Letter NS3 protease of genotype 3 subtype h HCV identified in southeastern France

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1 Antiviral Therapy 2011; 16: (doi: /IMP1765) Letter NS3 protease of genotype 3 subtype h HCV identified in southeastern France Philippe Colson 1,2 *, Stéphane Gayet 3, René Gerolami 4 1 Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Centre Hospitalo- Universitaire Timone, Marseille, France 2 URMITE UMR CNRS 6236 IRD 198, Facultés de Médecine et de Pharmacie, Université de la Méditerranée (Aix-Marseille-II), Marseille, France 3 Service de Médecine Interne et Therapeutique, Centre Hospitalo-Universitaire Sainte-Marguerite, Marseille, France 4 Service d Hépato-Gastro-Entérologie, Centre Hospitalo-Universitaire Conception, Marseille, France *Corresponding author philippe.colson@ap-hm.fr HCV displays considerable levels of nucleotide and amino acid diversity. Recently, the relevance of natural polymorphisms in worldwide isolates has been addressed in view of future protease inhibitor (PI)-based treatments; genotype- and subtype-specific natural polymorphisms within HCV NS3 protease were identified at amino acid sites associated either with resistance to PIs or with compensatory mutations. Here, we describe a case of chronic infection with HCV of genotype 3 subtype h (HCV-3h), formerly only described from three patients originating from Somalia, and we provide the first NS3 protease sequence for such strains. NS3 protease sequences of HCV-3h recovered in the present study harbour specific amino acid residues not encountered in other reference HCV genotypes and subtypes at nine of the 181 NS3 protease positions; none of these amino acids are known to confer resistance to PIs. Of note, 5 untranslated region sequence-based genotyping classifies them into genotype 1. Introduction Seven HCV genotypes and >80 subtypes have been described so far. The prevalence of these genotypes vary according to the geographical area and the number of subtypes within HCV genotypes is still expanding [1,2]. In an interesting article published in Antiviral Therapy, López-Labrador et al. [3] addressed the issue of relevance of natural polymorphisms in worldwide HCV isolates in view of future protease inhibitor (PI)- based treatments. In this work and in another study [3,4], genotype- and subtype-specific natural polymorphisms within the HCV NS3 protease were identified at amino acid sites associated either with resistance to PIs or with compensatory mutations. We describe here the first NS3 protease sequence for HCV of genotype 3 subtype h (HCV-3h), formerly only identified based on other regions of the HCV genome from three patients originating from Somalia [5,6]. We recovered this HCV RNA from the serum of an HIV-negative 64-year-old woman chronically infected with HCV, originating from the Republic of Djibouti. In 2009, her HCV RNA level was 1,188 IU/ml and her alanine aminotransferase levels were between 54 and 86 IU/l. Liver stiffness measured by transient elastography was 33 kpa, indicating fibrosis at stage of cirrhosis. HCV genotyping was performed based on phylogenetic analysis of nucleotide sequences corresponding to a partial region of the NS5b polymerase gene, which is the strategy used in first-line routine clinical practice in our laboratory [7]. The HCV NS5b sequence recovered from the patient serum (GenBank accession number HMM441245) was classified as HCV-3h by incorporating into the phylogenetic analysis 10 sequences corresponding to its BLAST hits with the highest scores found in the NCBI GenBank sequence database (Figure 1A). Indeed, nucleotide identity with the best BLAST hit found in our local HCV sequence database, a sequence classified subtype a of genotype 3, was only 71%. By contrast, nucleotide identity was 94% with the best BLAST hit found in the GenBank sequence database (accession number AF279120), a sequence classified as HCV-3h. Later on, HCV NS3 protease sequences (accession numbers HMM and HMM HMM441245) could also be recovered from the patient s serum by direct and clonal sequencing, as previously described [8]. The best BLAST hits found for these sequences in the GenBank sequence database (accession number GQ356204) and our local 2011 International Medical Press (print) (online) 615

2 P Colson et al. Figure 1. Phylogenetic trees based on nucleotide sequences corresponding to a partial region encoding for the NS5b polymerase of the HCV genome and to the full-length NS3 protease coding gene A Ref 7a_EF BBH_Mars-Timo_ BBH_Mars-Timo_ BBH_Mars-Timo_ Ref 3a_NC BBH_Mars-Timo_ BBH_Mars-Timo_ Ref 3a_X76918 BBH_Mars-Timo_ BBH_Mars-Timo_ BBH_Mars-Timo_ BBH_Mars-Timo_ BBH_Mars-Timo_ BBH_nr_AB3285 BBH_nr_FJ BBH_nr_EU Ref 3b_AY5161 Ref 3a_D28917 BBH_nr_Ref 3b_D49374 BBH_nr_D10585 BBH_nr_AF BBH_nr_AF BBH_nr_AF BBH_nr_EF ns5b_ _hmm44245 BBH_nr_AF Ref 3k_D63821 Ref 5a_Y13184 Ref 1b_AF Ref 1b_AY Ref 1c_D14853 Ref 1a_NC Ref 1a_AF Ref 4a_Y11604 Ref 4d_DQ Ref 2a_AY Ref 2k_AB Genotype 3 subtype h Ref 6b_NC (A) Nucleotide sequences corresponding to a partial region encoding for the NS5b polymerase of the HCV genome. (B) Nucleotide sequences corresponding to the full-length NS3 protease coding gene. Phylogenetic analysis included HCV sequences recovered in the present study (indicated by a black frame; GenBank accession numbers HMM HMM441245) and sequences corresponding to the hits with the highest BLAST scores to these sequences found in the NCBI GenBank database (indicated by a black background and a white font) and our local viral hepatitis sequence database (Timone hospital, Marseille, France; indicated by a grey background), and also from the genotype reference panel of the Los Alamos HCV sequence database (the names of these sequences are formatted as Ref_Genotype/ subtype_genbank accession number). For the HCV NS3 protease gene, clonal sequencing was performed in the present study as previously described [10], and six clonal sequences and the sequence recovered by direct sequencing were analysed concomitantly. Nucleotide alignments were performed using MUSCLE [16] and trees were built using the MEGA version 4.0 software [17] with the neighbour-joining method. Bootstrap values are indicated when >50% of 1,000 resamplings of the data. HCV sequence of genotype 7 was used as an outgroup. Scale bar indicates number of nucleotide substitutions per site International Medical Press

3 NS3 protease in HCV-3h Figure 1. Continued B Ref 7a_EF BBH_nr_FJ8647 BBH_nr_FJ BBH_nr_GQ Ref 3a_DQ BBH_nr_GQ BBH_nr_GQ BBH_Mars-Timo_ BBH_nr_GQ Ref 3a_EU BBH_nr_EU BBH_Mars-Timo_ BBH_Mars-Timo_ BBH_Mars-Timo_ BBH_nr_EU Ref 3a_X76918 BBH_nr_FJ BBH_Mars-Timo_ BBH_nr_GQ Ref 3b_DQ Ref 3b_D49374 Ref 3k_D63821 ns3_ _clonal sequence_hmm ns3_ _nonclonal sequence_hmm ns3_ _clonal sequence_hmm ns3_ _clonal sequence_hmm ns3_ _clonal sequence_hmm ns3_ _clonal sequence_hmm ns3_ _clonal sequence_hmm Ref 2k_AB Ref 2a_AY Ref 4d_DQ Ref 4a_DQ Ref 4f_EF Ref 6b_NC Ref 5a_Y13184 Ref 1a_NC Ref 1a_AF Ref 1c_D14853 BBH_Mars-Timo_ BBH_Mars-Timo_ Ref 1b_AJ Ref 1b_M58335 BBH_Mars-Timo_ BBH_Mars-Timo_ BBH_Mars-Timo_ Antiviral Therapy

4 P Colson et al. HCV sequence database showed only 73% and 71% nucleotide identity, respectively, and they were classified as genotype 3 subtype a. Moreover, phylogenetic analysis showed that HCV NS3 protease sequences recovered in the present study were clustered separately from the HCV genotype 3 reference sequences and from their 10 best BLAST hits found in the GenBank sequence database as well as our local sequence database (Figure 1B). Finally, a sequence corresponding to the 5 untranslated (UTR) region of the HCV genome was recovered from the patient s serum (accession number HMM441246). It showed 98% identity at the nucleotide level with the sequence corresponding to its best BLAST hit in the Gen- Bank sequence database (accession number AY766624) and 96% identity with its best BLAST hit in our local HCV sequence database; these two best hits were classified genotype 1 subtype b. Nevertheless, nucleotide identity was % with HCV 5 UTR sequences found in the GenBank sequence database and previously classified HCV-3h [5,6], but nucleotide query coverage was only 89 91% compared with % for sequences with the highest BLAST score and classified genotype 1 subtype b. HCV genotype 3 are classically associated with high rates of sustained virological response to the standard-of-care pegylated interferon-α and ribavirin combination therapy [9]. However, they also appear to exhibit high clinical resistance to the newly available HCV NS3 PIs [10]. This may be related to the natural presence in the NS3 protease of these viruses of amino acid residues conferring decreased sensitivity to PIs or the presence of different amino acids at positions that are crucial for PIs resistance, in particular amino acids 36L and 168Q [3,11,12]. The analysis of the amino acid pattern of HCV-3h NS3 protease recovered in the present study shows some similarities with that of other HCV genotype 3 subtypes, in particular regarding the presence of 36L and 168Q [3,4] (Figure 2 and Additional file 1). However, it also underscores the high diversity of this protein, including at the subtype level. Indeed, HCV-3h NS3 protease presents specific amino acid residues at 9 of the 181 protein positions that are not encountered in HCV sequences from the genotypes and subtypes reference panel of the Los Alamos HCV sequence database, including in other subtypes of genotype 3. None of these HCV-3h amino acids are known to confer resistance to PIs. Nonetheless, one of them is located at position 71, which has been suspected to harbour a compensatory mutation in PI-resistant HCV NS3 proteases [3,13]. Besides, amino acid residue 155R is encoded by codon CGT, which means that two nucleotide substitutions may be required for the selection of R155K, a PI resistance major mutation, instead of one nucleotide exchange for other genotype 3 HCV or for HCV-1a [10,8]. Finally, it may be questioned Figure 2. Alignment of NS3 protease amino acid residues for reference HCV genotype 3 Genbank accession no. HMM441238* Ref_3k_D63821 Ref_3a_DQ Ref_3a_EU Ref_3a_X76918 Ref_3b_DQ Ref_3b_D49374 Ref_1a_NC_ APITAYAQQTRGIFSTIVTSLTGRDNNEVTGHVQVLSTATQTFLGTTVGGVVWTVYHGAGSKSLAGKGRPWLQSYTNVDQDLVGWPAPPG ARSSDPCTCG...H...L.G...K.I...EI...S...S...M...RT...NK..A..M...S....K.LV......T...LLG...K.V...E...L...M...RT...AKH.A..M....K.LE......L.G...K.V...E...I...RT...VKH.A..M....K.LE......LLG...G...K.V...E...M...RT...AKH.A..M....K.LE..A.. S..S...L.G...K.V...E...M...GRT...NK..A..M...A. TK.L... S..S...L.G...K.V...E...M...RT...NK..A..M...A. TK.L......LLGC.I...K.Q.E.E..IV...A.CIN..C...TRTI.SPKG.VI.T...Q. S..LT... Genbank accession no. HMM441238* Ref_3k_D63821 Ref_3a_DQ Ref_3a_EU Ref_3a_X76918 Ref_3b_DQ Ref_3b_D49374 Ref_1a_NC_ SSDLYLVTRDADVIPARRRGDSTASLLSPRPLATLKGSSGGPLLCPAGHVAGIFRAAVVTRGVAKSLQFIPVETLSTQARS.A...I...L...C...IM..S...C...A...S..A.T...A...C...VM..S...C...A...T...T...C...VM..S...C...A....A...C...VM..S...C...A... A...M..E...L...K...T...SC...AM..S...M...I.V.C...A...V.....E...L...T...SC...VM..S...V...C...A...V.....H...V...RG...ISY...T..AV.L...C...AVD...N.E.TM.. The full-length NS3 protease nucleotide sequence (GenBank accession number HMM441238; 543 nucleotides) recovered from the present study was translated into amino acids and then aligned with HCV genotype 3 amino acid sequences from the genotype reference panel of the Los Alamos HCV sequence database [2]. The amino acid sequence for the reference genotype HCV-1a is also provided as a comparison. In the amino acid sequence accession number HMM441238, amino acid residues indicated by a black background are those that differ in other reference genomes (see also Additional file 1), whereas amino acid residues indicated by a grey background are those that differ in other genotype 3 reference genomes. The sequence recovered by direct sequencing in the present study is indicated with an asterisk. Ref, genotype reference HCV sequence International Medical Press

5 NS3 protease in HCV-3h whether the prevalence of such strains could have been underestimated. Indeed, 5 UTR sequence-based genotyping, which is the most commonly performed in virology laboratories worldwide [14], classifies them into genotype 1, which is the most common genotype worldwide. This finding is in agreement with previous studies that have described cases of inaccurate HCV classification based on 5 UTR sequences [7,15]. Acknowledgements We are thankful to Natacha Tivoli for performing the clonal sequencing. Disclosure statement The authors declare no competing interests. Additional file Additional file 1: A supplementary table showing the alignment of NS3 protease amino acid residues for reference HCV genotypes can be found at intmedpress.com/uploads/documents/avt-10-cor- 1763_Colson_Add_file1.pdf References 1. Simmonds P, Bukh J, Combet C, et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005; 42: Kuiken C, Yusim K, Boykin L, Richardson R. The HCV sequence database. Bioinformatics 2005; 21: López-Labrador FX, Moya A, Gonzàlez-Candelas F. Mapping natural polymorphisms of hepatitis C virus NS3/4A protease and antiviral resistance to inhibitors in worldwide isolates. Antivir Ther 2008; 13: Peres-da-Silva A, de Almeida AJ, Lampe E. Mutations in hepatitis C virus NS3 protease domain associated with resistance to specific protease inhibitors in antiviral therapy naive patients. Arch Virol 2010; 155: Abid K, Quadri R, Veuthey AL, Hadengue A, Negro F. A novel hepatitis C virus (HCV) subtype from Somalia and its classification into HCV clade 3. J Gen Virol 2000; 81: Bernier L, Willems B, Delage G, Murphy DG. Identification of numerous hepatitis C virus genotypes in Montreal, Canada. J Clin Microbiol 16; 34: Tamalet C, Colson P, Tissot-Dupont H, et al. Genomic and phylogenetic analysis of hepatitis C virus isolates: a survey of 535 strains circulating in southern France. J Med Virol 2003; 71: Colson P, Brouk N, Lembo F, Castellani P, Tamalet C, Gérolami R. Natural presence of substitution R155K within hepatitis C virus NS3 protease from a treatment-naive chronically infected patient. Hepatology 2008; 47: Pawlotsky JM. Therapy of hepatitis C: from empiricism to eradication. Hepatology 2006; 43 Suppl 1:S207 S Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138: Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132: Thibeault D, Bousquet C, Gingras R, et al. Sensitivity of NS3 serine proteases from hepatitis C virus genotypes 2 and 3 to the inhibitor BILN J Virol 2004; 78: Lu L, Pilot-Matias TJ, Stewart KD, et al. Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro. Antimicrob Agents Chemother 2004; 48: Bowden DS, Berzsenyi MD. Chronic hepatitis C virus infection: genotyping and its clinical role. Future Microbiol 2006; 1: Chevaliez S, Bouvier-Alias M, Brillet R, Pawlotsky JM. Hepatitis C virus (HCV) genotype 1 subtype identification in new HCV drug development and future clinical practice. PLoS ONE 2009; 4:e Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 2004; 32: Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 2007; 24: Accepted 6 October 2010; published online 30 March 2011 Antiviral Therapy

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