A multistep process of leukemogenesis in Moloney murine leukemia virus-infected mice that is modulated by retroviral pseudotyping and interference.

Mixed retroviral infections frequently exhibit pseudotyping, in which the genome of one virus is packaged in a virion containing SU proteins encoded by another virus. Infection of mice by Moloney murine leukemia virus (M-MuLV), which induces lymphocytic leukemia, results in a mixed viral infection composed of the inoculated ecotropic M-MuLV and polytropic MuLVs generated by recombination of M-MuLV with endogenous retroviral sequences. In this report, we describe pseudotyping which occurred among the polytropic and ecotropic MuLVs in M-MuLV-infected mice. Infectious center assays of polytropic MuLVs released from splenocytes or thymocytes of infected mice revealed that polytropic MuLVs were extensively pseudotyped within ecotropic virions. Late in the preleukemic stage, a dramatic change in the extent of pseudotyping occurred in thymuses. Starting at about 5 weeks, there was an abrupt increase in the number of thymocytes that released nonpseudotyped polytropic viruses. A parallel increase in thymocytes that released ecotropic M-MuLV packaged within polytropic virions was also observed. Analyses of the clonality of preleukemic thymuses and thymomas suggested that the change in pseudotyping characteristics was not the result of the emergence of tumor cells. Examination of mice infected with M-MuLV, Friend erythroleukemia virus, and a Friend erythroleukemia virus-M-MuLV chimeric virus suggested that the appearance of polytropic virions late in the preleukemic stage correlated with the induction of lymphocytic leukemia. We discuss different ways in which pseudotypic mixing may facilitate leukemogenesis, including a model in which the kinetics of thymic infection, modulated by pseudotyping and viral interference, facilitates a stepwise mechanism of leukemogenesis.