Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution

Abstract

Virus-specific CD8؉ T cell responses play an important role in the natural course of infection; however, the impact of certain CD8؉ T cell responses in determining clinical outcome has not been fully defined. A well-defined cohort of women inoculated with HCV from a single source showed that HLA-B27 has a strong association with spontaneous clearance. The immunological basis for this association is unknown. However, the finding is especially significant because HLA-B27 has also been shown to have a protective role in HIV infection. We report the identification of an HLA-B27 restricted hepatitis C virus (HCV)-specific CD8؉ T cell epitope that is recognized in the majority of recovered HLA-B27 positive women. In chronically HCV-infected individuals, analysis of the corresponding viral sequence showed a strong association between sequence variations within this epitope and expression of HLA-B27, indicating allele-specific selection pressure at the population level. T he hepatitis C virus (HCV) is a small positivestranded RNA virus within the Flaviviridae family that persists in 70% of infected individuals. Growing evidence suggests that the cellular host immune response against HCV plays an important role in the outcome of infection. Indeed, viral clearance is temporarily associated with sustained HCV-specific CD4ϩ and CD8ϩ T cell responses that accumulate in the infected liver. [1][2][3] In addition, the important antiviral role of virusspecific CD8ϩ T cells has recently been directly demonstrated by CD8ϩ cell depletion studies in chimpanzees. 4 The mechanisms that lead to the failure of the virus-specific T cell response and the persistence of HCV in most patients are still not well understood. 5 Several different pathways, such as a primary failure to induce T cells, functional exhaustion, or the emergence of viral escape mutations, have been discussed. [5][6][7] Indeed, a growing body of evidence suggests that T cell escape mutations develop early during acute HCV infection and that they remain fixed in the circulating quasispecies for several years. [8][9][10][11][12][13][14][15][16][17] However, the development of escape mutations during HCV infection is not universal. For example, viral clearance can occur with minimal epitope variation before From the

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…Together with few other HLA class I molecules of the B locus, the HLA-B27 is associated with long-term non-progression to AIDS in patients, called 'elite controllers', which maintain a low viral load and remain asymptomatic for longer [50]. Furthermore, recent studies have revealed in HLA-B27 subjects a high rate of spontaneous clearance of hepatitis C virus [48,51]. The reasons for this are not completely understood, although virological and immunological explanations have been anticipated.…”

Divergent adaptation of hepatitis C virus genotypes 1 and 3 to human leukocyte antigen-restricted immune pressure

“…Furthermore, when we expanded the dataset to include all available HCV sequences (including sequences with Ͻ90% sequence coverage), HLA-B*2705-associated viral polymorphisms at positions NS5B-2841 and 2846 were detected for genotype 1a, which fall within a described epitope 20 (Table 3). Two HLA-associated viral polymorphisms for genotype 3a fall within previously described epitopes, including the overlapping site at NS3-1444, which falls within the NS3-1436 epitope restricted by HLA-A*0101, where the consensus sequence is identical to that in genotype 1a (Fig.…”

“…Carriage of the restricting HLA allele was associated with viral polymorphisms at several sites within immunogenic epitopes, consistent with viral escape from HLA-restricted immune pressure. At multiple sites, including experimentally established viral escape sites (for example, NS3-1397-1398 for HLA-B*0801 and NS5B-2841 and 2846 for HLA-B*2705 20,[23][24][25], there was nearly complete conservation in the alternative genotype, even in individuals carrying the relevant HLA alleles (Fig. 2).…”

Identification of Three Novel CTL Epitopes within Nucleocapsid Protein of Hantaan Virus

“…During acute PUUV infection, the kinetics of the PUUV-specific tetramer-positive T cells and the PUUV-specific T cells that produced IFN-c in vitro were sharply different (19). CTL causes either pathology or virus control, possibly due to differences in viral proteins (5), HLA haplotypes (12), and altered efficiency of T-cell responses as a consequence of heterologous immunity (15), but only few CTL epitopes restricted by HLA-A1, A2.1, and B51 have been identified for HTNV (8,20), which limited the investigation of protective or pathologic immune responses against HTNV infection. In this article, we screened a panel of overlapping peptides spanning the sequence of the HTNV nucleocapsid protein for those that can stimulate IFN-c responses by ex vivo ELISPOT, and then determined the HLA context of the T-cell responses by in vitro ELISPOT.…”