Quasispecies and its impact on viral hepatitis

Abstract

Quasispecies dynamics mediates adaptability of RNA viruses through a number of mechanisms reviewed in the present article, with emphasis on the medical implications for the hepatitis viruses. We discuss replicative and non-replicative molecular mechanisms of genome variation, modulating effects of mutant spectra, and several modes of viral evolution that can affect viral pathogenesis. Relevant evolutionary events include the generation of minority virus variants with altered functional properties, and alterations of mutant spectrum complexity that can affect disease progression or response to treatment. The widespread occurrence of resistance to antiviral drugs encourages new strategies to control hepatic viral disease such as combination therapies and lethal mutagenesis. In particular, ribavirin may be exerting in some cases its antiviral activity with participation of its mutagenic action. Despite many unanswered questions, here we document that quasispecies dynamics has provided an interpretation of the adaptability of the hepatitis viruses, with features conceptually similar to those observed with other RNA viruses, a reflection of the common underlying Darwinian principles.

Figures

Fig. 1

Schematic representation of viral quasispecies and fitness variations. (A) An infected individual contains multiple, replicating viral quasispecies, even within the same organ. Here two mutant spectra are depicted with their consensus sequences. Each horizontal line represents a genome, and each symbol on a line represents a type of mutation. Real viral quasispecies can contain thousands of continuously mutating genomes that conform huge mutant clouds. (B) The passage regime of the virus can affect virus population fitness. Small arrows represent repeated bottleneck passages which result in fitness decrease. The large arrow represents large population passages that generally result in fitness gain. Fluctuations in fitness shown at high and low fitness values (at the two small angles of the fitness triangle) have been observed experimentally and interpreted as the stochastic effect of mutations on fitness when fitness gain is limited by population size or when fitness is very low. [Based in (Escarmís et al., 2006, Novella, 2003, Novella et al., 1999); figure modified from (Domingo et al., 2006), with permission].

Fig. 2

Diversity of viral sequences and shift in the HCV quasispecies in serum and liver over time, in a non-progressive patient chronically infected with HCV. Amino acid sequences at the coding junction region E2-p7-NS2 quasispecies in serum (S0 to S5) and liver (L0 and L5), were grouped in clusters represented by histograms. Groups were made according to similarity, so that any amino acid sequence in any subgroup shared one or more amino acid replacements which were not present together in the same amino acid sequence subset in the same or in other samples. That is, inter-group amino acid sequences consisted in one or two substitutions, and intra-group amino acid sequences differed in single point substitutions. The same colors and patterns identify identical subgroups. Mutations in the consensus sequences of the viral quasispecies over time are shown at the bottom of each histogram (each symbol represents one mutation). Shannon entropy and genetic distance are shown below the respective histogram. Based in (Cabot et al., 2001).