Analysis of 'driver' and 'passenger' CD8+ T-cell responses against variable viruses.
Variable viruses, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), persist despite host immune responses directed against them. Numerous lines of evidence have suggested that antiviral CD8+ T-cell responses are key among these immune responses, but these vary widely in their ability to contain virus. We propose that only a proportion of responses may exert significant antiviral pressure ('driver' responses), leading to control over viral replication (protection) and/or, ultimately, selection of escape mutants. Another set of responses may exert only weak pressure on the virus ('passenger' responses): these neither protect nor select. To examine this we have analysed (using established databases of HIV and HCV sequences and cytotoxic T-lymphocyte (CTL) epitopes, and published experimental datasets) two important features--predicted binding of the epitope to major histocompatibility complex molecule and observed variability of the epitope--that might distinguish such responses. We find that a high predicted binding estimate could only explain a limited set of 'driver' responses associated with protection or selection. There is statistical evidence that readily defined (and non-protective) CTL responses target regions associated with lower levels of viral variability. Taken together, this suggests that a large number of well-documented responses may represent 'passengers' and we propose a mechanism that might explain their presence.
Zafiropoulos
Andreas
A
Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford OX1 3SY, UK.
Barnes
Eleanor
E
Piggott
Clive
C
Klenerman
Paul
P
D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D014644:Genetic Variation; D006678:HIV / Q000235:genetics* / Q000276:immunology; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology*
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte