Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy.
The efficacy of specifically targeted anti-viral therapy for hepatitis C virus (HCV) (STAT-C), including HCV protease and polymerase inhibitors, is limited by the presence of drug-specific viral resistance mutations within the targeted proteins. Genetic diversity within these viral proteins also evolves under selective pressures provided by host human leukocyte antigen (HLA)-restricted immune responses, which may therefore influence STAT-C treatment response. Here, the prevalence of drug resistance mutations relevant to 27 developmental STAT-C drugs, and the potential for drug and immune selective pressures to intersect at sites along the HCV genome, is explored. HCV nonstructural (NS) 3 protease or NS5B polymerase sequences and HLA assignment were obtained from study populations from Australia, Switzerland, and the United Kingdom. Four hundred five treatment-naïve individuals with chronic HCV infection were considered (259 genotype 1, 146 genotype 3), of which 38.5% were coinfected with human immunodeficiency virus (HIV). We identified preexisting STAT-C drug resistance mutations in sequences from this large cohort. The frequency of the variations varied according to individual STAT-C drug and HCV genotype/subtype. Of individuals infected with subtype 1a, 21.5% exhibited genetic variation at a known drug resistance site. Furthermore, we identified areas in HCV protease and polymerase that are under both potential HLA-driven pressure and therapy selection and identified six HLA-associated polymorphisms (P <or= 0.05) at known drug resistance sites.


CONCLUSIONS
Drug and host immune responses are likely to provide powerful selection forces that shape HCV genetic diversity and replication dynamics. Consideration of HCV viral adaptation in terms of drug resistance as well as host "immune resistance" in the STAT-C treatment era could provide important information toward an optimized and individualized therapy for chronic hepatitis C.
Gaudieri
Silvana
S
Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Western Australia, Australia.
Rauch
Andri
A
Pfafferott
Katja
K
Barnes
Eleanor
E
Cheng
Wendy
W
McCaughan
Geoff
G
Shackel
Nick
N
Jeffrey
Gary P
GP
Mollison
Lindsay
L
Baker
Ross
R
Furrer
Hansjakob
H
Günthard
Huldrych F
HF
Freitas
Elizabeth
E
Humphreys
Isla
I
Klenerman
Paul
P
Mallal
Simon
S
James
Ian
I
Roberts
Stuart
S
Nolan
David
D
Lucas
Michaela
M
D000220:Adaptation, Biological; D000596:Amino Acids / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral / Q000235:genetics*; D014644:Genetic Variation; D016679:Genome, Viral; D005838:Genotype; D015658:HIV Infections / Q000150:complications; D006680:HLA Antigens / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D006801:Humans; D008969:Molecular Sequence Data; D012641:Selection, Genetic; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
D000596:Amino Acids; D000998:Antiviral Agents; D006680:HLA Antigens; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase