Association of Liver Damage and Quasispecies Maturity in Chronic HCV Patients: The Fate of a Quasispecies

Overview

Journal Microorganisms

Specialty Microbiology

Date 2024 Nov 27

PMID 39597607

Authors

Josep Gregori

Marta Ibanez-Lligona

Sergi Colomer-Castell

Carolina Campos

Damir Garcia-Cehic

Josep Quer

Affiliations

Soon will be listed here.

Abstract

Viral diversity and disease progression in chronic infections, and particularly how quasispecies structure affects antiviral treatment, remain key unresolved issues. Previous studies show that advanced liver fibrosis in long-term viral infections is linked to higher rates of antiviral treatment failures. Additionally, treatment failure is associated with high quasispecies fitness, which indicates greater viral diversity and adaptability. As a result, resistant variants may emerge, reducing retreatment effectiveness and increasing the chances of viral relapse. Additionally, using a mutagenic agent in monotherapy can accelerate virus evolution towards a flat-like quasispecies structure. This study examines 19 chronic HCV patients who failed direct-acting antiviral (DAA) treatments, using NGS to analyze quasispecies structure in relation to fibrosis as a marker of infection duration. Results show that HCV evolves towards a flat-like quasispecies structure over time, leading also to advanced liver damage (fibrosis F3 and F4/cirrhosis). Based on our findings and previous research, we propose that the flat-like fitness quasispecies structure is the final stage of any quasispecies in chronic infections unless eradicated. The longer the infection persists, the lower the chances of achieving a cure. Interestingly, this finding may also be applicable to other chronic infection and drug resistance in cancer.

References

Sheldon J, Beach N, Moreno E, Gallego I, Pineiro D, Martinez-Salas E . Increased replicative fitness can lead to decreased drug sensitivity of hepatitis C virus. J Virol. 2014; 88(20):12098-111. PMC: 4178724. DOI: 10.1128/JVI.01860-14. View

Gregori J, Soria M, Gallego I, Guerrero-Murillo M, Esteban J, Quer J . Rare haplotype load as marker for lethal mutagenesis. PLoS One. 2018; 13(10):e0204877. PMC: 6169937. DOI: 10.1371/journal.pone.0204877. View

Gallego I, Gregori J, Soria M, Garcia-Crespo C, Garcia-Alvarez M, Gomez-Gonzalez A . Resistance of high fitness hepatitis C virus to lethal mutagenesis. Virology. 2018; 523:100-109. DOI: 10.1016/j.virol.2018.07.030. View

Domingo E, Soria M, Gallego I, de Avila A, Garcia-Crespo C, Martinez-Gonzalez B . A new implication of quasispecies dynamics: Broad virus diversification in absence of external perturbations. Infect Genet Evol. 2020; 82:104278. DOI: 10.1016/j.meegid.2020.104278. View

Lotsch J, Ultsch A . A non-parametric effect-size measure capturing changes in central tendency and data distribution shape. PLoS One. 2020; 15(9):e0239623. PMC: 7514071. DOI: 10.1371/journal.pone.0239623. View

Colomer-Castell S, Gregori J, Garcia-Cehic D, Riveiro-Barciela M, Buti M, Rando-Segura A . In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments. Int J Mol Sci. 2023; 24(24). PMC: 10743355. DOI: 10.3390/ijms242417185. View

Chen Q, Perales C, Soria M, Garcia-Cehic D, Gregori J, Rodriguez-Frias F . Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure. Antiviral Res. 2019; 174:104694. DOI: 10.1016/j.antiviral.2019.104694. View

Gallego I, Sheldon J, Moreno E, Gregori J, Quer J, Esteban J . Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus. Antimicrob Agents Chemother. 2016; 60(6):3786-93. PMC: 4879421. DOI: 10.1128/AAC.00581-16. View

Magoc T, Salzberg S . FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics. 2011; 27(21):2957-63. PMC: 3198573. DOI: 10.1093/bioinformatics/btr507. View

10.

Hanley J, McNeil B . The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982; 143(1):29-36. DOI: 10.1148/radiology.143.1.7063747. View

11.

Nakagawa S, Cuthill I . Effect size, confidence interval and statistical significance: a practical guide for biologists. Biol Rev Camb Philos Soc. 2007; 82(4):591-605. DOI: 10.1111/j.1469-185X.2007.00027.x. View

12.

Garcia-Cehic D, Rando A, Rodriguez-Frias F, Gregori J, Costa J, Carrion J . Resistance-associated substitutions after sofosbuvir/velpatasvir/voxilaprevir triple therapy failure. J Viral Hepat. 2021; 28(9):1319-1324. DOI: 10.1111/jvh.13497. View

13.

Gallego I, Soria M, Garcia-Crespo C, Chen Q, Martinez-Barragan P, Khalfaoui S . Broad and Dynamic Diversification of Infectious Hepatitis C Virus in a Cell Culture Environment. J Virol. 2019; 94(6). PMC: 7158725. DOI: 10.1128/JVI.01856-19. View

14.

Gregori J, Colomer-Castell S, Ibanez-Lligona M, Garcia-Cehic D, Campos C, Buti M . In-Host Flat-like Quasispecies: Characterization Methods and Clinical Implications. Microorganisms. 2024; 12(5). PMC: 11124460. DOI: 10.3390/microorganisms12051011. View

15.

Moschouri E, Salemme G, Baserga A, Cerny A, Deibel A, Mullhaupt B . Real-life experience of chronic hepatitis C treatment in Switzerland: a retrospective analysis. Swiss Med Wkly. 2024; 154(6):3698. DOI: 10.57187/s.3698. View

16.

Gregori J, Ibanez-Lligona M, Colomer-Castell S, Campos C, Quer J . Virus Quasispecies Rarefaction: Subsampling with or without Replacement?. Viruses. 2024; 16(5). PMC: 11126021. DOI: 10.3390/v16050710. View

17.

Soria M, Gregori J, Chen Q, Garcia-Cehic D, Llorens M, de Avila A . Pipeline for specific subtype amplification and drug resistance detection in hepatitis C virus. BMC Infect Dis. 2018; 18(1):446. PMC: 6122477. DOI: 10.1186/s12879-018-3356-6. View

18.

Soria M, Garcia-Crespo C, Martinez-Gonzalez B, Vazquez-Sirvent L, Lobo-Vega R, de Avila A . Amino Acid Substitutions Associated with Treatment Failure for Hepatitis C Virus Infection. J Clin Microbiol. 2020; 58(12). PMC: 7685896. DOI: 10.1128/JCM.01985-20. View

19.

Kelley K, Preacher K . On effect size. Psychol Methods. 2012; 17(2):137-52. DOI: 10.1037/a0028086. View

20.

. EASL recommendations on treatment of hepatitis C: Final update of the series. J Hepatol. 2020; 73(5):1170-1218. DOI: 10.1016/j.jhep.2020.08.018. View