Research Institute

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Josan Chung

Scripps Research Institute

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Robert H. Purcell

National Institutes of Health

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Pablo Gastaminza

Spanish National Research Council

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