A reduction in selective immune pressure during the course of chronic hepatitis C correlates with diminished biochemical evidence of hepatic inflammation

Abstract

It is considered that selection pressure exerted by the host immune response during early HCV infection might influence the outcome of that infection particularly as it relates to persistence or clearance of the agent. However, it is unclear whether positive selection pressure plays a role in determining the severity of hepatitis C during the course of persistent HCV infection. To address the evolutionary mechanism by which HCV escapes from the host immune response and to assess the relationship between viral evolution and hepatic inflammation, we determined 57 sequences (3-5 serial samples per patient) from 5 individuals with persistent HCV infection of genotype 1a who were under long-term follow-up ranging from 15.6 to 21.6 years. We applied a novel method to estimate serial alternations of selective pressure against the HCV enveloped region and compared this to fluctuation in transaminase level over time. Positive selection pressure was reduced over time postinfection, as evidenced by a reduction in nonsynonymous substitutions in the later phase of infection. Furthermore, serum transaminase, as a measure of inflammatory necrosis of hepatocytes, was reduced in parallel with decreased positive selection pressure. These results suggest that during persistent HCV infection, the virus faces diminished immune pressure over time, either from mutation to an immune resistant sequence or from immunologic exhaustion, and that this diminished immune attack is reflected in diminished inflammatory activity. This observation may be applicable to other viruses characterized by a slow rate of disease progression.

Evidence of distinct populations of hepatitis C virus in the liver and plasma of patients co‐infected with HIV and HCV

“…Others have examined the association between hepatic injury—as measured by ALT/AST levels—and viral diversity [Nagayama et al, ; Bozdayi et al, ; Farci et al, ; Hanada et al, ]. In a pilot study of five patients, reduced transaminase levels were associated with decreased immune pressure targeting the E2 region, suggesting that the vigor of the immune response may drive both ALT elevations and viral diversity [Hanada et al, ]. HVR1 diversity also correlates with ALT levels in perinatally infected children [Farci et al, ].…”

“…However, the current study only included individuals with HCV genotype 1; therefore, the role of HCV genotype could not be examined further. Others have examined the association between hepatic injury-as measured by ALT/AST levels-and viral diversity [Nagayama et al, 1999;Bozdayi et al, 2000;Farci et al, 2006;Hanada et al, 2007]. In a pilot study of five patients, reduced transaminase levels were associated with decreased immune pressure targeting the E2 region, suggesting that the vigor of the immune response may drive both ALT elevations and viral diversity .…”

Identification and Characterization of a Ross River Virus Variant That Grows Persistently in Macrophages, Shows Altered Disease Kinetics in a Mouse Model, and Exhibits Resistance to Type I Interferon

“…The treatment of HCV patients with IFN is often stymied by the eventual development of IFN resistance by the virus. It has been suggested that exogenous IFN treatment could lead to selective pressure on the virus and the development of mutant strains able to resist IFN-mediated host defense (16,27,56). Sumpter et al (56) found that persistent growth of HCV in cell culture was associated with genetic variation of viral NS5A, NS3, and NS4A, which endowed the virus with the ability to disrupt IFN regulatory factor 1 (IRF-1) and IRF-3 signaling following IFN (41,57).…”

Prevalence of Amino acid mutation in hepatitis C virus core region among Japanese volunteer blood donors

“…Although several studies have verified the association between HCV amino acid substitution and IFN response, it should be noted that in such studies the HCV sequences that had been present before treatment were dealt with [Enomoto et al, 1996;Akuta et al, 2005]. By estimating serial alterations of selective pressure against HCV throughout the phylogenetic tree, sequential reduction of both the extent of positive selection pressure such as innate/acquired immunity or endogenous IFN and the degree of liver injury during the long course of chronic HCV infection was found [Hanada et al, 2007]. These findings indicate that the viruses mutate to an immune-resistant sequence to escape from innate/acquired immune pressures during long-term HCV infection.…”