Correlation between Mutations in the Interferon Sensitivity-Determining Region of NS5A Protein and Viral Load of Hepatitis C Virus Subtypes 1b, 1c, and 2a

Abstract

In the present study, we analyzed the possible relationship between interferon (IFN) sensitivity-determining region (ISDR) sequence variation of various hepatitis C virus (HCV) subtypes and serum HCV titers in Indonesian patients without IFN treatment. The viremia titers (mean ؎ standard deviation) of HCV subtype 1b (HCV-1b) isolates with low (three or fewer) and high (four or more) numbers of ISDR mutations were 5.4 ؎ 0.6 and 4.2 ؎ 0.9 log 10 RNA copies/ml, respectively, with the difference between the two groups being statistically significant (P < 0.01). Similarly, the viremia titers of HCV-1c isolates with low and high numbers of ISDR mutations were 5.3 ؎ 0.6 and <3.0 ؎ 0.0 log 10 RNA copies/ml, respectively, with the difference between the two groups being statistically significant (P < 0.01). Also, the virus titers of HCV-2a isolates with low and high numbers of ISDR mutations were 4.3 ؎ 0.7 and 3.5 ؎ 0.4 log 10 RNA copies/ml, respectively, with the difference between the two groups being statistically significant (P < 0.01). Thus, our results demonstrated that virus load in Indonesian patients infected with HCV-1b, HCV-1c, or HCV-2a correlated inversely with the number of mutations in the ISDR sequence, implying the possibility that the ISDR sequence plays an important role in determining the levels of HCV viremia.Hepatitis C virus (HCV) readily establishes a chronic persistent infection that often results in chronic hepatitis and more deteriorating disease such as liver cirrhosis and hepatocellular carcinoma (14). HCV is phylogenetically classified into at least six clades (formerly called genotypes), each of which can be further divided into a number of subtypes (4,26,30). We have previously reported the prevalence of each HCV subtype, including HCV subtype 1c (HCV-1c) (formerly referred to as HCV-1d), among various clinical populations in Surabaya, Indonesia (13, 31). HCV-1c has been found almost exclusively in Indonesia (12,13,23) and shown to be associated with high viral load and poor prognosis (18,31).Interferon (IFN) is the most successful therapeutic agent for the treatment of chronic hepatitis C, although less than half of the patients treated with IFN show sustained responses with eradication of the virus. It is now recognized that HCV viral load in the serum and the HCV genotype and/or quasispecies complexity as well as sequence diversity of particular regions of the viral genome may predict the effectiveness of IFN therapy (2,3,10,16,25,27). Lower pretreatment serum HCV RNA levels have been shown to be associated with a better response to IFN therapy. Patients infected with HCV-1b tend to exhibit poor IFN responsiveness compared with those infected with HCV-2a. Enomoto et al. (6,7) first demonstrated that amino acid mutations of the nonstructural protein 5A (NS5A) of HCV-1b in a region between residues 2209 and 2248 were associated with improved responsiveness to IFN in Japanese patients, and the region has therefore been designated as the IFN sensitivity-determining region (ISDR). This obser...

Novel Subgenotypes of Hepatitis B Virus Genotypes C and D in Papua, Indonesia

“…Nucleotide sequences of the amplified fragments were determined with the BigDye deoxy Terminator v1.1 cycle sequencing kit (Applied Biosystems) and an ABI Prism 310 genetic analyzer (Perkin Elmer) as described previously (8,16,17). The sequences were compared to those from the international DNA data bank (DDBJ/EMBL/GenBank).…”

Correlation between Secondary Structure of an Amino‐Terminal Portion of the Nonstructural Protein 3 (NS3) of Hepatitis C Virus and Development of Hepatocellular Carcinoma

“…Sera were collected from HCV-infected Japanese patients with and without HCC. The sera were tested for anti-HCV antibodies (Ortho HCV Ab ELISA Test III; Ortho Diagnostics, Tokyo), HCV viremia, HCV subtypes and HBsAg (AUSAB ® EIA; Abbott Diagnostics), as described previously (6,24). The diagnosis of HCC was made based on both clinical and histopathological criteria.…”

High Rates of Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and Human Immunodeficiency Virus Infections and Uncommon HBV Genotype/Subtype and HCV Subtype Distributions among Transgender Individuals in Surabaya, Indonesia

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