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In-Host Flat-like Quasispecies: Characterization Methods and Clinical Implications.

Josep Gregori1, Sergi Colomer-Castell1,2,3, Marta Ibañez-Lligoña1,2,4

  • 1Liver Diseases-Viral Hepatitis, Liver Unit, Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.

Microorganisms
|May 25, 2024
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Summary

Chronic hepatitis E (HEV) and C (HCV) infections resist treatment due to flat-like quasispecies. These viral populations evade therapies by maintaining numerous low-frequency, synonymous variants, hindering treatment development.

Keywords:
enhanced fitnessflat-like quasispeciesmutagensnear-flatregular quasispeciesresistance-associated mutations (RAS)viral treatment failures

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Area of Science:

  • Virology
  • Genetics
  • Infectious Diseases

Background:

  • Chronic hepatitis E (HEV) and C (HCV) infections are challenging to treat, even without detectable resistance-associated substitutions (RAS).
  • The complex quasispecies structure of viruses, beyond simple mutations, may explain treatment failures, particularly with mutagenic agents.
  • Flat-like quasispecies are hypothesized to possess high fitness and evade therapies by occupying extensive genetic space.

Purpose of the Study:

  • To investigate the role of quasispecies structure in treatment-refractory HEV and HCV infections.
  • To identify and characterize 'flat-like' quasispecies using high-depth next-generation sequencing (NGS).
  • To propose methods for identifying flat-like quasispecies to inform future treatment strategies.

Main Methods:

  • High-depth next-generation sequencing (NGS) was employed to analyze HEV and HCV samples.
  • Specific indices were developed and scored to quantify properties of flat-like quasispecies.
  • Quasispecies indices from chronic HEV/HCV were compared to those from acute respiratory viral infections.

Main Results:

  • Chronic HEV and HCV infections without RAS exhibited flat-like quasispecies characterized by numerous low-frequency haplotypes.
  • A lack of a dominant haplotype was observed in these chronic infections.
  • Surprisingly, low-frequency nucleotide variants showed high synonymity, leading to reduced phenotypic diversity.

Conclusions:

  • Flat-like quasispecies, defined by numerous low-frequency synonymous variants, contribute to treatment resistance in chronic HEV and HCV.
  • Current clinical strategies do not adequately address the management of flat-like quasispecies.
  • Developing methods to identify these quasispecies is crucial for exploring novel therapeutic approaches against resistant viral infections.