4.6 Review

Population Disequilibrium as Promoter of Adaptive Explorations in Hepatitis C Virus

Journal

VIRUSES-BASEL
Volume 13, Issue 4, Pages -

Publisher

MDPI
DOI: 10.3390/v13040616

Keywords

viral quasispecies; hepatitis C virus; mutational waves; residue conservation; sequence space; antiviral drug resistance; universal vaccines; COVID-19

Categories

Funding

  1. Ministerio de Economia y Competitividad (MINECO) [SAF2014-52400-R]
  2. Ministerio de Ciencia, Innovacion y Universidades (MCIU) [SAF2017-87846-R, BFU2017-91384-EXP]
  3. Comunidad de Madrid/FEDER [S2018/BAA-4370, S2013/ABI-2906]
  4. Miguel Servet program of the Instituto de Salud Carlos III [CPII19/00001]
  5. European Regional Development Fund (ERDF)
  6. Instituto de Salud Carlos III
  7. Fundacion Ramon Areces
  8. Centro para el Desarrollo Tecnologico Industrial (CDTI) from the MICIU [IDI-20200297]
  9. MINECO - EU under the FEDER program [BIO2016-79618R, PID2019-104903RB-I00]
  10. MCIU [PRE2018-083422]
  11. Fondo Social Europeo (FSE)
  12. Instituto de Salud Carlos III [PFIS FI19/00119]
  13. Banco Santander
  14. [PI19/00301]

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The replication of RNA viruses involves exploring sequence space to adapt to changing environments. Research on hepatitis C virus (HCV) has shown that despite prolonged replication, viral clones continue to expand in sequence space. The study suggests that HCV populations exhibit a permanent state of disequilibrium, potentially facilitating the finding of alternative mutational pathways for antiviral resistance.
Replication of RNA viruses is characterized by exploration of sequence space which facilitates their adaptation to changing environments. It is generally accepted that such exploration takes place mainly in response to positive selection, and that further diversification is boosted by modifications of virus population size, particularly bottleneck events. Our recent results with hepatitis C virus (HCV) have shown that the expansion in sequence space of a viral clone continues despite prolonged replication in a stable cell culture environment. Diagnosis of the expansion was based on the quantification of diversity indices, the occurrence of intra-population mutational waves (variations in mutant frequencies), and greater individual residue variations in mutant spectra than those anticipated from sequence alignments in data banks. In the present report, we review our previous results, and show additionally that mutational waves in amplicons from the NS5A-NS5B-coding region are equally prominent during HCV passage in the absence or presence of the mutagenic nucleotide analogues favipiravir or ribavirin. In addition, by extending our previous analysis to amplicons of the NS3- and NS5A-coding region, we provide further evidence of the incongruence between amino acid conservation scores in mutant spectra from infected patients and in the Los Alamos National Laboratory HCV data banks. We hypothesize that these observations have as a common origin a permanent state of HCV population disequilibrium even upon extensive viral replication in the absence of external selective constraints or changes in population size. Such a persistent disequilibrium-revealed by the changing composition of the mutant spectrum-may facilitate finding alternative mutational pathways for HCV antiviral resistance. The possible significance of our model for other genetically variable viruses is discussed.

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