REDUCED SENSITIVITY OF GENOTYPE 3 HEPATITIS C VIRUS TO DIRECT ACTING ANTIVIRALS
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Sofosbuvir is a uridine based nucleotide inhibitor of the hepatitis C viral (HCV)
polymerase that is the backbone of many treatment regimens. In combination with
drugs targeting other viral enzymes (including the poorly potent guanosine analogue
ribavirin or highly potent inhibitors of viral NS5A or protease) most patients clear virus
and resistance to sofosbuvir is rare, allowing effective retreatment with sofosbuvir.
Patients with Genotype 3 HCV respond less well than other genotypes and response
is reduced in those previously exposed to interferon. Here we show that patientderived
virus from patients with Genotype 3 HCV who relapse to sofosbuvir-based
therapies have a reduced sensitivity to SOF in an in-vitro phenotyping assay. Analysis
of viral sequencing data revealed two distinct polymorphisms (A150V and K206E) in
the HCV polymerase that are associated with treatment failure and in-vitro; they
reduce sofosbuvir sensitivity against genotype 3 hepatitis C virions. However both
polymorphisms modify the cellular response to type I interferon and in cells lacking
response to interferon the impact on sofosbuvir sensitivity is minimal. The A150V
polymorphism reduces the response to interferon 70 fold whereas the K206E
substitution has minimal effects on interferon in isolation but in combination with
A150V reduces the response 100 fold. Preliminary data indicates that the A150V
polymorphism interferes with the late response to type I interferons enabling the virus
to overcome the induction of interferon-stimulated genes. These data indicate a
complex interaction between direct acting antiviral drugs and the innate antiviral
response.
Authors
Wing, Peter Alexander CorneliusCollections
- Theses [4235]