title: Identification of drug resistance and immune-driven variations in hepatitis C virus (HCV) NS3/4A, NS5A and NS5B regions reveals a new approach toward personalized medicine.
abstract: Cellular immune responses (T cell responses) during hepatitis C virus (HCV) infection are significant factors for determining the outcome of infection. HCV adapts to host immune responses by inducing mutations in its genome at specific sites that are important for HLA processing/presentation. Moreover, HCV also adapts to resist potential drugs that are used to restrict its replication, such as direct-acting antivirals (DAAs). Although DAAs have significantly reduced disease burden, resistance to these drugs is still a challenge for the treatment of HCV infection. Recently, drug resistance mutations (DRMs) observed in HCV proteins (NS3/4A, NS5A and NS5B) have heightened concern that the emergence of drug resistance may compromise the effectiveness of DAAs. Therefore, the NS3/4A, NS5A and NS5B drug resistance variations were investigated in this study, and their prevalence was examined in a large number of protein sequences from all HCV genotypes. Furthermore, potential CD4+and CD8+T cell epitopes were predicted and their overlap with genetic variations was explored. The findings revealed that many reported DRMs within NS3/4A, NS5A and NS5B are not drug-induced; rather, they are already present in HCV strains, as they were also detected in HCV-naïve patients. This study highlights several hot spots in which HLA and drug selective pressure overlap. Interestingly, these overlapping mutations were frequently observed among many HCV genotypes. This study implicates that knowledge of the host HLA type and HCV subtype/genotype can provide important information in defining personalized therapy.
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan.
authors.forename: Aqsa
authors.initials: A
authors.lastname: Ikram
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Obaid
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan.
authors.forename: Faryal Mehwish
authors.initials: FM
authors.lastname: Awan
authors.affiliation: Department of Healtcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan.
authors.forename: Rumeza
authors.initials: R
authors.lastname: Hanif
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan.
authors.forename: Anam
authors.initials: A
authors.lastname: Naz
authors.affiliation: Department of Computer Sciences, RCMS, National University of Sciences and Technology (NUST), Pakistan.
authors.forename: Rehan Zafar
authors.initials: RZ
authors.lastname: Paracha
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan.
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan. Electronic address: janjua.hussnain@gmail.com.
authors.forename: Hussnain Ahmed
authors.initials: HA
authors.lastname: Janjua
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D030541:Databases, Genetic; D024882:Drug Resistance, Viral / Q000235:genetics*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006680:HLA Antigens; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000276:immunology / Q000821:virology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D006801:Humans; D020125:Mutation, Missense; D057285:Precision Medicine / Q000379:methods; D011480:Protease Inhibitors / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Direct acting antiviral drugs; Drug resistance mutations; Epitope mutations; Overlap