Induction of Type-C RNA Virus by Cycloheximide: Increased Expression of Virus-Specific RNA

Abstract

Mouse cells contain the genetic information for multiple endogenous type-C RNA viruses. The mechanisms by which the cell controls expression of these naturally integrated viruses are not yet known. Recently, chemicals that inhibit protein synthesis have been sl-Gwn to induce a specific type-C virus at high frequenc, f rom BALB/c mouse embryo cells. In the present studie'z. virus activation in response to a representative trans"I;inal inhibitor, cycloheximide, is demonstrated to be I i ansient, with virus release primarily occurring within the first 12-24 hr following drug exposure. Analysis of virus-specific RNA in cells by molecular hybridization revealed an absolute increase in viral RNA concentration in cycloheximide-treated cells. This was blocked by simultaneous exposure of the cells to actinomycin D. Further, inhibition of RNA synthesis during but not subsequent to cycloheximide exposure prevented virus activation. These findings show that virus induction by cycloheximide requires de novo RNA synthesis during but not after drug exposure and suggest that the required RNA species may be that of the virus itself. The present results are consistent with the hypothesis that translational inhibitors prevent synthesis of a labile protein whose normal action is to inhibit viral RNA transcription or to cause degradation of viral RNA.

Induction of mouse type-C virus by translational inhibitors: evidence for transcriptional derepression of a specific class of endogenous virus.

“…The actual release of virus would be expected to occur only following release from translational inhibition and would be likely to persist only until the control protein returned to its pretreatment level. This hypothesis is consistent with previous studies indicating that induction in response to inhibitors of protein synthesis requires cellular RNA synthesis during drug exposure and is rapidly reversed following drug removal (11).…”

“…Following release from protein synthesis inhibition, virus is transiently activated from a high frequency of cells. Both effects are dependent upon de novo cellular RNA synthesis during the time of drug exposure (11). These findings have suggested that the mechanism of virus activation by translational inhibitors may involve increased transcription of viral RNA or an alteration of its post-transcriptional processing.…”

Chemical Induction of Endogenous Retrovirus Particles from the Vero Cell Line of African Green Monkeys

“…In general, newly acquired endogenous retroviral sequences are more likely to be associated with an infectious virus, whereas ancient sequences may be transcriptionally active but defective for virus production (86) or produce noninfectious particles (38). In rodents, endogenous retroviruses can become activated in animals, as a consequence of age (4), or in cell lines, either spontaneously by long-term culture passage (2,49,63) or by treatment with a variety of inducers, including biological, immunological, and chemical agents (1,13,16,25,39,47,50). In humans or nonhuman primates (NHPs), spontaneous release of endogenous retroviruses has been reported from tumor tissues and cell lines, as well as from normal placenta (9, 12, 14, 15, 19, 20, 27, 28, 34, 43, 44, 51, 52, 58, 62, 64-66, 69, 72, 73).…”

Increased Expression of Endogenous Xenotropic Murine Retrovirus by Treatment with the Tetrapeptides, Tuftsin and Kentsin

“…Induction by both IdUrd and cycloheximide requires de novo cellular RNA synthesis and their activity as inducers can be blocked by treatment with actinomycin D (Aaronson et al, 1974). During activation by both classes of chemicals, virus-specific RNA accumulates in both nucleus and cytoplasm, suggesting that transcriptional derepression may occur (Besmer et al, 1975;Cabradilla et al, 1976).…”

“…With type C viruses, the virus genomes are transmitted from one generation to another as part of the host chromosome and expression can occur spontaneously with age or following chemical treatment. Chemicals that block protein synthesis (Aaronson & Dunn, 1974 a;Long et aL, 1978) and halogenated pyrimidines (Aaronson et al, 1971;Lowy et al, 1971) have been shown to be very efficient inducers of xenotropic virus. Spontaneous production of type C RNA viruses has been reported in mouse and rat ceils transferred frequently at high densities for extended periods of time (Aaronson et al, 1969;Aaronson & Todaro, 1968;Klement et al, 1973).…”