The issue of infection of peripheral blood mononuclear cells (PBMC) by the hepatitis C virus (HCV) has potentially important implications, but is still debated. We have used the severe combined immunodeficiency (SCID) mouse model to test for the persistence of HCV in PBMC. Hematopoietic cells isolated from 14 subjects infected by HCV were inoculated intraperitoneally into SCID mice. Serum and blood cell samples from these mice were obtained with a mean follow-up of 8 weeks. As controls, human fibroblasts and sheep PBMC, preincubated with a human HCV-positive serum, were inoculated concomitantly into mice and analyzed. HCV-RNA positive strands were detected in 7 of 26 serum samples and 8 of 26 cell fractions from SCID mice inoculated with HCV-positive PBMC, after 8 weeks of follow-up. In contrast, no HCV RNA was detectable in the 10 control mice. HCV-RNA negative strands were detected in only 2 of 10 tested samples from 2 mice, and both positive mice had been inoculated with PBMC from HCVpositive subjects with malignant hematopoietic syndrome. Our study offers strong evidence for the persistence of HCV infection in mononuclear cells. Our results are also consistent with a low rate of HCV multiplication. This SCID mouse model might therefore be useful in analyzing the mechanisms of HCV persistence in mononuclear cells. (HEPATOLOGY 1998;28:211-218.)The development of a chronic carrier state is a main feature of infection by the hepatitis C virus (HCV), and in fact, up to 60% to 70% of acutely infected patients show chronic infection during follow-up. The mechanisms involved are not known. It has been shown that chronic infection develops despite a strong and polyclonal humoral response to several structural and nonstructural viral proteins. In addition, a proliferative CD4-and CD8-positive T-cell response against various HCV proteins can also be detected among circulating or liver-derived mononuclear cells. 1,2 However, it is not known to what extent these immunologic parameters correlate with the outcome of the viral infection. HCV, as an RNA virus and a member of the Flaviviridae, shows marked genetic variability, and it has been proposed that this variability might favor its escape from the immune response. All the same, despite the evidence that supports this possibility, at least for the humoral response, the actual impact of this variability in viral persistence remains to be established (for review, see Bukh et al., 3 Simmonds, 4 and Bréchot 5 ).Another intriguing feature of HCV infection regards the clinical and virological profiles of infections by different genotypes of HCV. 6,7 Infection of mononuclear cells by HCV might be a further important parameter to be considered in the pathogenesis of HCV infection. Positive-strand HCV RNA has indeed been detected by reverse-transcription polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells (PBMC) in several studies investigating patients at various stages of the viral infection. [8][9][10][11][12][13][14][15][16][17][18][19][20][21] Furthermo...