The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection.
Hepatitis C virus (HCV) readily sets up a persistent infection and is a major cause of liver disease worldwide. Interferon alfa and ribavirin therapy lead to sustained clearance of virus in 31% to 64% of patients with type 1 and non-type 1 genotypes, respectively. It is not clear to what extent these drugs act directly to reduce HCV replication, or indirectly via host immune responses, and what evoked immune responses are associated with clinical outcome. We have examined prospectively 15 patients with chronic HCV infection before, during, and after combination therapy. Quantitative assays for HCV antigen-specific CD4+ and CD8+ T-cell responses, and flow cytometric assays for analysis of the phenotype of T cells, in addition to viral sequencing of core protein, were performed throughout the treatment and follow-up period over 18 months. We found enhancement of proliferative T-cell responses during therapy. Proliferative responses are strikingly heterogeneous in terms of specificity, kinetics, and magnitude. Proliferative responses are often not associated with interferon-gamma release. T-cell responses are rarely sustained irrespective of treatment outcome and this is not due to the evolution of new immune escape variants. T-cell responses tend to peak late in the course of treatment. In conclusion, combination therapy for HCV has a transient effect on host virus-specific T cells in the blood. Induction of sustained T-cell responses may require additional immune modulation later in therapy.
Barnes
Eleanor
E
Centre for Hepatology, Royal Free Hospital, London; and the Nuffield Department of Medicine, Oxford University, Oxford, UK. ellie.barnes@ntlworld.com
Harcourt
Gillian
G
Brown
Dave
D
Lucas
Michaela
M
Phillips
Rodney
R
Dusheiko
Geoffrey
G
Klenerman
Paul
P
D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D005075:Biological Evolution; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002455:Cell Division / Q000276:immunology; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D018936:Hepatitis C Antigens / Q000737:chemistry / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011446:Prospective Studies; D014758:Viral Core Proteins / Q000737:chemistry / Q000276:immunology
D000998:Antiviral Agents; D018936:Hepatitis C Antigens; D014758:Viral Core Proteins; D007371:Interferon-gamma