Liver Transplantation With Hepatitis C Virus–Infected Graft: Interaction Between Donor and Recipient Viral Strains

Abstract

Superinfection of different viral strains within a single host provides an opportunity for studying host-virus and virus-virus interactions, including viral interference and genetic recombination, which cannot be studied in infections with single viral strains. Hepatitis C virus (HCV) is a positive single-strand RNA virus that establishes persistent infection in as many as 85% of infected individuals. However, there are few reports regarding coinfection or superinfection of HCV. Because of the lack of tissue culture systems and small animal models supporting efficient HCV replication, we explored these issues in the setting of liver transplantation where both recipient and donor were infected with different HCV strains and therefore represent a distinct model for HCV superinfection. Serial serum samples collected at multiple time points were obtained from 6 HCV-positive liver donor/recipient pairs from the National Institute of Diabetes and Digestive and Kidney Diseases liver transplantation database. At each time point, HCV genotype was determined by both restriction fragment length polymorphism analysis and phylogenetic analysis. Furthermore, we selectively sequenced 3 full-length HCV isolates at the earliest time points after liver transplantation, including both 5 and 3 ends. Detailed genetic analyses showed that only one strain of HCV could be identified at each time point in all 6 cases. Recipient HCV strains took over in 3 cases, whereas donor HCV strains dominated after liver transplantation in the remaining 3 cases. In conclusion, in all 6 cases studied, there was no genetic recombination detected among HCV quasispecies or between donor and recipient HCV strains. (HEPATOLOGY 2003;38: 25-33.)H epatitis C virus (HCV), a single-strand, positive RNA virus, has been well documented as the major etiologic agent responsible for most posttransfusional and community-acquired hepatitis. 1 HCVrelated liver disease is now a leading cause for liver transplantation in the United States. One striking characteristic of HCV infection is its high chronicity rate; that is, it easily establishes persistent infection in up to 85% of infected individuals and causes a wide spectrum of clinical profiles. The high chronicity rate of HCV may be partially attributed to its great genetic variability, which favors its rapid adaptation to a given biological environment. HCV may be divided into at least 6 major genotypes and more than 30 subtypes according to the phylogenies of available HCV sequences. 2 Moreover, even in patients infected with a single HCV subtype, HCV circulates as a group of variants with up to 10% nucleotide sequence difference, termed quasispecies. [3][4][5][6][7] Superinfection with different viral strains within a single host is a useful model for studying host-virus and virus-virus interactions. In HCV, perhaps due to the lack of protective immunity, 8 superinfection by different HCV isolates in patients with chronic HCV is clinically observed, in particular in individuals at very high risk for infection, suc...

Hepatitis C virus superinfection of liver grafts: a detailed analysis of early exclusion of non-dominant virus strains

“…accordance with previous studies reporting that between 30 and 60 % of the patients retained their original strain (Fan et al, 2003;Laskus et al, 1996;Vargas et al, 1999).…”

Progression of Fibrosis during Chronic Hepatitis C Is Associated with Rapid Virus Evolution

“…The persistence of such mixed infection has been reported previously, though most longitudinal studies have found that only one strain persists, with exclusion of the other (7,21,48). Another recent study examining IDUs with HCV superinfection also found no evidence for recombination (1).…”

Use of Hepatitis C–Infected Deceased Donors in Liver Transplantation

“…In a later review of the clinical outcomes of these patients, the investigators found that if the recipient strain became the remaining strain, the patient had a significantly greater incidence of recurrent hepatitis. These data suggest that different genotypes, or strains/quasispecies within the genotype, may have independent virulence and infection with a "new" viral strain or quasispecies may allow donor HCV characteristics to have a significant role in the posttransplant infectious course [17,38,44,45]. Evaluation of genotype mismatching and genotype switching will comprise an important component of future research.…”

“…These findings may result from a previously up-regulated defense, or an inherent resistance, to hepatic injury resulting from the HCV virus infection. It has also been suggested that HCV-infected allograft recipients may experience genotype switching, in which the more virulent virus that led to cirrhosis in the recipient is downgraded to a less virulent strain through replacement of the liver [17]. These findings are particularly important in the HCV population because older data suggest that living donor split allografts have worse outcomes in HCV recipients, and many centers will not use split grafts in patients with HCV, although more recent studies suggest similar outcomes [10,18,19].…”