Persistent infection II. Interferon-inducing temperature-sensitive mutants as mediators of cell sparing: Possible role in persistent infection by vesicular stomatitis virus

Abstract

We demonstrate that like the interferon-inducing [±]RNA DI particles of vesicular stomatitis virus (VSV), ts mutants, also commonly implicated in the establishment and maintenance of persistent infection, can be excellent inducers of interferon—both at non-permissive (40°) and at semipermissive (37°) temperatures. Mutants capable of inducing interferon ( ifp +) were characteristically negative or delayed in the expression of cellular protein synthesis inhibition— psi − and delayed psi + phenotypes, respectively. We contend that in cells competent for the interferon system, virus phenotypes selected during persistent infection are characterized by interferon-inducing particles ( ifp +) activity. Interferon induction by ifp + mutants (or the [±]RNA class of DI particles) of VSV provides, through the subsequent action of that interferon, a common mechanism for the sparing of cells, i.e., the persistence of normally susceptible cells in the presence of lethal virus. The critical role we propose for interferon-mediated cell sparing in persistent infection by VSV in interferon-competent cells predicts that specific anti-interferon serum will shift the equilibrium between cell sparing ⇆ cell killing, and virus inhibition ⇆ virus replication, and precipitate a “crisis”, i.e., cell death and termination of persistent infection. Such results have been observed in the virus-cell systems thus far tested with anti-interferon serum.