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Drug-related mutational patterns in hepatitis B virus (HBV) reverse transcriptase proteins from Iranian treatment-naive chronic HBV patients.

ABSTRACT: BACKGROUND:Immunomodulators and Nucleotide analogues have been used globally for the dealing of chronic hepatitis B virus (HBV) infection. However, the development of drug resistance is a major limitation to their long-term effectiveness. OBJECTIVES:The aim of this study was to characterize the hepatitis B virus reverse transcriptase (RT) protein variations among Iranian chronic HBV carriers who did not receive any antiviral treatments. MATERIALS AND METHODS:Hepatitis B virus partial RT genes from 325 chronic in active carrier patients were amplified and directly sequenced. Nucleotide/amino acid substitutions were identified compared to the sequences obtained from the database. RESULTS:All strains belonging to genotype D.365 amino-acid substitutions were found. Mutations related to lamivudine, adefovir, telbivudine, and entecavir occurred in (YMDD) 4% (n = 13), (SVQ) 17.23% (n = 56), (M204I/V + L180M) 2.45% (n = 8) and (M204I) 2.76% (n = 9) of patients, respectively. CONCLUSIONS:RT mutants do occur naturally and could be found in HBV carriers who have never received antiviral therapy. However, mutations related to drug resistance in Iranian treatment-naïve chronic HBV patients were found to be higher than other studies published formerly. Chronic HBV patients should be monitored closely prior the commencement of therapy to achieve the best regimen option.

SUBMITTER: Mahabadi M

PROVIDER: S-EPMC3626233 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Drug-related mutational patterns in hepatitis B virus (HBV) reverse transcriptase proteins from Iranian treatment-naïve chronic HBV patients.

Mahabadi Mostafa M Norouzi Mehdi M Alavian Seyed Moayyed SM Samimirad Katayoon K Azad Talat Mokhtari TM Saberfar Esmaeil E Mahmoodi Mahmood M Ramezani Fatemeh F Karimzadeh Hadi H Malekzadeh Reza R Montazeri Ghodrat G Nejatizadeh Azim A Ziaee Masood M Abedi Farshid F Ataei Behrooz B Yaran Majid M Sayad Babak B Sayad Babak B Hossein Somi Mohammad M Sarizadeh Gholamreza G Sanei-Moghaddam Ismaeil I Mansour-Ghanaei Fariborz F Rafatpanah Houshang H Pourhosseingholi Mohammad Amin MA Keyvani Hossain H Kalantari Ebrahim E Saberifiroozi Mehdi M Ali Judaki Mohammad M Ghamari Shiva S Daram Maryam M Fazeli Zeinab Z Goodarzi Zahra Z Khedive Abolfazl A Moradi Abdolvahab A Jazayeri Seyed Mohamad SM

Hepatitis monthly 20130120 1

<h4>Background</h4>Immunomodulators and Nucleotide analogues have been used globally for the dealing of chronic hepatitis B virus (HBV) infection. However, the development of drug resistance is a major limitation to their long-term effectiveness.<h4>Objectives</h4>The aim of this study was to characterize the hepatitis B virus reverse transcriptase (RT) protein variations among Iranian chronic HBV carriers who did not receive any antiviral treatments.<h4>Materials and methods</h4>Hepatitis B vir ...[more]

PMID: 23596461

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Project description:Amino acid Lys(65) is part of the highly flexible beta3-beta4 loop in the fingers domain of the 66 kDa subunit of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Recent crystal data show that the epsilon-amino group of Lys(65) interacts with the gamma-phosphate of the bound deoxynucleoside triphosphate ('dNTP') substrate [Huang, Chopra, Verdine and Harrison (1998) Science 282, 1669-1675]. In order to biochemically define the function of RT Lys(65), we have used site-specific mutagenesis to generate RT with a variety of substitutions at this position, including K65E, K65Q, K65A and K65R. Kinetic analyses demonstrate that if Lys(65) in RT is substituted with an amino acid other than arginine the enzyme exhibits dramatic decreases in the binding affinity (K(m)) for all dNTP substrates, in RT catalytic efficiency (k(cat)/K(m)) and in the mutant enzyme's ability to carry out pyrophosphorolysis, the reverse reaction of DNA synthesis. The pH optimum for the DNA polymerase activity of K65E RT was 6.5, compared to 7.5 for the wild-type enzyme, and 8.0 for the K65R, K65A and K65Q mutants. Molecular modelling studies show that mutations of Lys(65) do not affect the geometry of the loop's alpha-carbon backbone, but rather lead to changes in positioning of the side chains of residues Lys(70) and Arg(72). In particular, Glu in K65E can form a salt bridge with Arg(72), leading to the diminution of the latter residue's interaction with the alpha-phosphate of the dNTP residue. This alteration in dNTP-binding may explain the large pH-dependent changes in both dNTP-binding and catalytic efficiency noted with the enzyme. Furthermore, the K65A, K65Q and K65E mutant enzymes are 100-fold less sensitive to all dideoxynucleoside triphosphate ('ddNTP') inhibitors, whereas the K65R mutation results in a selective 10-fold decrease in binding of ddCTP and ddATP only. This implies that mutations at position 65 in HIV-1 RT influence the nucleotide-binding specificity of the enzyme.

Dataset Information

Drug-related mutational patterns in hepatitis B virus (HBV) reverse transcriptase proteins from Iranian treatment-naive chronic HBV patients.

Publications

Drug-related mutational patterns in hepatitis B virus (HBV) reverse transcriptase proteins from Iranian treatment-naïve chronic HBV patients.

Similar Datasets

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