Analysis of hepatitis C virus-inoculated chimpanzees reveals unexpected clinical profiles

Abstract

The clinical course of hepatitis C virus (HCV) infections in a chimpanzee cohort was examined to better characterize the outcome of this valuable animal model. Results of a cross-sectional study revealed that a low percentage (39%) of HCV-inoculated chimpanzees were viremic based on reverse transcription (RT-PCR) analysis. A correlation was observed between viremia and the presence of anti-HCV antibodies. The pattern of antibodies was dissimilar among viremic chimpanzees and chimpanzees that cleared the virus. Viremic chimpanzees had a higher prevalence of antibody reactivity to NS3, NS4, and NS5. Since an unexpectedly low percentage of chimpanzees were persistently infected with HCV, a longitudinal analysis of the virological profile of a small panel of HCV-infected chimpanzees was performed to determine the kinetics of viral clearance and loss of antibody. This study also revealed that a low percentage (33%) of HCV-inoculated chimpanzees were persistently viremic. Analysis of serial bleeds from six HCV-infected animals revealed four different clinical profiles. Viral clearance with either gradual or rapid loss of anti-HCV antibody was observed in four animals within 5 months postinoculation. A chronic-carrier profile characterized by persistent HCV RNA and anti-HCV antibody was observed in two animals. One of these chimpanzees was RT-PCR positive, antibody negative for 5 years and thus represented a silent carrier. If extrapolated to the human population, these data would imply that a significant percentage of unrecognized HCV infections may occur and that silent carriers may represent potentially infectious blood donors.

FIG. 1

Current HCV status of the chimpanzees at the Southwest Foundation for Biomedical Research. During the past 2 to 19 years, 52 of the 249 chimpanzees were inoculated with various NANBH inocula. HCV infection was confirmed in 46 animals. Serum samples collected in 1995 were analyzed for HCV RNA by RT-PCR analysis and for anti-HCV antibody by ELISA.

FIG. 2

Serial passage of the Hutchinson strain of HCV in chimpanzees. Chimpanzees x007 and x194 were inoculated with 10^2.5 CID₅₀ of the Hutchinson strain (H77) of HCV in March and April 1988 (3/88 and 4/88), respectively. Acute-phase plasma from x007 was inoculated into x174 in August 1988. Concentrated tissue culture medium from hepatocytes obtained from x007 liver was used to inoculate x196 in September 1988 (27, 28). Acute-phase plasma from x174 was concentrated and inoculated into x268 in May 1989. Chimpanzee x198 was inoculated with acute-phase plasma from x268 in September 1989.

FIG. 3

ALT levels and anti-HCV status in HCV-inoculated chimpanzees with persistent viremia. The presence (+) or absence (−) of HCV RNA, detected by RT-PCR, is indicated. The arrow indicates the ALT upper normal limit (55 U/liter). The solid line indicates the ALT values. The bars represent the anti-HCV ELISA (Ortho HCV 2.0) OD values. The dashed line indicates the ELISA cutoff OD value.

FIG. 4

ALT levels and anti-HCV status in HCV-inoculated chimpanzees with a gradual reduction in anti-HCV antibody. For details, see the legend to Fig. 3.

FIG. 5

ALT levels and anti-HCV status in HCV-inoculated chimpanzees with a rapid loss of anti-HCV antibody. For details, see the legend to Fig. 3.