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From the Departments of Laboratory Medicine,* Microbiology, Medicine, and Surgery,¶ University of Washington Medical Center, Seattle; and the Scientific Imaging Laboratory and the Division of Infectious Diseases,|| Fred Hutchinson Cancer Research Center, Seattle, Washington
Hepatitis C virus (HCV) replication at the cellular level is not fully understood. This study describes an optimized system for quantifying replication of HCV in hepatocytes and in liver tissues. A digital image analysis method was developed to quantify signal intensities of HCV genomic and replicative-intermediate RNAs in infected human liver tissues and to examine their spatial distribution. The average number of viral genomes per productively infected hepatocyte ranged from 7 to 64 RNA molecules. The maximal concentrations of genomic and replicative-intermediate RNAs at the single cell level were 74 and 34 molecules per hepatocyte, respectively. A gradient dispersion of genomes was observed around virus-producing cells, suggesting infection of neighboring hepatocytes as one mechanism of viral spread in the liver. There was no significant difference in total hepatic load of HCV genomes between the post- and nontransplant patients, whereas serum titers in the former group were much higher that that in the latter group. HCV replication varied among infected hepatocytes, occurred in a subset of cells, and proceeded at a low level, confirming one mechanism by which individual hepatocytes are cumulatively able to generate steady state concentrations of millions of HCV genomes per milliliter of blood. Lower viral clearance rates in circulating blood may explain the phenomenon of increased serum titers of viral RNA in posttransplant immunosuppressed patients.
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