Pathology
>>Published online before print November 19, 2002
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.202608299
Inaugural Article
Microbiology
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 , and Francis V. Chisari *¶
*Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; University Hospital Freiburg, Department of Medicine II, Hugstetterstrasse 55, 79106 Freiburg, Germany; Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Liver Research Laboratory, Rancho Los Amigos Medical Center, Downey, CA 90242
Contributed by Francis V. Chisari, October 8, 2002
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 30, 2002.
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-/; that viral clearance follows the entry and accumulation of HCV-specific IFN--producing T cells in the liver; and that it may not require the destruction of infected cells.<<
>>Published online before print November 19, 2002
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.202608199
Microbiology
Genomic analysis of the host response to hepatitis C virus infection
Andrew I. Su *, John P. Pezacki , Lisa Wodicka ¶, Amy D. Brideau ||, Lubica Supekova *, Robert Thimme ||, Stefan Wieland ||, Jens Bukh **, Robert H. Purcell **, Peter G. Schultz *, and Francis V. Chisari ||
Departments of *Chemistry and ||Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121; Steacie Institute for Molecular Sciences, National Research Council of Canada, Ottawa, ON, Canada K1A 0R6; and **Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-8009
Contributed by Francis V. Chisari, October 8, 2002
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- response that correlated with the magnitude and duration of infection. Transient and sustained viral clearance were uniquely associated with induction of IFN--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.
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A.I.S and J.P.P contributed equally to this work.
¶Present address: Ambit Biosciences, San Diego, CA 92121.
To whom correspondence may be addressed.
E-mail: fchisari@scripps.edu.
www.pnas.org/cgi/doi/10.1073/pnas.202608199<<
Cheers, Tuck |
