Abstract
Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception. Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they are increasingly employed in the clinic. We put the experimental observations in the context of quasi-species dynamics, in particular what the genetic and phenotypic barriers to resistance mean in terms of exploration of sequence space while HCV replicates in the liver of infected patients or in cell culture. Strategies to diminish the probability of viral breakthrough during treatment are briefly outlined.
Highlights
Virologists define quasi-species as dynamic collections of viral genomes subjected to genetic variation, competition, and selection, and which may act collectively as a unit of selection
Six main parameters deserve a comment: (i) the average mutation rate during viral genome replication; (ii) the replication rate that relates to the capacity of exploration of the sequence space; (iii) the viral population size that measures the sequence space occupied by the virus; (iv) the genetic barrier to drug resistance that depends on the number and types of mutations needed to attain the resistance phenotype; (v) the phenotypic barrier to resistance that can be quantified as the fitness cost inflicted upon the virus by the resistance mutations; and (vi) the prior evolutionary history of the virus that may have fixed mutations that alter drug sensitivity or barriers to resistance
With respect to the first question several studies have demonstrated that mutations conferring resistance to NS3/4A, NS5A, or NS5B inhibitors can pre-exist in hepatitis C virus (HCV)-infected patients that have not been previously treated with DAAs [110,111,112,113,114,115]
Summary
Virologists define quasi-species as dynamic collections of viral genomes subjected to genetic variation, competition, and selection, and which may act collectively as a unit of selection This definition arose as a consequence of the comparison of nucleotide sequences of individual genomes present in RNA viral populations, and modification of mutant composition as a function of time, both in cell culture and in vivo. In a strict sense according to theory, the term viral quasi-species should refer to the ensemble of genomes present in a single replicative unit; for example, at a replication complex inside an infected cell where a direct dynamics of mutation, competition, and selection occurs. Current developments with HCV offer an interesting counterpart to the extensive experience gained with antiretroviral agents used to control HIV-1 infections, and the consequences of implementing highly active antiretroviral therapies (HAART) since 1996
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