title: Complete nucleotide sequence of genotype 4 hepatitis C viruses isolated from patients co-infected with human immunodeficiency virus type 1.
abstract: The hepatitis C virus (HCV) genotype 4 is spreading among southern European intravenous drug users, who are frequently co-infected with human immunodeficiency virus type 1 (HIV-1). Response to interferon (IFN) alpha-based therapies in HIV-1 positive patients co-infected with HCV genotype 4 is poor, similar to that obtained for HCV genotype 1 and much lower than for HCV genotypes 2 and 3. The lack of sequence data related to HCV of genotype 4 prompted us to sequence the complete genome of two genotype 4 variants isolated from two HIV-1 co-infected patients (24 and 25). Our aim was to investigate the evolutionary relationships of the former variants with other genotypes and/or genotype 4 subtypes. Sequence alignments and phylogenetic analysis from genomic regions 5'NC, core-E1 and NS5B revealed that the variants isolated from patients 24 and 25 (both subtyped 4c/4d by INNO-LIPA II HCV) belong to subtypes 4d and 4a, respectively. When looking at the complete genome sequence one of the variants showed a new genotype 4 subtype. Interestingly, sequence length differences in the interferon sensitivity determining region coding regions were observed when compared with sequences from other genotypes. Similarly, when the catalytic efficiency of the NS3/4 protease from patients 24 and 25 samples were determined, they displayed 70.6+/-7.7 and 23.5+/-3.4%, respectively, of the activity shown by genotype 1 NS3/4 proteases. Overall, pairwise comparison and phylogenetic analysis of nucleotide sequences of the complete genome or the different protein-encoding regions showed that genotype 4 sequences were more closely related to genotype 1 sequences. The description of new HCV genome variants may help our understanding of the HCV biology as well as the role of different genotypes in HCV treatment and therapy response.
authors.affiliation: Fundació irsiCaixa, Universitat Autònoma de Barcelona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Franco
authors.forename: Cristina
authors.initials: C
authors.lastname: Tural
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martínez
mesh_terms: D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D016679:Genome, Viral; D015658:HIV Infections / Q000150:complications*; D015497:HIV-1; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000150:complications / Q000821:virology*; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000235:genetics; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus