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

Abstract

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.

Appearance of Mink Cell Focus-Inducing Recombinants during In Vivo Infection by Moloney Murine Leukemia Virus (M-MuLV) or the Mo+PyF101 M-MuLV Enhancer Variant: Implications for Sites of Generation and Roles in Leukemogenesis

“…inoculated mice was that once formed, MCF recombinants propagate to higher levels in the thymus, i.e., 1 to 2 log units higher than in bone marrow or spleen. This was consistent with results of previous studies (20). It was interesting and somewhat surprising that the patterns of initial appearance of MCF recombinants were different for mice inoculated with M-MuLV s.c. vs. i.p.…”

“…Our previous studies suggested that the bone marrow might be involved in MCF virus formation or propagation (2,6), but other candidate hematopoietic compartments included the spleen and thymus. High levels of ecotropic virus infection are established in all three tissue compartments at early times postinfection (Ͻ14 days) (1), and MCF recombinants have been detected in the spleen and thymus of M-MuLV-infected mice as early as 3-4 weeks, although the bone marrow was not examined (14,20). Our initial strategy to identify the site(s) of MCF recombinant generation was to search different tissues for the earliest appearance of MCF recombinants.…”

Introduction of acis-Acting Mutation in the Capsid-Coding Gene of Moloney Murine Leukemia Virus Extends Its Leukemogenic Properties

“…Genetic mapping of these differences includes gag sequences at the 3Ј end of the capsid gene, downstream of the mutations introduced in MSD1 (30). Therefore, it remains conceivable that the mutations present in MSD1 modulate the types of MCF recombinant MuLVs that are generated with new pseudotyping envelopes, allowing extended cell lineages to be targeted (29).…”

Human endogenous retroviruses in neurologic disease

“…In numerous other species, from mice (8,19) to cats (20) to koalas (21), (some) endogenous retroviruses are demonstrably pathogenic, whereas in humans a role for HERVs in the etiology of a number of diseases have been suggested (5,6,(22)(23)(24), but an unequivocal pathogenetic cause-effect relationship is as yet unknown.…”