Genetic Variability in HCV and its Role in Antiviral Treatment Response
Genetic Variability in HCV and its Role in Antiviral Treatment Response
Hepatitis C virus (HCV) is a major health problem worldwide, infecting an estimated 170 million people. The high genetic variability of HCV contributes to the chronicity of hepatitis C. Here, we report results from a large-scale sequence analysis of 67 patients infected with HCV genotype 1, 23 with subtype 1a and 44 with subtype 1b. Two regions of the HCV genome were analysed in samples prior to combined therapy with alpha interferon plus ribavirin, one compressing the hypervariable regions (HVR1, HVR2 and HVR3) of the E2 glycoprotein and another one including the interferon-sensitive determining region (ISDR) and the V3 domain of the NS5A protein. Genetic diversity measures showed a clear tendency to higher genetic variability levels in nonresponder patients to antiviral treatment than in responder patients, although highly disperse values were present within each response group for both subtypes. A more detailed analysis of amino acid composition revealed the presence of several subtype-specific variants in a few positions, but no discriminating positions between responder and nonresponder patients were detected. Our results also revealed that most amino acid positions were highly conserved, especially for subtype 1a. We conclude that the outcome of the antiviral treatment might depend not only on the nature of one or a few independent positions, but more likely on the combination of several positions along the HCV genome. Moreover, the own host's ability to generate an appropriate systemic response, in combination with the action of antivirals, is also likely to be essential for treatment outcome.
Hepatitis C virus (HCV) affects an estimated 170 million individuals worldwide. Although antiviral therapies have improved in recent years, they have severe side effects and are effective in only about one-half of treated patients. Up to 20% of those infected may develop complications such as cirrhosis, liver failure or hepatocellular carcinoma.
Hepatitis C virus is a single-stranded, positive-sense RNA virus, whose genome is about 9.6 kb in length and encodes for a polyprotein of about 3000 amino acids. This polyprotein is processed by host and viral proteases to release three structural (core, E1, E2) and seven nonstructural (p7, NS2-NS5B) proteins (reviewed in ).
The response to anti-HCV therapy depends on the HCV genotype. Patients infected with HCV genotypes 1 or 4 show significantly lower sustained response rates than those infected with genotypes 2 or 3. Moreover, although considerable genetic heterogeneity exists among different HCV isolates, subtypes 1a and 1b are the most prevalent worldwide.
The high persistence of HCV infections, together with the low susceptibility to antiviral treatments, is probably due to a complex interaction between the genetic diversity of the virus and the host immune response. The high levels of genetic variability enable HCV to escape from immune response and usually lead to chronic disease. The selective pressure exerted by the immune system is stronger in those regions with the highest degree of genetic variability. This is the case of HVR1, which has been extensively studied and seems to be involved in target cell recognition and virus attachment. Moreover, the genetic variability of other regions has also been studied, such as the interferon-sensitive determining region (ISDR) or the V3 domain of the NS5A protein. Interestingly, a potential role in responsiveness to interferon has been hypothesized for the ISDR and the V3 domain.
Here, we have studied the association between initial genetic diversity of HCV populations and the response to treatment for two HCV genome fragments including hypervariable regions in the envelope 2 glycoprotein and the ISDR and V3 domains of the NS5A protein. For this, we have analysed a cohort of 67 patients infected with HCV genotype 1, 23 of them with subtype 1a and 44 with subtype 1b. For each patient, a serum sample was obtained before a combined treatment with alpha interferon plus ribavirin was started. A slight trend to higher diversity in nonresponder patients was found, although the heterogeneity of variability measures in all groups was remarkable. Moreover, an analysis of amino acid composition allowed us to detect some subtype-specific positions, whereas positions discriminating between responder and nonresponder patients were not detected, apart from some nonconclusive cases.
Abstract and Introduction
Abstract
Hepatitis C virus (HCV) is a major health problem worldwide, infecting an estimated 170 million people. The high genetic variability of HCV contributes to the chronicity of hepatitis C. Here, we report results from a large-scale sequence analysis of 67 patients infected with HCV genotype 1, 23 with subtype 1a and 44 with subtype 1b. Two regions of the HCV genome were analysed in samples prior to combined therapy with alpha interferon plus ribavirin, one compressing the hypervariable regions (HVR1, HVR2 and HVR3) of the E2 glycoprotein and another one including the interferon-sensitive determining region (ISDR) and the V3 domain of the NS5A protein. Genetic diversity measures showed a clear tendency to higher genetic variability levels in nonresponder patients to antiviral treatment than in responder patients, although highly disperse values were present within each response group for both subtypes. A more detailed analysis of amino acid composition revealed the presence of several subtype-specific variants in a few positions, but no discriminating positions between responder and nonresponder patients were detected. Our results also revealed that most amino acid positions were highly conserved, especially for subtype 1a. We conclude that the outcome of the antiviral treatment might depend not only on the nature of one or a few independent positions, but more likely on the combination of several positions along the HCV genome. Moreover, the own host's ability to generate an appropriate systemic response, in combination with the action of antivirals, is also likely to be essential for treatment outcome.
Introduction
Hepatitis C virus (HCV) affects an estimated 170 million individuals worldwide. Although antiviral therapies have improved in recent years, they have severe side effects and are effective in only about one-half of treated patients. Up to 20% of those infected may develop complications such as cirrhosis, liver failure or hepatocellular carcinoma.
Hepatitis C virus is a single-stranded, positive-sense RNA virus, whose genome is about 9.6 kb in length and encodes for a polyprotein of about 3000 amino acids. This polyprotein is processed by host and viral proteases to release three structural (core, E1, E2) and seven nonstructural (p7, NS2-NS5B) proteins (reviewed in ).
The response to anti-HCV therapy depends on the HCV genotype. Patients infected with HCV genotypes 1 or 4 show significantly lower sustained response rates than those infected with genotypes 2 or 3. Moreover, although considerable genetic heterogeneity exists among different HCV isolates, subtypes 1a and 1b are the most prevalent worldwide.
The high persistence of HCV infections, together with the low susceptibility to antiviral treatments, is probably due to a complex interaction between the genetic diversity of the virus and the host immune response. The high levels of genetic variability enable HCV to escape from immune response and usually lead to chronic disease. The selective pressure exerted by the immune system is stronger in those regions with the highest degree of genetic variability. This is the case of HVR1, which has been extensively studied and seems to be involved in target cell recognition and virus attachment. Moreover, the genetic variability of other regions has also been studied, such as the interferon-sensitive determining region (ISDR) or the V3 domain of the NS5A protein. Interestingly, a potential role in responsiveness to interferon has been hypothesized for the ISDR and the V3 domain.
Here, we have studied the association between initial genetic diversity of HCV populations and the response to treatment for two HCV genome fragments including hypervariable regions in the envelope 2 glycoprotein and the ISDR and V3 domains of the NS5A protein. For this, we have analysed a cohort of 67 patients infected with HCV genotype 1, 23 of them with subtype 1a and 44 with subtype 1b. For each patient, a serum sample was obtained before a combined treatment with alpha interferon plus ribavirin was started. A slight trend to higher diversity in nonresponder patients was found, although the heterogeneity of variability measures in all groups was remarkable. Moreover, an analysis of amino acid composition allowed us to detect some subtype-specific positions, whereas positions discriminating between responder and nonresponder patients were not detected, apart from some nonconclusive cases.