Genomic masking and rescue of dual-tropic murine leukemia viruses: role of pseudotype virions in viral lymphomagenesis.

The kinetics of genomic masking of nondefective dual-tropic murine leukemia viruses (MuLV) by ecotropic MuLV in mixedly infected mouse cells was studied. The ratio of virus infection (ecotropic to dual-tropic) determined the kinetics of genomic masking. Some dual-tropic virus isolates could be masked routinely (i.e., converted to virions containing a dual-tropic genome and possessing the ecotropic host range) at all ratios of initial infection of mixedly infected mouse cells. The masked genomes could be rescued as infectious viruses of dual-tropic genotype and host range by an infectious center assay of the infected mouse cells on mink lung cells. Infectious center rescue of masked dual-tropic MuLV took place readily, even from cells that had been kept in continuous culture for many months after the onset of genomic masking. Some dual-tropic virus clones did not undergo genomic masking at any infection ratio with ecotropic virus. Nevertheless, such mixedly infected cultures also gave rise to phenotypically mixed virions, which contained a dual-tropic genome and had an ecotropic host range. (The phenotypically mixed virions found among the progeny of mixedly infected mouse cells were not pseudotypes, as both types of viruses were genetically nondefective, nor was the process leading to their generation a bona fide phenotypic mixing [Fischinger et al., Science 201:457-459, 1978]. Nevertheless, in this paper we use the terms pseudotype and phenotypic mixing because of the lack of a better description.) The lymphomagenic potential of dual-tropic lymphomagenic MuLV was compared with that of phenotypically mixed virions possessing an ecotropic host range and with that of a simple mixture of dual-tropic and ecotropic viruses. The phenotypically mixed pseudotype virions were more potent lymphoma inducers than were those of dual-tropic, cloned genotype. Inoculation of a simple mixture of the viruses did not increase dual-tropic virus tumorigenicity. The reason for this was probably the highly efficient inactivation of dual-tropic virus by oncovirus-inactivating factor, which is present in normal mouse serum and did not inactivate the phenotypically mixed virions. Simple mixtures of dual-tropic lymphomagenic and ecotropic virus preparations behaved like the cloned, dual-tropic virus in vivo and were equally sensitive to oncovirus-inactivating factor in vitro. Thus, phenotypic mixing of dual-tropic and ecotropic MuLV with or without concomitant genomic masking may be a highly significant phenomenon in naturally occurring lymphomagenesis. It may also be important to use phenotypically mixed viruses in the procedures used for in vivo testing of lymphomagenic dual-tropic MuLV isolates.