Tracking HCV protease population diversity during transmission and susceptibility of founder populations to antiviral therapy

Autor: Lieven Verhoye, Philip Meuleman, Robert Geffers, Thomas Pietschmann, Ali Farhoudi, C. Patrick McClure, Koen Vercauteren, Thomas F. Baumert, Daniel Todt, Sabin Bhuju, Richard J. C. Brown, Eike Steinmann, Tanvi Khera
Přispěvatelé: Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Helmholtz Centre for infection research, Inhoffenstr. 7., 38124 Braunschweig, Germany.
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
HCV protease
medicine.medical_treatment
Hepacivirus
Viral Nonstructural Proteins
medicine.disease_cause
Mice
Protease Inhibitors/administration and dosage/therapeutic use
0302 clinical medicine
Genotype
Viral
Serine Endopeptidases/chemistry/*genetics/*metabolism
Genetics
Antiviral Agents/therapeutic use
education.field_of_study
Genome
Serine Endopeptidases
Hepatitis C
3. Good health
Hepacivirus/drug effects/*enzymology/*genetics
030211 gastroenterology & hepatology
Sequence Analysis
Evolution
Hepatitis C virus
Population
RAS emergence
Viral Nonstructural Proteins/chemistry/*genetics/*metabolism
Genome
Viral
Founder populations
Biology
Antiviral Agents
Article
Evolution
Molecular
03 medical and health sciences
Virology
Genetic variation
medicine
Animals
Humans
Transmission
Protease Inhibitors
education
Illumina dye sequencing
Pharmacology
NS3
Protease
Animal
Longitudinal evolution
Molecular
Genetic Variation
Sequence Analysis
DNA
DNA
Hepatitis C/drug therapy/*transmission/virology
Disease Models
Animal
030104 developmental biology
Population bottleneck
Disease Models
Mutation
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: Antiviral Research
Antiviral Research, Elsevier Masson, 2017, 139, pp.129-137. ⟨10.1016/j.antiviral.2017.01.001⟩
ISSN: 0166-3542
1872-9096
DOI: 10.1016/j.antiviral.2017.01.001⟩
Popis: PMC5292934; Due to the highly restricted species-tropism of Hepatitis C virus (HCV) a limited number of animal models exist for pre-clinical evaluation of vaccines and antiviral compounds. The human-liver chimeric mouse model allows heterologous challenge with clinically relevant strains derived from patients. However, to date, the transmission and longitudinal evolution of founder viral populations in this model have not been characterized in-depth using state-of-the-art sequencing technologies. Focusing on NS3 protease encoding region of the viral genome, mutant spectra in a donor inoculum and individual recipient mice were determined via Illumina sequencing and compared, to determine the effects of transmission on founder viral population complexity. In all transmissions, a genetic bottleneck was observed, although diverse viral populations were transmitted in each case. A low frequency cloud of mutations ( 1% restricted to a subset of nucleotides. The population of SNVs >1% was reduced upon transmission while the low frequency SNV cloud remained stable. Fixation of multiple identical synonymous substitutions was apparent in independent transmissions, and no evidence for reversion of T-cell epitopes was observed. In addition, susceptibility of founder populations to antiviral therapy was assessed. Animals were treated with protease inhibitor (PI) monotherapy to track resistance associated substitution (RAS) emergence. Longitudinal analyses revealed a decline in population diversity under therapy, with no detectable RAS >1% prior to therapy commencement. Despite inoculation from a common source and identical therapeutic regimens, unique RAS emergence profiles were identified in different hosts prior to and during therapeutic failure, with complex mutational signatures at protease residues 155, 156 and 168 detected. Together these analyses track viral population complexity at high-resolution in the human-liver chimeric mouse model post-transmission and under therapeutic intervention, revealing novel insights into the evolutionary processes which shape viral protease population composition at various critical stages of the viral life-cycle.
Databáze: OpenAIRE
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