A murine retrovirus induces proliferation of unique lymphoid cell lines expressing T-cell-receptor structures utilizing common variable region alpha and beta chain genes.

A murine radiation leukemia virus (RadLV) has been shown to induce in vitro proliferation of an unusual subset of lymphoid cells from spleen. They have the unusual property of expressing CD3/T-cell receptor alpha and beta chains (TCR-alpha beta) in the absence of other T-cell markers such as Thy-1, CD4, and CD8. Cell lines induced in two mouse strains with RadLV produced by the C6VL/1 thymoma all specifically utilize common V alpha 3 and V beta 8.2 variable region genes in the formation of a TCR structure. Each of these cell lines has now been found to express both class I and class II major histocompatibility antigens and the beta 2 integrin specific for spleen dendritic cells. Analysis of functional properties of these cells has revealed a subset that can endocytose proteins and function alone as antigen-presenting cells. They have therefore been called D-T cells (i.e., dendritic cells expressing TCR-alpha beta). A retroviral-driven event has been implicated in the proliferation of dendritic-like cells expressing a common TCR epitope.

U3 long terminal repeat-mediated induction of intracellular immunity by a murine retrovirus: a novel model of latency for retroviruses.

BL/VL3 radiation leukemia virus (RadLV) is a thymotropic, highly leukemogenic murine leukemia virus (MuLV) which is unable to replicate in vitro in mouse fibroblasts. We have previously reported that the U3 long terminal repeat region of its genome is responsible for this block (E. Rassart, Y. Paquette, and P. Jolicoeur, J. Virol. 62:3840-3848, 1988). By using hybrids of permissive and resistant cells infected with BL/VL3 RadLV or fibrotropic MuLV, we found that the resistant phenotype was dominant. Investigation to determine at which step of the virus cycle the block operates revealed that integration, transcription, and translation of the BL/VL3 viral genome occurred at normal levels in nonpermissive cells. The BL/VL3 RadLV Pr65gag proteins made in nonpermissive cells were also myristylated and located at the membrane, and the levels of their cleaved products were similar to those of fibrotropic MuLV. However, processing of BL/VL3 RadLV Pr85env was impaired in nonpermissive cells. Virions were not released into the culture medium of nonpermissive cells, as measured by reverse transcriptase activity and by content in p30 or gp70 protein and as documented by lower levels of budding particles seen by electron microscopy. These results indicate that BL/VL3 RadLV replication is blocked at a late stage of the virus cycle, i.e., at virion assembly. Interestingly, these BL/VL3 RadLV-infected nonpermissive fibroblasts were resistant to superinfection by fibrotropic Moloney MuLV, and this resistance also occurred at a late step of the Moloney virus cycle. Since this block is dominant, it appears that the U3 long terminal repeat region of the BL/VL3 viral genome has the ability to induce a cellular suppressor factor(s), thus bringing intracellular immunity against itself and against other ecotropic MuLVs.

Treatment of premalignancy: prevention of lymphoma in radiation leukemia virus-inoculated mice by cyclosporin A and immunotoxin.

Radiation leukemia virus (RadLV)-induced preleukemic (PL) latency is characterized by the appearance of virus-infected PL cells in the thymus. The survival of these PL cells is dependent upon autostimulation with interleukin 4 (IL-4). We have intervened prophylactically in RadLV-induced preleukemia by using cyclosporin-A (CSA), which inhibits IL-4 production, and an immunotoxin (ITx) that kills PL cells. CSA efficiently inhibited IL-4 secretion from RadLV-induced PL and leukemic cells, and its administration to PL mice caused a significant delay in their death. An ITx consisting of anti-RadLV glycoprotein-70 (gp70) antibody coupled to ricin A chain efficiently inhibited protein synthesis in virus-infected cells in vitro and, when injected into PL mice, also delayed their death. Combined treatment with CSA and ITx prevented 75% of the treated PL mice from developing lymphoma. These results show that the development of malignancy from a premalignant state can be averted by a combination of therapeutic modalities that decrease the size and growth rate of the premalignant cell population.

I-region linked complementing loci in resistance to viral leukemogenesis in the mouse.

A-RadLV, a variant of the radiation leukemia virus, inoculated intrathymically into adult mice, causes a high frequency of leukemia in haplotypes b, f, k, d, p and j on the B10 background, whereas H-2s mice are resistant. Resistance is dominant and segregates with H-2s in the offspring of (b x s)b and (b x t2)b backcrosses. Analysis of recombinant strains revealed that resistance is associated with I-A and I-B. B10.A(5R), a recombinant of two sensitive haplotypes, was found to be resistant, suggesting intra-H-2-gene complementation. The resistance of such complementing loci was demonstrated also in the trans position by testing F1 mice bred from sensitive parents. These data are taken to suggest that I-region linked complementing loci, similar to classical Ir genes, may be involved in resistance to murine leukemia.