Article

Hepatitis C Virus Genotype 1a NS5A Pretreatment Sequence Variation and Viral Kinetics in African American and White Patients

Department of Medicine, University of Illinois at Chicago, 60612, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 10/2005; 192(6):1078-87. DOI: 10.1086/432760
Source: PubMed

ABSTRACT

In hepatitis C virus (HCV) infection, race is a determinant of treatment response and interferon (IFN) effectiveness. Here,
we investigated whether there were differences in the pretreatment viral strains between African American patients and white
patients and whether these differences correlated with viral kinetics. IFN effectiveness was calculated using a viral kinetic
model. The HCV NS5A region from 21 treated patients with HCV genotype 1a was sequenced and analyzed. White patients displayed
more mutations in the V3 region (mean±SD, 4.5±1.4 vs. 2.9±1.6; P=.016), and treatment responders tended to have more mutations
in this region than did nonresponders. There was a significant positive correlation between IFN effectiveness and the number
of mutations in the V3 region (P=.03). There was no clustering of strains by race, treatment response, or IFN effectiveness
in phylogenetic analyses. The results of this study, in conjunction with those of a previous study illustrating the impaired
IFN effectiveness in African Americans, suggest a role for host-related factors

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    • ", which has been postulated to be involved in responsiveness to interferon [Duverlie et al., 1998; Durante et al., 2003; Layden-Almer et al., 2005]. Again, no clear patterns of adaptation were detected in any region. "
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    ABSTRACT: Hepatitis C virus (HCV) presents several regions involved potentially in evading antiviral treatment and host immune system. Two regions, known as PKR-BD and V3 domains, have been proposed to be involved in resistance to interferon. Additionally, hypervariable regions in the envelope E2 glycoprotein are also good candidates to participate in evasion from the immune system. In this study, we have used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples obtained just before initiation of therapy and after 6 or/and 12 months of treatment were available. A range of 25-100 clones per patient, genome region and time sample were obtained. The predominant amino acid sequences for each time sample and patient were determined. Next, the sequences of the PKR-BD and V3 domains and the hypervariable regions from different time samples were compared for each patient. The highest levels of variability were detected at the three hypervariable regions of the E2 protein and, to a lower extent, at the V3 domain of the NS5A protein. However, no clear patterns of adaptation to the host immune system or to antiviral treatment were detected. In summary, although high levels of variability are correlated to viral adaptive response, antiviral treatment does not seem to promote convergent adaptive changes. Consequently, other regions must be involved in evasion strategies likely based on a combination of multiple mechanisms, in which pools of changes along the HCV genome could confer viruses the ability to overcome strong selective pressures.
    Full-text · Article · Apr 2009 · Journal of Medical Virology
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    • ", which has been postulated to be involved in responsiveness to interferon [Duverlie et al., 1998; Durante et al., 2003; Layden-Almer et al., 2005]. Again, no clear patterns of adaptation were detected in any region. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) presents several regions involved potentially in evading antiviral treatment and host immune system. Two regions, known as PKR-BD and V3 domains, have been proposed to be involved in resistance to interferon. Additionally, hypervariable regions in the envelope E2 glycoprotein are also good candidates to participate in evasion from the immune system. In this study, we have used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples obtained just before initiation of therapy and after 6 or/and 12 months of treatment were available. A range of 25-100 clones per patient, genome region and time sample were obtained. The predominant amino acid sequences for each time sample and patient were determined. Next, the sequences of the PKR-BD and V3 domains and the hypervariable regions from different time samples were compared for each patient. The highest levels of variability were detected at the three hypervariable regions of the E2 protein and, to a lower extent, at the V3 domain of the NS5A protein. However, no clear patterns of adaptation to the host immune system or to antiviral treatment were detected. In summary, although high levels of variability are correlated to viral adaptive response, antiviral treatment does not seem to promote convergent adaptive changes. Consequently, other regions must be involved in evasion strategies likely based on a combination of multiple mechanisms, in which pools of changes along the HCV genome could confer viruses the ability to overcome strong selective pressures. J. Med. Virol. 81:650-656, 2009 (c) 2009 Wiley-Liss, Inc
    Full-text · Article · Feb 2009
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    ABSTRACT: We present an analysis of the selective forces acting on two hepatitis C virus genome regions previously postulated to be involved in the viral response to combined antiviral therapy. One includes the three hypervariable regions in the envelope E2 glycoprotein, and the other encompasses the PKR binding domain and the V3 domain in the NS5A region. We used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples were obtained before initiation of therapy and after 6 or/and 12 months of treatment. A range of 25-100 clones per patient, genome region and time sample were sequenced. These were used to detect general patterns of adaptation, to identify particular adaptation mechanisms and to analyze the patterns of evolutionary change in both genome regions. These analyses failed to detect a common adaptive mechanism for the lack of response to antiviral treatment in these patients. On the contrary, a wide range of situations were observed, from patients showing no positively selected sites to others with many, and with completely different topologies in the reconstructed phylogenetic trees. Altogether, these results suggest that viral strategies to evade selection pressure from the immune system and antiviral therapies do not result from a single mechanism and they are likely based on a range of different alternatives, in which several different changes, or their combination, along the HCV genome confer viruses the ability to overcome strong selective pressures. cuevast@uv.es; mtorresp@uv.es; njimenez@uv.es; bracho@uv.es; garciai@uv.es; wrobel@uv.es; moya@uv.es; gonzalef@uv.es
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