HCV NS3 Genotype-1a
Description
Introduction to HCV NS3 Genotype-1a
The HCV NS3 protein is a multifunctional nonstructural protein essential for viral replication, incorporating helicase, nucleotide triphosphatase, and RNA-binding domains. Genotype-1a is one of the most prevalent HCV subtypes globally, accounting for approximately 40% of infections in the U.S. and Europe . It is associated with reduced responsiveness to interferon-based therapies and higher propensity for developing drug resistance compared to genotype 1b .
Key Features
Table 1: NS3 Sequence Identity Across HCV Genotypes
| Genotype | 1a | 1b | 2b | 3a |
|---|---|---|---|---|
| Identity | 100% | 93.4% | 85% | 87% |
| Binding Region Identity | 100% | 94% | 88% | 90% |
| Data derived from full-length and fluoroquinolone-binding region alignments . |
Primary Resistance Mutations
| Mutation | Position | Fold Resistance | Genotype-Specificity | Source |
|---|---|---|---|---|
| R155K | 155 | 5–21x | 1a | |
| D168G | 168 | 16–400x | 1b | |
| I170T | 170 | 5–21x | 1a | |
| Q80K | 80 | Reduces simeprevir efficacy | 1a (clade I) |
Key Observations:
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Q80K Polymorphism: Strongly associated with clade I and reduces susceptibility to simeprevir but not newer protease inhibitors like glecaprevir .
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Escape Pathways: Genotype 1a exhibits distinct escape mutations (e.g., S1368P upstream of immunodominant CD8+ T-cell epitopes) compared to other genotypes .
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Baseline Variability: NS3 resistance-associated substitutions (RASs) are detected in >50% of treatment-naïve patients, often as quasispecies .
Culture Systems and Resistance
| Viral Strain | Adaptations | Infectivity | Key Utility | Source |
|---|---|---|---|---|
| H77-S | Five adaptive mutations | High RNA secretion | Antiviral/vaccine testing | |
| TNcc | Eight mutations | ~5 log₁₀ FFU/mL | Broad-spectrum inhibitor testing |
Clinical Data:
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Q80K Impact: No significant SVR reduction with simeprevir/PR in phase 2 trials, but testing remains recommended .
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Replicon Resistance: Asunaprevir selects D168 substitutions in 1b (170–400x resistance) but R155K/I170T in 1a (5–21x resistance) .
Clade-Specific Trends
| Clade | Geographic Dominance | Q80K Prevalence | Escape Mutations |
|---|---|---|---|
| I | U.S., non-European regions | 51.6% | S1368P (epitope flanking) |
| II | Europe | 0% | Rare internal mutations |
Key Drivers:
Product Specs
Product Science Overview
Hepatitis C Virus (HCV) is a significant global health concern, primarily affecting the liver. It can lead to severe liver diseases such as fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. HCV was first identified in 1989, and since then, extensive research has been conducted to understand its structure, function, and ways to combat the infection .
The NS3 protein of HCV is a nonstructural protein that plays a crucial role in the virus’s life cycle. It is a multifunctional enzyme with protease, helicase, and nucleoside triphosphatase (NTPase) activities. The NS3 protein is essential for the replication of the viral RNA and the processing of the viral polyprotein .
HCV has several genotypes, with genotype 1 being the most prevalent and studied. Within genotype 1, there are subtypes 1a and 1b. Genotype-1a is particularly significant because it is commonly found in North America and Europe and is associated with a higher rate of resistance to antiviral therapies compared to other genotypes .
The recombinant NS3 protein of HCV genotype-1a, spanning amino acids 1192 to 1459, is a crucial tool for research and diagnostic purposes. This recombinant protein is typically expressed in Escherichia coli (E. coli) and purified using proprietary chromatographic techniques . The region from amino acids 1192 to 1459 includes the immunodominant regions of the NS3 protein, making it highly immunoreactive with sera from HCV-infected individuals .
The recombinant NS3 protein is used in various applications, including:
- Diagnostic Assays: It is used in enzyme-linked immunosorbent assays (ELISA) and Western blot assays to detect antibodies against HCV in patient sera .
- Vaccine Development: The immunodominant regions of the NS3 protein are potential targets for vaccine development. Research is ongoing to develop vaccines that can elicit a strong immune response against these regions .
- Drug Screening: The NS3 protein’s protease and helicase activities make it an important target for antiviral drug development. Inhibitors targeting these activities are being screened and developed to combat HCV infection .
