Rapid early innate control of hepatitis C virus during IFN-α treatment compromises adaptive CD4+ T-cell immunity.
The ability to control HCV with IFN-α-based treatments provides an opportunity in humans to study how the rate of viral clearance in vivo impinges on the development of antiviral responses. Ex vivo (IFN-γ-producing) and cultured antiviral CD4(+)  T cells, serum cytokines, and viral loads were measured repeatedly in a cohort of chronically HCV-infected subjects (n = 33) receiving IFN-α. Rapid control of virus indicated by an increased calculated rate of virus clearance, occurred in those subjects demonstrating absent/minimal T-cell responses (p < 0.0006). Surprisingly, in subjects who demonstrated the most robust T-cell responses (and reduced serum IL-10), there was actually a reduced rate of early virus clearance. A subsequent analysis of NK-cell function in available subjects (n = 8) revealed an inverse correlation between pretreatment NK-cell expression of NKp46 and the potential to upregulate cytotoxic function on exposure to IFN-α (p < 0.004), as well as the subsequent measured rate of viral clearance (p = 0.045). Thus, the CD4(+)  T-cell response during IFN-α treatment appears to be shaped by the rate of innate virus suppression. These data suggest that individuals who respond most effectively to immune intervention may be most in need of subsequent vaccination to prevent reinfection.
School of Medicine, Institute of Infection and Immunity, Cardiff University, The Henry Wellcome Building, Cardiff, UK.
Tom
T
Pembroke
Ian
I
Rees
Kathleen
K
Gallagher
Emma
E
Jones
Paul
P
Mizen
Timur
T
Navruzov
Andrew
A
Freedman
Ceri
C
Fielding
Ian R
IR
Humphreys
Eddie C Y
EC
Wang
Awen M
AM
Gallimore
Andrew
A
Godkin
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D048708:Cell Growth Processes / Q000187:drug effects; D015331:Cohort Studies; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology* / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000276:immunology; D016896:Treatment Outcome; D019562:Viral Load / Q000276:immunology
D016898:Interferon-alpha; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D016753:Interleukin-10; D000410:Alanine Transaminase