Recognition of a leukemia-related antigen by an antiidiotypic antiserum to an anti-gp70 monoclonal antibody.

The possibility that receptors for retroviral gp70 share structural elements with the antigen-binding sites of anti-retroviral gp70 antibodies was investigated. A monoclonal antibody (1416) was produced that reacted with the gp70 of a cloned recombinant leukemogenic retrovirus, termed P1. An antiidiotypic antiserum raised to 1416 was tested for its ability to bind to the thymic leukemia induced by P1 (P1 Thy). A membrane structure was identified on the surface of P1 Thy that reacted with the antibody against the idiotypic determinant of 1416. A similar structure was identified on the surface of several different, independently derived murine leukemias of T cell, B cell, and erythroid lineage. The expression of the idiotype-like determinant on these leukemia cells was independent of the serological relatedness of their expressed retroviral envelope glycoproteins to P1 gp70. The determinant recognized by the antiidiotype was not detected on normal lymphoid cells. The recognition by the anti-(anti-gp70) idiotype of determinants on unrelated murine leukemias suggests that receptors for different leukemogenic viruses may share common structures.

Expression of leukemogenic recombinant viruses associated with a recessive gene in HRS/J mice.

HRS/J inbred mice carry a mutant autosomal recessive gene (hr), which in homozygotes coincides with susceptibility to spontaneous thymic leukemia. Unlike their heterozygote (hr/+) littermates, hr/hr homozygotes express high levels of xenotropic virus during the preleukemic period, and viruses with a broadened host range (termed polytropic viruses) can be isolated from their preleukemic and leukemic tissues. Because hr/hr and hr/+ mice are otherwise genetically identical, the virological differences between them support the role of polytropic viruses in the generation of thymic leukemia. In the present report we show that the HRS/J polytropic viruses are env gene recombinants with unique oligonucleotide and peptide maps. These polytropic viruses appear to arise by recombination between ecotropic virus and an unidentified genome related, but not identical to, the endogenous xenotropic viruses. Moreover, polytropic viruses not only accelerate leukemogenesis in HRS/J mice, but also induce thymic leukemia in the low leukemia strain CBA/J. By contrast, cloned ecotropic and xenotropic viruses have no leukemogenic action.

A single dominant gene determines susceptibility to a leukaemogenic recombinant retrovirus.

The production of recombinant retroviruses is an important episode in the natural history of thymic leukaemia in AKR and HRS/J (hr/hr) mices. These viruses apparently originate from ecotropic and xenotropic precursors in the late preleukaemic stage of the disease. Analyses of their structural proteins and genomic oligonucleotides indicate that they arise by recombination of env genes of the precursor viruses. This event leads to a viral envelope glycoprotein (gp70) with some peptides that have features of the gp70 glycoproteins of ecotropic and xenotropic viruses, and others that are unique for each recombinant virus. The former property explains the broad host range of recombinant viruses, and hence their designation as dual tropic or polytropic viruses. It has been postulated that the unique aspect of each recombinant's gp70 determines the phenotypes of leukaemic cells. Polytropic viruses may be highly thymotropic. Their systemic administration results in an infection that confines itself virtually to the thymus. Moreover, these viruses are leukaemogenic whereas their precursors are not, or only weakly so. The leukaemogenicity of polytropic viruses is, however, restricted to certain inbred strains of mice. The HRS/J isolate PTV-1 is leukaemogenic in HRS/J and CBA/J mice, but not in SWR/J or NIH/Swiss mice. The experiments described here demonstrate that a single dominant gene permits infection by thymocytes by a leukaemogenic polytrophic virus. CBA/J mice, which develop thymic leukaemia after infection by this virus, posesses this gene, whereas leukaemia-resistant NFS mice lack it.

Surface phenotypes in T-cell leukaemia are determined by oncogenic retroviruses.

Spontaneous thymic leukaemia in experimental mice is the result of a complex series of genetically controlled events. An important step in this process involves the production by thymocytes of recombinant polytropic retroviruses (MCF viruses). These leukaemogenic agents arise by recombination of genes from the env regions of endogenous precursor viruses. Sequences in these regions encode the envelope glycoprotein gp70 (ref. 6). Thus far, each cloned isolate of recombinant virus from AKR and HRS/J mice has been found to possess unique oligonucleotide sequences in its env region, as well as clone-specific peptides in its gp70 (refs 7,8). Therefore, the polytropic viruses of these leukaemia-susceptible mice are extremely diverse. These findings suggest that random recombination of env genes gives rise to leukaemogenic polytropic viruses. McGrath and Weissman have proposed that thymocytes with cell surface receptors for the gp70 of a particular leukaemogenic virus are the target cells for malignant transformation by that specific virus. In view of the diversity of polytropic viral gp70, their hypothesis would predict extensive phenotypic diversity among spontaneous thymic leukaemias. In contrast, leukaemias induced by a particular leukaemogenic recombinant virus would always have the same phenotype. Here we verify these predictions experimentally.