Evolutionary trends of the first hypervariable region of the hepatitis C virus E2 protein in individuals with differing liver disease severity

Abstract

Hepatitis C virus (HCV) exists as a complex swarm of genetically related viruses known as a quasispecies. Recent work has shown that quasispecies complexity and evolutionary rates are associated with the outcome of acute infection. Knowledge of how the virus population evolves at different stages of chronic infection is less clear. We have studied rates of evolution of the first hypervariable region (HVR1) of the E2 envelope protein in six individuals with disparate liver disease severity. These data show that virus populations present in individuals with mild nonprogressive liver disease evolve in a typical Darwinian fashion, with a consistent accumulation of non-synonymous (amino acid-changing) substitutions. By contrast, the virus population remains relatively static in individuals with severe progressive liver disease. Possible mechanisms for this disparity are discussed.

Hepatitis C virus dynamics and pathology: the role of CTL and antibody responses

“…As severe pathology develops, the number of susceptible host cells is reduced and this can prevent invasion of further antigenic variants. The hypothesis that virus evolution can drive disease progression is supported further by the observation that the population diversity, as well as the ratio of amino acid changing to silent substitutions was higher in individuals with severe liver disease (Cabot et al, 2000;Curran et al, 2002). Similar patterns have been observed in studies of virus evolution following liver transplants in patients with mild and severe disease (Lyra et al, 2002).…”

“…While the chimpanzee data argue against a role of escape for virus persistence, this study does not address the role of escape for disease progression, which occurs over a much longer period of time. Curran et al (2002) reported a consistent accumulation of amino acid-changing substitutions in patients with mild liver disease. In patients with severe liver disease, however, they reported significantly lower rates of virus evolution.…”

“…This concept is very difficult to test with data. Studies have quantified sequence diversity and the rate of virus evolution in patients who differ in the severity of liver disease (Cabot et al, 2000;Curran et al, 2002;Farci, 2001;Lyra et al, 2002;Major et al, 1999;Thomson et al, 2001). Even if virus evolution does drive disease progression -as suggested here -this does not mean that one would expect higher virus diversity or faster evolution in patients with severe compared to mild disease.…”

“…Therefore, if pathology develops as a result of virus evolution towards antigenic escape, it is possible that patients with severe disease show reduced levels of virus diversification and evolution compared to patients with milder disease. Data on virus diversity have given rise to different and contradictory results (Cabot et al, 2000;Curran et al, 2002;Farci, 2001;Lyra et al, 2002;Major et al, 1999;Thomson et al, 2001). Studies with HCV-infected patients report the emergence of antibody escape mutants early after infection (Farci et al, 2000), while data from the chimpanzee model argue against the frequent occurrence of antibody escape mutants during the early stages of the infection (Major et al, 1999).…”

Genetic variability of hepatitis C virus NS3 protein in human leukocyte antigen-A2 liver transplant recipients with recurrent hepatitis C

“…5 In patients with chronic HCV, several attempts have been made to associate the genetic heterogeneity of HCV with the clinical features of chronic infection, but this issue remains still controversial. [6][7][8][9] In the liver transplantation setting, some studies have also analyzed the effect of the heterogeneity in the envelope region of HCV, with discrepant results. 10,11 In contrast, the potential influence of viral variability in T-cell epitopes on the outcome of recurrent infection after transplantation has been explored only rarely.…”