IMMUNE AVOIDANCE STRATEGIES IN RNA VIRUSES - FITNESS CONTINUA ARISINGFROM TRADE-OFFS BETWEEN IMMUNOGENICITY AND ANTIGENIC VARIABILITY

Highly exposed and protruding amino acid sites on the surface of viral capsids are subject to fewer residue interactions and packing constra ints than those buried within protein interiors. Consequently they oft en experience higher rates of non-synonymous substitution and exhibit greater genetic variability than buried interior sites. However such p rotrusive surface structures often induce host immune responses and ar e likely to constitute B cell epitopes. Genetic variation at these sur face sites is therefore likely to correspond to antigenic variation. T his may be of adaptive value to the virus for two quite different reas ons. The first is that antigenic variation arising over the course of a viraemia may result in greater net viral replication, and increased opportunities for viral transmission. The second is that antigenic var iation generated rapidly over a single infection or incrementally over several sequential infections may give rise to variants that are suff iciently immunologically distinct that they can reinfect host individu als with previous infection experience of related virus. This would le ad to an extension of the susceptible host pool with consequent increa se in transmission opportunities. The surface architecture of viral ca psid proteins is therefore conceivably subject to two opposing selecti on pressures: one to minimize the surface area accessible to interacti on with elements of the immune system, the other to increase the poten tial access to antigenic variation by adoption of exposed and unconstr ained protein conformations. Therefore, there exists a possible trade- off between the fitness benefits deriving from potential ability to ge nerate antigenic variation, and the increased immunogenicity with whic h such potential may be associated. We propose that the existence of t his trade-off would lead to a continuum of different strategies by whi ch a virus might combat an immune response. We explore this strategy s pace with simple mathematical models, and show that peak loads of infe ctious virus particles are proportional to levels of antigenic diversi ty, and inversely proportional to immunogenicity, thereby creating the potential for a trade-off by which fitness might be maintained with a continuum of strategies. This may remain possible even if the antigen ic variants are not transmissible between hosts, so long as immune res ources are sufficiently dispersed between antigenic variants. The dive rsity of possible strategies is discussed with reference to the Picorn avirus family. (C) 1998 Academic Press.