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

Abstract

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) have been shown to play a role in host defense and pathogenesis of chronic HCV infection. Our aim was to test the hypothesis that intrahepatic HCV-specific CTL activity may impact subsequent response to interferon alfa (IFN-␣) therapy. Of the 37 patients that we have prospectively evaluated for HCV-specific CTL activity in liver, 21 received IFN therapy, and 19 completed a 6-month course and attended 6 to 18 months of follow-up. Intrahepatic CD8 ؉ cells were isolated from liver biopsy tissue and tested against target cells expressing HCV antigens to determine intrahepatic CTL activity. The relationship between treatment response and HCV-specific CTL activity and other factors known to associate with response (genotype, viremia, histology) was analyzed. HCV-specific CTL activity was detected in 9 of 21 patients (and 9 of 19 who completed therapy). After 6 months of IFN therapy, 8 of 19 (42%) patients had normal serum alanine transaminase (ALT) (complete responders). After 18 months of follow-up, only 3 patients (16%) had a sustained biochemical response. Of the 9 patients with detectable HCV-specific CTL activity in their liver before treatment, 7 (78%) developed a complete response. In contrast, only 1 of the 10 patients with no detectable HCV-specific CTL activity developed a complete response to IFN (P F .01). In 6 of 8 patients with a complete response, including the 3 sustained responders, the CTL response appeared to be directed predominately to the HCV core region. These data suggest that the host immune response, particularly that mediated by CD8 ؉ CTL, may be important in determining the outcome of IFN therapy for chronic HCV infection. Further understanding of the mechanism of action of IFN should impact the design of better therapeutic strategies against chronic HCV infection. (HEPATOLOGY 1998;28:225-230.)The host cellular immune defense, including the CD4 ϩ and CD8 ϩ T-cell response, is activated in patients with hepatitis C virus (HCV) infection. The intensity of the T-cell response during the early stages of infection may be a critical determinant of disease resolution and control of infection. 1,2 In chronic viral infection, viral-specific CD8 ϩ cytotoxic T lymphocytes (CTL) have been shown to be important in host defense and in the control of the viral infection. [3][4][5][6][7] In lymphocytic choriomeningitis virus infection, virus-specific CTL activity reduces viral titers by 4 to 5 logs. 8 It is felt that CTL might lead to viral clearance through either direct lysis of infected cells or cytokine-mediated mechanisms. We and others have shown that HCV-specific CTL activity is detectable in the liver in a proportion of patients with chronic HCV infection. The presence of HCV-specific CTL activity in bulk-expanded CTL was found to be associated with a lower level of viremia and a greater inflammatory activity in the liver, suggesting that HCV-specific CTLs may assist in the control HCV infection, but, in so doing, contribute to hepatoce...

Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX™ vaccine: A phase I study in healthy volunteers

“…33 Th1-type responses are also thought to be associated with recovery from HCV infection 34 and Th-1 type responses are also associated with better outcomes following interferon and ribavirin treatment. 12,29 Interestingly IL-5, indicative of a Th2-type response, was detected in five subjects and is consistent with the strong antibody responses observed. Both IL-5 and IL-10 were elicited in addition to IL-2, TNFα and IFNγ which indicates that the vaccine induced a mixed Th1-type and Th-2-type.…”

“…[25][26][27][28] The core protein is the most highly conserved HCV protein among the different genotypes. Cellular immune responses to core protein have been associated with a positive response to anti-viral treatments 29 and with a milder course of disease. 30 We previously assessed the immunogenicity of this candidate therapeutic vaccine in rhesus macaques 31 where we observed CD4 + and CD8 + T cell responses, cytotoxic T lymphocyte (CTL) responses and antibody responses.…”

Selective decrease in hepatitis C virus–specific immunity among African Americans and outcome of antiviral therapy†

“…Considering the importance of CD4ϩ Type 1 helper (Th1) response in promoting the generation of CTLs, it is conceivable that impairment in HCV-specific cell-mediated immunity might result in less hepatic immunopathology but also be associated with a greater likelihood of nonresponse to antiviral therapy. 28 We recognize that race is a construct that reflects social stratification of groups according to phenotypic and cultural characteristics; 29 nonetheless, our findings have important implications in understanding the basis for variable outcomes in HCV infection, including differential response to antiviral therapy.…”

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

“…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. Among the relevant human leukocyte antigen (HLA)-A2-restricted T-cell epitopes mapped in the HCV polyprotein, those in the NS3 protein are commonly recognized by CD8-positive T-cells in the peripheral blood [12][13][14] and liver [14][15][16] of chronically infected patients. In nontransplant patients, some studies have detected viral escape mutants in T-cell epitopes.…”

“…Several studies indicate that HCV Class I restricted T-cell epitopes located within the NS3 protein are commonly recognized by liver-infiltrating and circulating cytotoxic T lymphocytes (CTL) of HCV-infected patients. [12][13][14][15][16][17] Briefly, total RNA was extracted from 140 L of serum or plasma specimens with the QiaAmp HCV-RNA column kit (Qiagen GmbH, Hilden, Germany) following the instructions from the manufacturer. Reverse transcription of viral RNA and primary PCR were performed in a single tube containing 5 L of RNA, 1 L of AMV-Expand HiFidelity enzyme mix (Roche Molecular Biochemicals, Mannheim, Germany), and 25 pmol of primers NS3-5 (5Ј-ACG TAC TCC ACC TAC GGC AA-3Ј; positions 4228 -4248) and NS3-6 (5Ј-AAG GTA GGG TCA AGG CTG AA-3Ј; positions 4745-4765).…”