Genetic diversity of NS3 protease from Brazilian HCV isolates and possible implications for therapy with direct-acting antiviral drugs

Peres-da-Silva, Allan; Almeida, Adílson José de; Lampe, Elisabeth

doi:10.1590/s0074-02762012000200016

Cited by 22 publications

(19 citation statements)

References 31 publications

(37 reference statements)

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“…Brazilian isolates belong mainly to one of these clades [45], and even form a cluster inside this clade [46]. Venezuelan HCV isolates do not group together with Brazilian isolates (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Prevalence of amino acid mutations in hepatitis C virus core and NS5B regions among Venezuelan viral isolates and comparison with worldwide isolates

Jaspe

Sulbarán

et al. 2012

Virol J

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BackgroundRecent reports show that R70Q and L/C91M amino acid substitutions in the core from different hepatitis C virus (HCV) genotypes have been associated with variable responses to interferon (IFN) and ribavirin (RBV) therapy, as well to an increase of hepatocellular carcinoma (HCC) risk, liver steatosis and insulin resistance (IR). Mutations in NS5B have also been associated to IFN, RBV, nucleoside and non-nucleoside inhibitors drug resistance. The prevalence of these mutations was studied in HCV RNA samples from chronically HCV-infected drug-naïve patients.MethodsAfter amplification of core and NS5B region by nested-PCR, 12 substitutions were analyzed in 266 Venezuelan HCV isolates subtype 1a, 1b, 2a, 2c, 2b, 2j (a subtype frequently found in Venezuela) and 3a (n = 127 and n = 228 for core and NS5B respectively), and compared to isolates from other countries (n = 355 and n = 646 for core and NS5B respectively).ResultsR70Q and L/C91M core substitutions were present exclusively in HCV G1b. Both substitutions were more frequent in American isolates compared to Asian ones (69% versus 26%, p < 0.001 and 75% versus 45%, p < 0.001 respectively). In Venezuelan isolates NS5B D310N substitution was detected mainly in G3a (100%) and G1a (13%), this later with a significantly higher prevalence than in Brazilian isolates (p = 0.03). The NS5B mutations related to IFN/RBV treatment D244N was mainly found in G3a, and Q309R was present in all genotypes, except G2. Resistance to new NS5B inhibitors (C316N) was only detected in 18% of G1b, with a significantly lower prevalence than in Asian isolates, where this polymorphism was surprisingly frequent (p < 0.001).ConclusionsGenotypical, geographical and regional differences were found in the prevalence of substitutions in HCV core and NS5B proteins. The substitutions found in the Venezuelan G2j type were similar to that found in G2a and G2c isolates. Our results suggest a high prevalence of the R70Q and L/C91M mutations of core protein for G1b and D310N substitution of NS5B protein for the G3a. C316N polymorphism related with resistance to new NS5B inhibitors was only found in G1b. Some of these mutations could be associated with a worse prognosis of the disease in HCV infected patients.

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Section: Discussionmentioning

confidence: 99%

Prevalence of amino acid mutations in hepatitis C virus core and NS5B regions among Venezuelan viral isolates and comparison with worldwide isolates

Jaspe

Sulbarán

et al. 2012

Virol J

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“…Antibodies targeting the anti-NS3 area appear in the early stages of infection, usually earlier than or simultaneously with the core antibody. Immunization in vivo experiments have shown that CD4+ and CD8+ response induced by HCV core antigen C dendritic cells are weaker than that induced by HCV/NS3 gene-modified dendritic cells (Peres-da-Silva et al, 2012;Vicenti et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Artemisia annua polysaccharides as an adjuvant to hepatitis C vaccination

Ren¹,

L.²,

Wang³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The traditional Chinese medicine Artemisia annua can prevent and treat hepatitis following an unclear mechanism. The aim of this study was to evaluate the effects of A. annua polysaccharides (AAP) on hepatitis C virus (HCV). A pcDNA3.1/NS3 expression vector was constructed. Ninety female BALB/c mice were randomly divided into six groups: high-dose AAP (1 mg/mL) + HCV/NS3 plasmid; middle-dose AAP (0.5 mg/mL) + HCV/NS3 plasmid; lowdose AAP (0.1 mg/mL) + HCV/NS3 plasmid; HCV/NS3 plasmid; high-dose AAP (1 mg/mL); normal saline control (N = 15). Except the control group and the high-dose AAP group, other groups were inoculated with 50 μg pcDNA3.1-HCV/NS3 plasmid. Serum antigenic-specific antibody was detected after the last immunization, and the levels of secreted IFN-γ and IL-4 were measured. pcDNA3.1/ NS3 plasmid was successfully constructed, and the extracted product contained HCV/NS3 sequence. Compared with single inoculation with HCV/NS3 DNA vaccine, the specific antibody levels induced L.D. Bao et al. 4958©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 4957-4965 (2015) by middle-dose AAP plus HCV/NS3 DNA vaccine were significantly different in weeks 1, 3 and 5 (P < 0.05). However, there were no significant differences in the antibody levels induced by high-dose and low-dose AAP as adjuvant compared with those of single inoculation with DNA vaccine (P > 0.05). The level of serum IFN-γ secretion was significantly higher than that of IL-4 secretion. Compared with the single HCV/NS3 DNA vaccine group, AAP plus HCV/NS3 DNA vaccine groups had significant increased IFN-γ levels (P < 0.05), but the IL-4 levels were not significantly different among these groups (P > 0.05). AAP, as the adjuvant of HCV/NS3 DNA vaccine, can widely regulate the humoral immunity and cellular immune function of normal and cyclophosphamide-induced immunocompromised mice. AAP can promote IFN-γ secretion probably by inducing Th1-type cellular immune response.

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“…There is no vaccine available for preventing HCV infections. The main antiviral treatment until 2011, was PEGylated interferon-alfa (aPeg-IFN) alone or in combination with ribavirin, leading to a sustained virological response (SVR) in 50% of treated patients, depending on the virus genotype causing the HCV infection (Peres-da-Silva et al, 2012;Paolucci et al, 2013;Gross et al, 2018). Nowadays, direct-acting antiviral agents (DAAs) have been approved for HCV infection treatment, with an average SVR above 95%, at least for genotypes 1 and 4 (Leuw and Stephan, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…However, a challenge in HCV treatment is the emergence of viral resistance mutations that reduces susceptibility of the virus to DAA therapies (Hoffmann et al, 2015;Gededzha et al, 2017). The development of resistance-associated variants (RAVs) is due to the high level of virus variability, from the combination of the virus' high replication rate, low RNA polymerase fidelity rate, and selective pressure for drug or immunomediated treatment (Peres-da-Silva et al, 2012;Paolucci et al, 2013;Gededzha et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Resistance mutations of NS3 and NS5b in treatment-naïve patients infected with hepatitis C virus in Santa Catarina and Rio Grande do Sul states, Brazil

Andrade

Rocha²,

Fontana-Maurell³

et al. 2020

Genet. Mol. Biol.

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Hepatitis C virus (HCV) infection is a worldwide health problem. Nowadays, direct-acting antiviral agents (DAAs) are the main treatment for HCV; however, the high level of virus variability leads to the development of resistance-associated variants (RAVs). Thus, assessing RAVs in infected patients is important for monitoring treatment efficacy. The aim of our study was to investigate the presence of naturally occurring resistance mutations in HCV NS3 and NS5 regions in treatment-naïve patients. Ninety-six anti-HCV positive serum samples from blood donors at the Center of Hematology and Hemotherapy of Santa Catarina State (HEMOSC) were collected retrospectively in 2013 and evaluated in this study. HCV 1a (37.9%), 1b (25.3%), and 3a (36.8%) subtypes were found. The frequency of patients with RAVs in our study was 6.9%. The HCV NS5b sequencing reveled 1 sample with L320F mutation and 4 samples with the C316N/R polymorphism. The analysis of the NS3 region revealed the D168A/G/T (3.45%), S122G (1.15%), and V55A (2.3%) mutations. All samples from genotype 3a (36.8%) presented the V170 I/V non-synonymous mutation. In conclusion, we have shown that mutations in NS3 and NS5b genes are present in Brazilian isolates from therapy-naïve HCV patients.

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Genetic diversity of NS3 protease from Brazilian HCV isolates and possible implications for therapy with direct-acting antiviral drugs

Abstract: The hepatitis C virus (HCV)NS3

Cited by 22 publications

References 31 publications

Prevalence of amino acid mutations in hepatitis C virus core and NS5B regions among Venezuelan viral isolates and comparison with worldwide isolates

Prevalence of amino acid mutations in hepatitis C virus core and NS5B regions among Venezuelan viral isolates and comparison with worldwide isolates

Efficacy of Artemisia annua polysaccharides as an adjuvant to hepatitis C vaccination

Resistance mutations of NS3 and NS5b in treatment-naïve patients infected with hepatitis C virus in Santa Catarina and Rio Grande do Sul states, Brazil

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