Cytotoxic T Lymphocyte Response and Viral Load in Hepatitis C Virus Infection

Abstract

1liver-infiltrating lymphocytes 4 of patients with chronic hepa-A cytotoxic T lymphocyte (CTL) response to the hepatitis C, the role of CTL responses in HCV infection is untitis C virus (HCV) nucleoprotein residues 88-96 that are known. HCV infection frequently persists and is implicated the minimal and optimal epitope for human leukocyte in the development of chronic hepatitis, cirrhosis, and hepatoantigen (HLA) B44-restricted CTLs was assessed in 27 cellular carcinoma. 5 Posttransfusion HCV infection has de-HLA B44-positive patients with chronic HCV infection.creased substantially after introduction of an anti-HCV assay Serum HCV RNA concentration and the amino acid sefor blood screening, but community-acquired HCV infection quence of the residues 81-100 were also determined.still occurs. Interferon therapy is effective in less than 50% Three patients were infected with HCV with uncommon of patients with chronic hepatitis C. 6 Understanding the role amino acid substitutions within the epitope. One was of CTL responses in HCV infection may contribute to the infected with HCV with an amino acid substitution in development of strategies for the prevention of HCV infection the flanking residues of the epitope. To stimulate CTLs and the elimination of HCV from infected individuals. in the peripheral blood, 9-mer peptides that correRecently, we showed the presence of CTLs that recognize sponded to the residues 88-96 of the individual patients endogenously synthesized HCV antigen in the peripheral were synthesized and used. Seven of the 27 patients demblood of some patients with HCV infection by stimulation onstrated a CTL response to the residues 88-96 with of peripheral blood lymphocytes (PBLs) with HCV synthetic specific cytotoxic activities higher than 20%. The CTL peptides.3 activities were significantly higher in patients with a The CTLs recognized an epitope in the HCV nucleoprotein low titer of serum HCV RNA than in those with a high residues 81-100 in association with human leukocyte antigen titer of serum HCV RNA (P Å .0006). Some of the patients (HLA) B44. The minimal and optimal epitope was further dethat demonstrated a CTL response to the residues 88-fined to be the residues 88-96. 7 The 9-mer peptide of the resi-96 also demonstrated a CTL response to a newly identidues 88-96 was recognized by and stimulated the CTLs more fied HLA B44-restricted CTL epitope or a known HLA efficiently than the 20-mer peptide of the residues 81-100. A11-restricted CTL epitope or both. No apparent associa-In a characteristic antiviral CTL response in vivo, immunotion was observed between the CTL response and the dominant CTLs recognize only one or a few multiple immunostage of disease, or between the CTL response and the genic CTL epitopes in the antigen, 8,9 but as many as five grade of necroinflammatory activity. The results suggest different epitopes for HCV-specific CTLs were detected in a that the HLA B44-restricted CTLs together with other single individual. 10 CTL activities to HCV could not be dem-HCV-specific CTLs ...

Intrahepatic hepatitis C virus-specific cytotoxic T lymphocyte activity and response to interferon alfa therapy in chronic hepatitis C

“…We and others have reported that patients with higher levels of HCV-specific CTL activity have lower levels of viremia. 7,24,25 Viral levels tended to be lower within those patients that had intrahepatic HCV-specific CTL in this study, but this did not reach statistical significance. This is likely because of the relatively small patient numbers in this report.…”

“…Imawari et al recently reported that a high HCV-specific CTL response to the nucleoprotein (aa 88-96) was associated with a low titer of serum HCV RNA in HLA B44-positive patients infected with HCV. 24 Thus, CTL response to the core protein may also improve response through lower pretreatment viral levels. A similar role for CD4 ϩ core epitopes has been described for the CD4 ϩ response to HCV.…”

Comprehensive Analyses of CD8+ T Cell Responses During Longitudinal Study of Acute Human Hepatitis C *

“…[12][13][14][15] In contrast, chronic infection is characterized by low frequencies of CD8 ϩ T cells in peripheral blood. [16][17][18][19][20][21] Although the cellular immune response may be less vigorous and more narrowly directed in those who fail to clear the infection, a cellular immune response is nonetheless often present in early infection and may even persist into chronic infection. Why those immune responses fail to control infection is unclear, but responses generated in acute infection have been shown to decline in a few subjects who remained persistently infected.…”

Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection

“…Most immunological studies in this setting have thus focused on peripheral blood cells, which may not accurately reflect the composition and function of the hepatic infiltrate. The low frequency of HCV-specific CD8 T cells in the circulation of chronically infected patients [4][5][6][7][8] has been attributed to their sequestration in the liver. This is based on work on intrahepatic lymphocytes isolated from liver biopsy material and studied either after in vitro amplification [9][10][11] or directly ex vivo.…”