Genetic similarity of hepatitis C virus and fibrosis progression in chronic and recurrent infection after liver transplantation F.-X. Lo ´pez-Labrador, 1,2 * M. A. Bracho, 2 * M. Berenguer, 3 M. Coscolla `, 2 J. M. Rayo ´n, 4 M. Prieto, 3 D. Carrasco, 3 M. D. Go ´mez, 1 A. Moya 2 and F. Gonza ´lez-Candelas 2 1 Microbiology/Exp. Immunology, Research Centre, Hospital Universitari La Fe; 2 Institut Cavanilles de Biodiversitat i Biologia Evolutiva, Universitat de Vale `ncia; 3 Hepatogastroenterology; and 4 Pathology Service, Hospital Universitari La Fe, Valencia, Spain Received February 2004; accepted for publication December 2004 SUMMARY. The effect of hepatitis C virus (HCV) genetic heterogeneity on clinical features of post-transplantation hepatitis C is controversial. Different regions of the HCV genome have been associated with apoptosis, fibrosis, and other pathways leading to liver damage in chronic HCV infection. Besides, differences in immunodominant regions, such as NS3, may influence HCV-specific immune re- sponses and disease outcome. In the liver transplant set- ting, a recent study has reported a positive association between HCV-1b Core region genetic relatedness 5-year post-transplantation and histological severity of recurrent hepatitis C. We have compared nucleotide sequences of HCV Core, NS3 and NS5b regions in HCV-1b-infected pa- tients 3 years post-transplantation (n ¼ 22). A cohort of nontransplanted patients (n ¼ 22) was used as control of natural chronic HCV-1b infection. Histological evaluation was used to define the rate of fibrosis progression. Molecular variance analysis did not show significant differences in HCV sequences between transplanted and nontransplanted patients, or between those with fast or slow fibrosis progression. The same results were obtained when analysing phylogenetic trees for Core, NS3 and NS5b regions. A more appropriate clustering method (using minimum spanning networks) revealed a significant posi- tive relationship between HCV genetic similarity in Core (r ¼ 0.550, P < 0.01) and NS5b regions (r ¼ 0.847, P < 0.01) and the yearly rate of fibrosis progression in nontransplanted patients which, in contrast, was not observed in transplanted patients. Our results indicate that some strains of HCV-1b might be more pathogenic in the natural course of chronic infection by this virus subtype. In the liver transplant setting, when the immune response is severely compromised, other mechanisms are probably more important in determining hepatitis C progression. Keywords: cirrhosis, disease progression, graft survival, minimum spanning network, phylogenetic tree, viral heterogeneity. INTRODUCTION Hepatitis C virus (HCV) infection is the major cause of chronic hepatitis, cirrhosis and end-stage liver disease lead- ing to liver transplantation (OLT) world-wide. HCV contains a positive ssRNA of approximately 9600 nucleotides en- coding a polyprotein of 3000–3010 amino acids. The HCV genome is characterized by a high replication error rate which leads to extensive genetic heterogeneity reflected in a number of distinct genotypes and subtypes [1], and in the so- called quasispecies distribution of the viral genome [2,3]. The degree of this variability depends on the genomic region analysed: from highly conserved regions (such as the 5¢ end noncoding region – NCR-), regions with moderate variability (including the Core and nonstructural – NS- regions), and regions with a high degree of heterogeneity (such as the hypervariable region 1 – HVR-1 – in the envelope gene E2) [4]. Re-infection of the graft by HCV following OLT leads to histologically proven chronic hepatitis in the vast majority of patients [5]. The outcome of this infection is accelerated (with a faster progression of liver fibrosis) compared to that observed in nontransplanted patients [6,7]. Disease pro- gression is however rather heterogeneous and, while some patients develop cirrhosis within 1 year of transplantation, others remain with stable histology for prolonged periods of time [8]. Prognosis in these patients is highly related to the evolution of HCV [9,10]. Because of the increasing need for *These authors contributed equally to this work. Abbreviations: GTR, Generalized Time Reversible; HCC, hepatocel- lular carcinoma; HCV, hepatitis C virus; IVDU, intravenous drug use. Correspondence: Dr Fernando Gonza ´lez-Candelas, Institut Cavanilles de Biodiversitat i Biologia Evolutiva and Departament de Gene `tica, Universitat de Vale `ncia, Apartado Oficial 22085, 46071-Vale `ncia, Spain. E-mail: fernando.gonzalez@uv.es Journal of Viral Hepatitis, 2006, 13, 104–115 doi:10.1111/j.1365-2893.2005.00670.x Ó 2005 Blackwell Publishing Ltd