TRACKING HEPATITIS-C VIRUS QUASI-SPECIES MAJOR AND MINOR VARIANTS IN SYMPTOMATIC AND ASYMPTOMATIC LIVER-TRANSPLANT RECIPIENTS

To evaluate the possibility that distinct viral quasispecies play. a r ole in the pathogenesis of progressive hepatitis C virus (HCV) infecti on, we performed a detailed evaluation of HCV quasispecies before and after liver transplantation in five patients infected with HCV genotyp e 1, three of whom developed severe recurrent hepatitis C and two of w hom developed asymptomatic posttransplant infections with high-titered viremia, HCT I quasispecies were characterized by using a combination of nucleotide sequencing plus heteroduplex tracking assay of the seco nd envelope gene hypervariable region (HVR). An average of 30 HVR clon es were analyzed per specimen; an average of five specimens were analy zed per patient over a 6- to 24 month study period. The complexity of HCV quasispecies in pretransplant serum varied, ranging from one to ni ne genetically distinct variants for the five patients. However, in al l five cases, relatively homogenous quasispecies variants emerged afte r liver transplantation. In the three patients who developed recurrent hepatitis, quasispecies major variants present in pretransplant serum were efficiently propagated immediately after liver transplantation a nd were propagated throughout the course of acute and chronic hepatiti s. In contrast, in the two asymptomatic cases, we observed rapid deple tion of pretransplant quasispecies major variants from posttransplant serum, followed by emergence of new quasispecies variants by posttrans plant day 30. Genetic analysis suggested that in these cases, the new quasispecies variants were derived from minor variants present at rela tively low clonal frequency (less than 5% of HVR clones) within the pr etransplant quasispecies populations. These data demonstrate that quas ispecies tracking patterns are associated with the rapidity and severi ty of HCV-associated liver disease after liver transplantation. Furthe r characterization of HCV quasispecies in animal model systems is warr anted.