Premium
Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees
Author(s) -
Major Marian E.,
Dahari Harel,
Mihalik Kathleen,
Puig Montserrat,
Rice Charles M.,
Neumann Avidan U.,
Feinstone Stephen M.
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20239
Subject(s) - viremia , virus , biology , seroconversion , hepatitis c virus , immunology , titer , viral replication , immune system , pathogenesis , alanine transaminase , viral load , virology , interferon , hepacivirus , medicine , endocrinology
Abstract To study determinants of clinical outcome following HCV infection, viral kinetics, immune events, and intrahepatic cytokine markers were compared in 10 naive chimpanzees. Four of the animals cleared HCV; 6 developed persistent infections. All animals developed similar acute infections with increasing viremia from 1 to 2 weeks, followed by alanine aminotransferase (ALT) elevations and seroconversion. This viremia pattern consisted of a biphasic increase, a rapid slope (mean doubling time [t 2 ] = 0.5 days) followed by a slower slope after the second week (t 2 = 7.5 days). This slowing of virus replication correlated in all animals with increased intrahepatic 2′5′ oligoadenylate synthetase 1 (2OAS‐1) messenger RNA (mRNA) levels and was independent of disease outcome. An effective control of virus replication was observed following increases in intrahepatic interferon γ (IFN‐γ) mRNA and ALT levels. Although this control was associated in all animals with a 2‐log decrease in virus titer, the timing occurred approximately 2 weeks later in the chronic group ( P < .05). Additionally, while cleared infections were characterized by a continual decrease in virus titer, the titers in the persistent infections reached a steady state level of 10 4 to 10 5 RNA copies/mL. This inability of the immune response to sustain viral clearance in the persistent infections was associated with a reduced intrahepatic CD3e and monocyte‐induced protein 1α (MIP‐1α) mRNA induction. In conclusion , these data indicate that, regardless of outcome, chimpanzees generate responses that control HCV replication during the early and late acute phase. However, the pathogenesis of HCV may be determined by a more rapid onset of the induced response and the cell population that migrates to the liver. (H EPATOLOGY 2004;39:1709–1720.)