Induction of CXCR3- and CCR5-associated chemokines during acute hepatitis C virus infection.
OBJECTIVE
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.
Center for the Study of Hepatitis C and Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA.
Marija
M
Zeremski
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA.
Giles
G
Hooker
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.
Marla A
MA
Shu
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.
Emily
E
Winkelstein
Center for the Study of Hepatitis C and Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA.
Queenie
Q
Brown
Baron Edmond de Rothschild Chemical Dependency Institute, Beth Israel Medical Center, New York, NY, USA.
Don C
DC
Des Jarlais
Blood Systems Research Institute, San Francisco, CA, USA.
Leslie H
LH
Tobler
Immunology Section, Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, Bethesda, MD, USA.
Barbara
B
Rehermann
Blood Systems Research Institute, San Francisco, CA, USA; University of California, San Francisco, CA, USA.
Michael P
MP
Busch
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.
Brian R
BR
Edlin
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.
Andrew H
AH
Talal
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D054405:Chemokine CCL3 / Q000097:blood; D054407:Chemokine CCL4 / Q000097:blood; D018946:Chemokine CCL5 / Q000097:blood; D054357:Chemokine CXCL10 / Q000097:blood; D054371:Chemokine CXCL11 / Q000097:blood; D054370:Chemokine CXCL9 / Q000097:blood; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C / Q000097:blood* / Q000276:immunology; D006801:Humans; D008297:Male; D012367:RNA, Viral / Q000097:blood*; D019713:Receptors, CCR5 / Q000097:blood*; D054367:Receptors, CXCR3 / Q000097:blood*; D018709:Statistics, Nonparametric; D013997:Time Factors; D055815:Young Adult
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D012367:RNA, Viral; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D000410:Alanine Transaminase
J Exp Med. 2003 Jun 16;197(12):1645-55
12810686
Hepatology. 2009 Feb;49(2):676-88
19177577
Test (Madr). 2010 May 1;19(1):50-53
21151714
Hepatology. 2004 Jun;39(6):1709-20
15185313
J Virol. 2001 Aug;75(15):7059-66
11435586
Science. 2003 Oct 24;302(5645):659-62
14576438
Semin Liver Dis. 2004;24 Suppl 2:3-8
15346240
J Viral Hepat. 2007 Oct;14(10):675-87
17875002
J Viral Hepat. 2009 Jan;16(1):10-20
18647233
Nat Rev Immunol. 2005 Mar;5(3):215-29
15738952
Rev Gastroenterol Disord. 2001;1(1):42-7
12120119
Cell Mol Life Sci. 2009 Mar;66(5):733-56
19011759
J Clin Microbiol. 2008 Feb;46(2):499-506
18032621
J Virol. 2004 Dec;78(24):13779-92
15564486
Cytokine Growth Factor Rev. 2007 Oct-Dec;18(5-6):535-44
17702639
J Infect Dis. 2009 Dec 1;200(11):1774-80
19848607
Hepatology. 2008 Nov;48(5):1440-50
18798334
Am J Addict. 2004 Jan-Feb;13(1):1-20
14766434
J Virol. 2004 Feb;78(3):1575-81
14722311
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15669-74
12441396
J Clin Invest. 2009 Jul;119(7):1745-54
19587449
J Virol. 2009 Apr;83(8):3719-33
19176632
Lancet Infect Dis. 2005 Sep;5(9):558-67
16122679
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15661-8
12441397