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Evidence for deleterious hepatitis C virus quasispecies mutation loads that
differentiate the response patterns in IFN-based antiviral therapy
#MMPMID26581744
Ren Y
; Wang W
; Zhang X
; Xu Y
; Di Bisceglie AM
; Fan X
J Gen Virol
2016[Feb]; 97
(2
): 334-343
PMID26581744
show ga
Viral quasispecies (QS) have long been considered to affect the efficiency of
hepatitis C virus (HCV) antiviral therapy, but a correlation between QS diversity
and treatment outcomes has not been established conclusively. We previously
measured HCV QS diversity by genome-wide quantification of high-resolution
mutation load in HCV genotype 1a patients achieving a sustained virological
response (1a/SVR) or a null response (1a/null). The current study extended this
work into HCV 1a patients experiencing relapse (1a/relapse, n = 19) and genotype
2b patients with SVR (2b/SVR, n = 10). The mean mutation load per patient in
2b/SVR and 1a/relapse was similar, respectively, to 1a/SVR (517.6 ± 174.3 vs 524
± 278.8 mutations, P = 0.95) and 1a/null (829.2 ± 282.8 vs 805.6 ± 270.7
mutations, P = 0.78). Notably, a deleterious mutation load, as indicated by the
percentage of non-synonymous mutations, was highest in 2b/SVR (33.2 ± 8.5%) as
compared with 1a/SVR (23.6 ± 7.8%, P = 0.002), 1a/null (18.2 ± 5.1%, P = 1.9 ×
10(-7)) or 1a/relapse (17.8 ± 5.3%, P = 1.8) × 10(-6). In the 1a/relapse group,
continuous virus evolution was observed with excessive accumulation of a
deleterious load (17.8 ± 5.3% vs 35.4 ± 12.9%, P = 3.5 × 10(-6)), supporting the
functionality of Muller's ratchet in a treatment-induced population bottleneck.
Taken together, the magnitude of HCV mutation load, particularly the deleterious
mutation load, provides an evolutionary explanation for the emergence of multiple
response patterns as well as an overall high SVR rate in HCV genotype 2 patients.
Augmentation of Muller's ratchet represents a potential strategy to reduce or
even eliminate viral relapse in HCV antiviral therapy.
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