Persistent infection I. Interferon-inducing defective-interfering particles as mediators of cell sparing: Possible role in persistent infection by vesicular stomatitis virus

Abstract

Defective-interfering (DI) particles have been implicated in modulating the lethal action of infectious virus during persistent infection. However, in the case of vesicular stomatitis (VS) virus, conventional [−]RNA DI particles (nonlethal themseleves) do not block the lethal action of infectious or cell-killing (CK) particles of VS virus, even though no new infectious virus is produced. The discovery of a class of interferon-inducing defective-interfering (DI → IF) particles with covalently linked, self-complementary [±]RNA, and the capacity of a single such particle to induce interferon, coupled with the demonstration that interferon action prevents cell killing by VS virus, led us to postulate that defective-interfering particles of the [±]RNA class present initially or arising during infection might activate the interferon system and prevent CK particle activity and hence contribute to the establishment and possible maintenance of persistent infection in some cell systems. We provide evidence to support this hypothesis: Single cell survival experiments established that GMK-BSC or mouse L cells retain the capacity to form colonies, i.e., are spared from killing, if they are pretreated with interferon-inducing [±]RNA DI-011 particles 24 hr prior to challenge with either homologous or heterologous viruses. Mouse interferon antiserum present during the pretreatment phase eliminated cell sparing. Pretreatment with DI-011 particles of GMK-Vero cells, which lack the capacity to produce interferon, did not spare these cells from the lethal action of VS virus. Activation of the interferon system by the [±]RNA class of defective-interfering particles provides a means whereby normally susceptible cells may survive in the presence of lethal virus — an aspect of persistent infection by VS virus not satisfactorily accounted for by current models.