Positive selection of cytotoxic T lymphocyte escape variants during acute hepatitis C virus infection

Abstract

Cellular immune responses are induced during hepatitis C virus (HCV) infection and acute-phase CD8 + T cells are supposed to play an important role in controlling viral replication. In chimpanzees, failure of CD8 + T cells to control HCV replication has been associated with acquisition of mutations in MHC class I-restricted epitopes. In humans, although selection of escape mutations in an immunodominant CTL epitope has been recently described, the overall impact of immune escape during acute HCV infection is unclear. Here, by performing an in depth analysis of the relationship between early cellular immune responses and viral evolution in a chronically evolving HCV acutely infected individual, we demonstrate: (i) the presence of a potent and focused CD8 + T cell response against a novel epitope in the NS3 protein, (ii) the elimination of the quasispecies harboring the original amino acid sequence within this epitope, and (iii) the selection for a virus population bearing amino acid changes at a single residue within the cytotoxic T cell epitope that strongly diminished T cell recognition. These results support the view that acute-phase CD8 + T cell responses exert a biologically relevant pressure on HCV replication and that viruses escaping this host response could have a significant survival advantage.

Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27–restricted human immune response

“…Viral escape mutations within the immunodominant HLA-B27-restricted HCV-specific CD8 + T cell epitope NS5B 2841-2849 (ARMILMTHF) occur in the vast majority of patients in clusters ( Figure 1A; clonal sequence data are shown in Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI36587DS1); e.g., viruses analyzed in 11 of 15 patients showed 2 or 3 mutations (6 patients with 2 mutations; 5 patients with 3 mutations), while viruses in only 4 patients showed no or only 1 mutation within the otherwise highly conserved epitope region. This is a striking finding, since T cell escape mutations forced by other HLA alleles typically harbor a single (90% and 81%), less frequently 2 (10% and 17%), and rarely 3 amino acid substitutions (0% and 3%), as has been shown in comprehensive analyses of patients with acute (22)(23)(24)(25)(26)(27) or chronic (24,(28)(29)(30)(31)(32)(33) HCV infection (P < 0.0001; Figure 1B). In addition, escape mutations within the dominant HLA-B27 epitope were observed…”

“…Sequences for HLA-B27 -subjects were taken from the literature: for acute HCV infection, longitudinal sequences or sequences from a known donor and the patient were compared (22)(23)(24)(25)(26)(27), while for chronic HCV infection, patient sequences were compared with genotype/subtype-matched consensus sequences (24,(28)(29)(30)(31)(32)(33). Sequences in HLA-B27 + patients with chronic HCV infection were included from this study ( Figure 1A) and from a previous, independent report (32).…”

Increased frequency of CD56Bright NK‐cells, CD3−CD16+CD56− NK‐cells and activated CD4+T‐cells or B‐cells in parallel with CD4+CDC25High T‐cells control potentially viremia in blood donors with HCV

“…Many hypotheses have been proposed, including the inability of the host to carry out an efficient humoral and cellular response, allowing immune escape of these highly changeable viruses (quasispecies) [Guglietta et al, 2005]; the high rate of HCV replication, which would lead to the exhaustion of CD4 þ T-cells through the production of large amounts of HCV antigens [Kantzanou et al, 2003]; the suppression of HCV-specific CD4 þ T-cell expansion [Klugewitz et al, 2002]; the intrahepatic compartmentalization and induction of apoptosis of virus-specific CD8 þ T-cells [Crispe et al, 2000]; the production of immunomodulatory proteins by HCV [Large et al, 1999]; and the inability of the innate immune response to promote appropriate T-cell stimulation [Bertoletti and Ferrari, 2003].…”

Transmission of Clonal Hepatitis C Virus Genomes Reveals the Dominant but Transitory Role of CD8+T Cells in Early Viral Evolution

“…CD4 ϩ T cells appear to exert limited selection pressure against the virus because mutations in major histocompatibility complex (MHC) class II epitopes are uncommon (19,21). Mutational escape from CD8 ϩ T cells is well established (8,16,23,24,45,46). In chimpanzees, the only animal model of human HCV infection, this process has been linked to positive Darwinian selection pressure (16).…”