RAPID CELL VARIATION CAN DETERMINE THE ESTABLISHMENT OF A PERSISTENT VIRAL-INFECTION

Evidence for a mechanism of initiation of viral persistence in which t he cell, and not the virus, plays a critical role has been obtained us ing the important animal pathogen foot and-mouth disease virus (FMDV). We have developed a virulence assay consisting of quantification of t he ability of virus to kill cells and of cells to divide in the presen ce of virus and to initiate a carrier state. Cells were cured of FMDV at early times following a cytolytic infection of BHK-21 monolayers wi th FMDV. When cured cells were subjected to the virulence assay they s howed an increased ability to survive a second infection by FMDV but n ot by other RNA viruses. This altered phenotype was maintained as a st able genetic trait. When the virus present in such early surviving cel ls was used to infect BHK-21 cells, it proved to be as virulent as the initial cytolytic FMDV and, furthermore, its ability to kill BHK-21 c ells increased upon replication in the surviving cells. Both the level of genetic heterogeneity and the rate of evolution of FMDV were simil ar to those previously documented during acute and persistent FMDV inf ections. The results suggest that, in contrast to most other viral sys tems, the critical element in the establishment of a persistent infect ion of BHK-21 cells with FMDV is the ability of the host cells to vary genetically and phenotypically, which promotes selection of cells wit h increased resistance to virus. The possible relevance of this mechan ism to viral persistence in vivo is discussed.