Marija Zeremski1, Giles Hooker2, Marla A Shu3, Emily Winkelstein3, Queenie Brown1, Don C Des Jarlais4, Leslie H Tobler5, Barbara Rehermann6, Michael P Busch7, Brian R Edlin3, Andrew H Talal8. 1. Center for the Study of Hepatitis C and Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA. 2. Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA. 3. Center for the Study of Hepatitis C and Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA; Department of Medicine, State University of New York Downstate College of Medicine, Brooklyn, NY, USA. 4. Baron Edmond de Rothschild Chemical Dependency Institute, Beth Israel Medical Center, New York, NY, USA. 5. Blood Systems Research Institute, San Francisco, CA, USA. 6. Immunology Section, Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, Bethesda, MD, USA. 7. Blood Systems Research Institute, San Francisco, CA, USA; University of California, San Francisco, CA, USA. 8. Center for the Study of Hepatitis C and Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA. Electronic address: aht2002@med.cornell.edu.
Abstract
BACKGROUND & AIMS: Characterization of inflammatory mediators, such as chemokines, during acute hepatitis C virus (HCV) infection might shed some light on viral clearance mechanisms. METHODS: Plasma levels of CXCR3 (CXCL9-11)- and CCR5 (CCL3-4)-associated chemokines, ALT, and HCV RNA were measured in nine injection drug users (median 26 samples/patient) before and during 10 acute (eight primary and two secondary) HCV infections. Using functional data analysis, we estimated smooth long-term trends in chemokine expression levels to obtain the magnitude and timing of overall changes. Residuals were analyzed to characterize short-term fluctuations. RESULTS: CXCL9-11 induction began 38-53days and peaked 72-83days after virus acquisition. Increases in ALT levels followed a similar pattern. Substantial negative auto-correlations of chemokine levels at 1 week lags suggested substantial week-to-week oscillations. Significant correlations were observed between CXCL10 and HCV RNA as well as ALT and CXCR3-associated chemokines measured in the preceding week, CCL3-4 expression levels did not change appreciably during acute HCV infection. CONCLUSIONS: Elevation of CXCR3-associated chemokines late during acute HCV infection suggests a role for cellular immune responses in chemokine induction. Week-to-week oscillations of HCV RNA, chemokines, and ALT suggest frequent, repeated cycles of gain and loss of immune control during acute hepatitis C.
BACKGROUND & AIMS: Characterization of inflammatory mediators, such as chemokines, during acute hepatitis C virus (HCV) infection might shed some light on viral clearance mechanisms. METHODS: Plasma levels of CXCR3 (CXCL9-11)- and CCR5 (CCL3-4)-associated chemokines, ALT, and HCV RNA were measured in nine injection drug users (median 26 samples/patient) before and during 10 acute (eight primary and two secondary) HCV infections. Using functional data analysis, we estimated smooth long-term trends in chemokine expression levels to obtain the magnitude and timing of overall changes. Residuals were analyzed to characterize short-term fluctuations. RESULTS:CXCL9-11 induction began 38-53days and peaked 72-83days after virus acquisition. Increases in ALT levels followed a similar pattern. Substantial negative auto-correlations of chemokine levels at 1 week lags suggested substantial week-to-week oscillations. Significant correlations were observed between CXCL10 and HCV RNA as well as ALT and CXCR3-associated chemokines measured in the preceding week, CCL3-4 expression levels did not change appreciably during acute HCV infection. CONCLUSIONS: Elevation of CXCR3-associated chemokines late during acute HCV infection suggests a role for cellular immune responses in chemokine induction. Week-to-week oscillations of HCV RNA, chemokines, and ALT suggest frequent, repeated cycles of gain and loss of immune control during acute hepatitis C.
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