Transmission genetics of drug-resistant hepatitis C virus.
Nicholas van BuurenTimothy L TellinghuisenChristopher D RichardsonKarla KirkegaardPublished in: eLife (2018)
Antiviral development is plagued by drug resistance and genetic barriers to resistance are needed. For HIV and hepatitis C virus (HCV), combination therapy has proved life-saving. The targets of direct-acting antivirals for HCV infection are NS3/4A protease, NS5A phosphoprotein and NS5B polymerase. Differential visualization of drug-resistant and -susceptible RNA genomes within cells revealed that resistant variants of NS3/4A protease and NS5A phosphoprotein are cis-dominant, ensuring their direct selection from complex environments. Confocal microscopy revealed that RNA replication complexes are genome-specific, rationalizing the non-interaction of wild-type and variant products. No HCV antivirals yet display the dominance of drug susceptibility shown for capsid proteins of other viruses. However, effective inhibitors of HCV polymerase exact such high fitness costs for drug resistance that stable genome selection is not observed. Barriers to drug resistance vary with target biochemistry and detailed analysis of these barriers should lead to the use of fewer drugs.
Keyphrases
- hepatitis c virus
- drug resistant
- dengue virus
- human immunodeficiency virus
- multidrug resistant
- acinetobacter baumannii
- combination therapy
- wild type
- zika virus
- genome wide
- single cell
- copy number
- physical activity
- density functional theory
- oxidative stress
- dna methylation
- emergency department
- cell cycle arrest
- signaling pathway
- adverse drug
- south africa
- endoplasmic reticulum stress
- genetic diversity