Los Alamos Hepatitis C Virus Sequence and Human Immunology Databases: An Expanding Resource for Antiviral Research

Hraber, Peter; Leach, Robert W.; Reilly, Lee Philip; Thurmond, J. Peter; Yusim, Karina; Kuiken, Carla

doi:10.1177/095632020701800407

Cited by 4 publications

(4 citation statements)

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“…A previous study in 1997 [40] reported that subtype 1b was the most prevalent subtype (76%), followed by subtype 3a (19%) and single cases of subtypes 1a and 2a, which suggests that the prevalence of subtype 3a has increased and that fewer subtype 1b strains are now circulating. Subtypes 1b and 3a are also dominant over other subtypes in Russia, Estonia and western Europe [41]. While both subtypes have a similar prevalence (45%) in Russia, the relative prevalence of subtype 1b over subtype 3a is three‐fold greater in Estonia (71% vs. 24%; [30]) and 6.5‐fold higher in western Europe (58% vs. 9%).…”

Section: Resultsmentioning

confidence: 99%

Multiple genotypes and subtypes of hepatitis B and C viruses in Belarus: similarities with Russia and western European influences

Olinger¹,

Lazouskaya

2008

Clinical Microbiology and Infection

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The Republic of Belarus reports a seroprevalence of 4.8% for hepatitis B virus (HBV) and 1.26% for hepatitis C virus (HCV), but little is known about the molecular characteristics of the circulating viruses. This study analysed 69 HBV surface antigen (HBsAg)-positive and 113 anti-HCV-positive donors attending a national reference hospital in Minsk. Among the HCV patients, 70% were co-infected with human immunodeficiency virus (HIV). Phylogenetic analysis of 12 complete genomes and 31 partial HBV sequences, as well as 78 core/E1 HCV sequences, revealed that multiple genotypes and subtypes of both viruses were circulating in Belarus. Of the HBV strains, 11.6% were genotype A2 and 88.6% were genotype D. The genotype D strains segregated into four recently described subtypes, with D2 being the most prevalent (58.1%), followed by D3 (16.3%), D1 (11.6%) and D4 (2.3%), but with inter-subtypic distances lower than the minimal 4% distance proposed to define subtypes. The 78 HCV strains belonged to subtypes 1b (53.8%), 3a (38.5%), 1a (5.1%), 4a (1.3%) and 4d (1.3%). Subtype 1b was less prevalent (45.1% vs. 70.4%) among HCV/HIV co-infected donors, while subtype 3a was more prevalent (29.6% vs. 43.1%). The relative prevalence of HBV and HCV genotypes in Belarus corresponded to the prevalence in Russia, although with a clear European influence that reflected the socio-political context of the country.

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Section: Resultsmentioning

confidence: 99%

Multiple genotypes and subtypes of hepatitis B and C viruses in Belarus: similarities with Russia and western European influences

Olinger¹,

Lazouskaya

2008

Clinical Microbiology and Infection

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“…Fast, accurate, and reliable classification methods are important for many reasons. Knowledge of viral subtypes is useful because it helps to determine routes of disease transmission, can provide therapeutic decision support, facilitates monitoring for new variants, improves understanding of how genetic diversity influences host immune response, and simplifies analysis of treatment-resistance mutations (Korber et al , 2001; Fried et al , 2002; Leitner, 2002; Hadziyannis et al , 2004; Hraber et al , 2006; Hraber et al , 2007). Therefore, we seek to facilitate classification of HIV-1 and HCV sequences.…”

Section: Introductionmentioning

confidence: 99%

Classification of hepatitis C virus and human immunodeficiency virus-1 sequences with the branching index

Hraber

Kuiken

Waugh

et al. 2008

Journal of General Virology

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Classification of viral sequences should be fast, objective, accurate and reproducible. Most methods that classify sequences use either pair-wise distances or phylogenetic relations, but cannot discern when a sequence is unclassifiable. The branching index (BI) combines distance and phylogeny methods to compute a ratio that quantifies how closely a query sequence clusters with a subtype clade. In the hypothesis-testing framework of statistical inference, the BI is compared with a threshold to test whether sufficient evidence exists for the query sequence to be classified among known sequences. If above the threshold, the null hypothesis of no support for the subtype relation is rejected and the sequence is taken as belonging to the subtype clade with which it clusters on the tree. This study evaluates statistical properties of the BI for subtype classification in hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1). Pairs of BI values with known positive-and negative-test results were computed from 10 000 random fragments of reference alignments. Sampled fragments were of sufficient length to contain phylogenetic signals that grouped reference sequences together properly into subtype clades. For HCV, a threshold BI of 0.71 yields 95.1 % agreement with reference subtypes, with equal false-positive and false-negative rates. For HIV-1, a threshold of 0.66 yields 93.5 % agreement. Higher thresholds can be used where lower false-positive rates are required. In synthetic recombinants, regions without breakpoints are recognized accurately; regions with breakpoints do not represent any known subtype uniquely. Web-based services for viral subtype classification with the BI are available online.

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“…Thus, further studies will be important to determine the prevalence of resistant strains as minor viral populations in HCV-infected individuals. In this regard, several web-based methods to facilitate the analysis of mutations related to treatment resistance are already available in both the EuHCVdb and Los Alamos HCV sequence databases [53,54].…”

Section: Discussionmentioning

confidence: 99%

Mapping Natural Polymorphisms of Hepatitis C virus NS3/4A Protease and Antiviral Resistance to Inhibitors in Worldwide Isolates

2008

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Background Several inhibitors for the hepatitis C virus (HCV) NS3/4A protease are under development. Although previous studies identified viral resistance mutations, there is little information on the natural variability of proteases from the different viral subtypes. Here, we aimed to determine both the natural variability and presence of resistance or compensatory mutations to new protease inhibitors (PI) in NS3/4A proteases from worldwide HCV isolates. Methods A comprehensive analysis was performed in 380 HCV NS3 sequences (275 genotype 1; 105 other genotypes) from public HCV databases (EuHCVdb and Los Alamos). Amino acid polymorphism and signature patterns were deduced in the protease domain, including all sites associated with resistance to the PIs BILN-2061, Telaprevir (VX-950), Boceprevir (SCH-503034), SCH-6 and ITMN-191. Results Few of the residues in the catalytic triad or in substrate/metal-binding sites were polymorphic, and were identified in only 4/380 isolates. However, a relevant polymorphism was found in sites associated either with resistance to PI (V36, I170 and D168) or with compensatory mutations (I71, T72, Q86 and I153). Furthermore, some unique genotype-specific signature patterns associated with resistance to PI were also identified. Conclusions We describe for the first time the relevant natural polymorphisms of the HCV NS3/4A protease in worldwide isolates. Although the prevalence of major resistance mutations is very low, many compensatory sites are naturally polymorphic among proteases from several HCV subtypes. These data will help to determine whether HCV resistance is likely to be selected with new PIs and will aid the design of genotypic resistance testing.

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Los Alamos Hepatitis C Virus Sequence and Human Immunology Databases: An Expanding Resource for Antiviral Research

Abstract: Owing to a printing error, Figure 3 was not aligned correctly on the page. The figure below has been corrected. The publisher apologies for this error. [Figure: see text]

Cited by 4 publications

References 0 publications

Multiple genotypes and subtypes of hepatitis B and C viruses in Belarus: similarities with Russia and western European influences

Multiple genotypes and subtypes of hepatitis B and C viruses in Belarus: similarities with Russia and western European influences

Classification of hepatitis C virus and human immunodeficiency virus-1 sequences with the branching index

Mapping Natural Polymorphisms of Hepatitis C virus NS3/4A Protease and Antiviral Resistance to Inhibitors in Worldwide Isolates

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