Analysis of ‘driver’ and ‘passenger’ CD8 + T-cell responses against variable viruses

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Abstract
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.