Christine Rouer, Joost zyxwvutsr A. R. Drexhage, Babs E. Verstrepen, Ernst J. Verschoor, Ronald E. Bontrop, Gerrit Koopman, and Jonathan L. Heeney Chronic hepatitis C virus (HCX) infection in humans is associated with an impairment of dendritic cells (DC). It has been hypothesized that impairment of DC function may be a central mechanism facilitating the establishment of a chronic carrier state. However, the majority of patients studied with DC impairment to date have been identified and, thus, inadvertently selected because of clinical manifestations leading to their diagnosis, which may have been many years following actual infection. We set out to determine whether impaired DC function occurred in the earlier asymptomatic phase of infection and turned to a well-defined cohort of HCV-infected chimpanzees in which the specific date of infection and the nature of the inoculum were well characterized. Results revealed that, in contrast to the observations in human subjects with advanced clinical hepatitis, there was neither im- pairment of the allostimulatory capacity of monocyte-derived DC from HCV chronic car- riers nor impairment of the maturation process. Decreased allostimulatorycapacity was only detected in zyxwvu 2 animals and, interestingly, in those that possessed the highest viral loads. Nevertheless, HCV sequences were undetectable in any of the DC derived from HCV- infected chimpanzees. In conclusion, these findings suggest that the mechanisms of estab- lishing persistent HCV infection are separate and independent from those responsible for impaired DC function. Indeed, the maturation and allostimulatory impairment, zy as de- scribed in patient studies, are not necessaryprerequisitesbut rather possible consequences of persistent and active HCV infection associated with disease progression. (HEPATOLOGY 2003; 38851-858.) H epatitis C virus (HCV) is the leading cause of chronic liver infections and is strongly corre- lated with the risk of developing cirrhosis and hepatocellular carcinoma. HCV is capable of causing persistent infection in up to 80% of infected individuals, and there are more than 180 million HCV chronic carri- ers worldwide.2For a large number of these patients, there zyxwvu Abbreviations:HCK hepatitis C virus; APC antigen-presenting cells; zyxwvuts DC, den- driticcells; PBMC peripheral blood mononuclear cells; N-DC, DCfrom non-HCV inficted animak HCV-DC, DC from chronically HCV-inficted animals; HLA, human leukocyte antigen; MFIj mean zyxwvutsrqpo juorescence intensity; MHC, major histo- compatibility complex; Pam, Pan troglodytes MHC. From the Department of Virology, Biomedical Primate Research Centre, RijswijR 2280 GH, The Netherhndr. Received Febnrary 26, 2003; acceptedJuly 30,2003. Supported in part by the European Community, contract HCVacc cluster No. Address reprint requests to:Jonathan L. Heeney, BPRC, Postbur3306, 2280 GH Copyright zyxwvutsrqpon 0 2003 by the American Association fir the Study of Liver Diseases. doi:lO.1053/jhep.2003.50426 QLK2-CT-1999-00356 within the 5thfiameworkprogram. Rijswijk, The Netherlands. E-mail: heeney@bprc.nL fm: (31) 15-284-3986 0270-9139/03/3804-0010$30.00/0 is no satisfactorytherapeutic treatment.3 To optimize new therapeutic strategies, it is essential to identifj. the mech- anism by which HCV establishes persistent infection. Persistence of HCV is associated with the inability of the host to develop an effective immune response capable of clearing HCV-infected cells in vivo. The specific im- munologic factors determining whether an individual de- velops a chronic HCV carrier state are unknown.* Different mechanisms could account for this. Current evidence suggests that HCV is able to evade host re- sponses by inducing defects of the antigen-presenting cells (APC).*APC, such as the dendritic cells (DC), are of key importance as sentinels that capture the foreign anti- gens and as the initiators of the immune response by presenting antigens and activating T cells.5 Alterations of D C functions have been associated with the development of severe chronic viral infections, including AIDSGand measles.7 Four independent laboratories have reported that HCV infection in humans with chronic active hepa- titis is associated with a drastic impairment of allostimu- 85 zy 1