Genetic complexity of the hypervariable region 1 (HVR1) of hepatitis C virus (HCV): Influence on the characteristics of the infection and responses to interferon alfa therapy in patients with chronic hepatitis C

• Published in: Journal of medical virology Vol. 54; no. 4; pp. 256 - 264
• Main Authors: Pawlotsky, Jean-Michel, Pellerin, Muriel, Bouvier, Magali, Roudot-Thoraval, Françoise, Germanidis, Georgios, Bastie, Anne, Darthuy, Françoise, Rémiré, Jocelyne, Soussy, Claude-James, Dhumeaux, Daniel
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 01.04.1998; Wiley-Liss
• Subjects: Adolescent; Adult; Aged; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - therapeutic use; Base Sequence; Biological and medical sciences; Female; genetic complexity; Genetic Variation; Hepacivirus - drug effects; Hepacivirus - genetics; hepatitis C virus; Hepatitis C, Chronic - drug therapy; Human viral diseases; Humans; hypervariable region 1; Infectious diseases; interferon alpha; Interferon-alpha - therapeutic use; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Pharmacology. Drug treatments; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; quasispecies; Sequence Alignment; Sequence Homology, Nucleic Acid; Viral diseases; Viral Envelope Proteins - genetics; Viral hepatitis; Human; Genetic variability; RNA; Alpha interferon; Cytokine; Hepatic disease; Hypervariable region; Infection; Virus; Chemotherapy; Treatment; Viral disease; Molecular epidemiology; Digestive diseases; Antiviral; Flaviviridae; Hepatitis C virus; Hepacivirus; Viral hepatitis C
• DOI: 10.1002/(SICI)1096-9071(199804)54:4<256::AID-JMV4>3.0.CO;2-3
• ISSN: 0146-6615

HCV exists within its host as pools of related genetic variants referred to as quasispecies. The hypervariable region 1 (HVR1) of the E2 envelope gene is subjected to strong selective pressure from neutralizing antibodies. The genetic complexity of this region is defined as the total number of genetic variants within the quasispecies population. The genetic complexity of the HVR1 region was examined in patients with chronic hepatitis C and its relationship with the epidemiology of HCV infection, and its influence on liver disease and the response to interferon treatment were determined in 114 patients with chronic hepatitis C. The genetic complexity of the HVR1 major variants was measured before treatment by using a polymerase chain reaction (PCR)‐single‐strand conformation polymorphism (SSCP) technique, and was compared with epidemiological, clinical, virological and histological features. The patients were treated with 3 megaunits of interferon (IFN) alfa for 3 to 6 months and the response to treatment was assessed at 3, 6 and 12 months. The HVR1 could be studied in 101 of the 114 patients (89%). Genetic complexity was significantly higher in patients infected through blood transfusion than intravenous drug use (mean complexity index: 5.7 ± 2.3 vs. 4.7 ± 1.5, respectively; P = 0.04). This relationship was independent of age and the estimated time since infection. No significant relationship was found with other parameters of infection or liver disease. In univariate analysis, the genetic complexity of HVR1 major variants did not affect the rates of ALT normalization at months 3 and 6 of IFN treatment. HVR1 genetic complexity was lower in patients with a sustained virological response than in non‐responders (4.0 ± 1.7 vs. 5.4 ± 2.0, respectively; P = 0.07). In multivariate analysis of pretreatment parameters associated with a sustained virological response to treatment, three parameters appeared to be independent predictors of such a response: a low viral load (P < 0.04), a low anti‐HCV core IgM titer (P = 0.03) and a low genetic complexity of HVR1 major variants (P < 0.04). In conclusion, the HVR1 of HCV has a quasispecies distribution in infected individuals. Its genetic complexity is significantly higher in transfusion recipients than in intravenous drug users, suggesting that the size of the initial inoculum affects the later emergence and development of viral quasispecies. The genetic complexity of HVR1, together with viral load and the anti‐HCV IgM titer, are independent predictors of a sustained virological response to IFN alfa in patients with chronic hepatitis C. J. Med. Virol. 54:256–264, 1998. © 1998 Wiley‐Liss, Inc.