High multiplicities of infection favor rapid and random evolution of vesicular stomatitis virus

Abstract

T 1 oligonucleotide mapping of vesicular stomatitis virus RNA shows that the genome undergoes continuous and extensive mutation during repeated high-multiplicity lytic passages in vitro. In contrast, repeated low-multiplicity lytic passages lead to few if any oligonucleotide map changes. Many factors such as intergenomic complementation, selection by defective interfering particles, and genome competition may be involved in the more rapid genome evolution occurring during high-multiplicity passages. In matched high-multiplicity passage series passaged in parallel, the accumulation of genome mutations proceeded not along determined pathways but rather randomly, since dissimilar map changes usually accumulated in matched sets of parallel-passage series. Random virus evolution was also observed in persistently infected cells maintained in parallel cultures, or in vivo as tumors in different nude mice. No attempt is made here to relate genome changes to phenotypes, but numerous interesting phenotypes emerge during persistence. One clone isolated following 70 months of persistent infection replicates very poorly, and produces enormous particle-to-infectious unit ratios. Such phenotypes could be partly responsible for low virus yields, and for difficulties and failures to isolate RNA viruses from persistently infected cells and tissues.