Taking as a starting point the previously demonstrated genetic variability of in vitro cultivated murine leukemia viruses ( M u L V ) , with particular regard to their leukemogenic potential, an attempt was made to accumulate and study Rauscher leukemia virus ( R L V ) variants selected by long-term cultivation at a supra-optimal temperature of 40.5" C (h0.5" C ) . The most significant results were obtained with cells of the CL91 line originating from normal C57BL lung tissue, initially virus-free and infected with a highly leukemogenic R L V prepared from leukemic spleens. After I84 days of cultivation, the infected cells were divided into two parallel series: ( I ) the CL91RR which was continued at 37" C, ( 2 ) the CL9IRRHT series which was transferred, after a transitory adaptation period at 39" C, for permanent culture at 40.5" C.Supernatants from the parallel series were checked periodically for their leukemogenic capacity as related to the number of virions found in the supernatant aliquots inoculated into sensitive weanling or new-born BALBIc mice. The number of virions present in the CL91 R RHT supernatants was regularly at least equal but usually significantly higher than in parallel CL91 R R cultures. However, the leukemia-producing capacity of the first was very low: only 11 % of leukemias were obtained after an average of 98 days' latency with the CL91RRHT supernatants, when checked after 201 or more days of culture at 40.5" C, as compared with an average of' 89% rapidly evolving leukemias (within an average of 23 days) obtained with material from CL91RR cultures. These differences were seen repeatedly in 19 independent assays performed on a total of 132 and 111 animals, respectively, and extending over an experimental period of 586 days following the in vitro infection. These results were discussed in the light of other data concerning temperature-dependent selection of variants of pathogenic viruses.As previously demonstrated, the leukemogenic potential of Rauscher murine leukemia virus (RLV) decreases considerably during long-term cultivation of this virus in vitro Youn, 1965, 1966) or following repeated passages of the RLV-infected cells in adult animals in vivo (Barski et al., 1967). Similar findings were reported by other authors for Rauscher (Wright and Lasfargues, 1966;Sinkovics et al., 1966) or Friend leukemia viruses (Tkaczevski et al., 1968 ;Yoshikura et al., 1969). Evidence was produced more recently (Barski and Youn, 1971a;Barbieri and Barski, 1973) that the lowered leukemogenic capacity of the RLV from long-term cultures is not related either to a decreased rate of its production or to a loss on infectivity as demonstrated on cultures of mouse fibroblasts in vitro.These and other data pointed to the conclusion that, in the case of RLV, as for a number of other RNA and DNA oncogenic viruses, variants
Two neoplastic cell strains derived from the CS7BL/6 mice, P4bis originating from normal adult lung tissue '' spontaneously " transformed in vitro, and TBLC2 developed from a methylcholanthrene-induced sarcoma, were both infected in vitro with Rauscher leukemia virus. Consecutive to this infection, the tumor-producing capacity of these cells, which continued to multiply normally in vitro, dropped considerably when checked in syngeneic mice. This was evidenced by a dramatic decrease of takes and a significant prolongation of latency period. The high leukemogenic R R L f and the low leukemogenic RCL-virus variants were equally ejicient in infecting cells in vitro andproducing a decrease of their tumorigenic potential in vivo. This decrease coincided with the massive appearance in the cells and culture supernatant of C-type particles and of a new surface antigen reacting specifically in the immunofluorescence test with anti-Rauscher virus serum. The specific immunological nature of decreased tuniorigenicity was confirmed by the fact that the rejection of the virus-infected cells could be prevented by total irradiation of intact recipient animals, whereas animals preimmunized and laterirradiated continued to reject the infected cells. On the other hand, the rare tumors which appeared in non-irradiated adults after a long latency period were composed of virus-fuee cells whereas cells fvom tumors obtained by inoculation of new-born animals regularly contained the virus and were rejected when grafted on normal adults.
MECHANISM OF PREVENTIVE IMMUNIZATION WITH THE AID OF RAUSCHER VIRUS CULTURE HAVING A N ATTENUATED LEUKEMOGENIC POTENTIALThe experiments reported here were aimed at elucidating mechanisms involved in the immunization of mice against Rauscher leukemia with the aid of in vitro cultivated cells chronically infected with the '' attenuated " Rauscher virus.BALBIc mice were implanted intraperitoneally with Algire-type, 0.45 ,u porosity, Millipore chambers containing Rauscher-virus-irtfected cells. The animals developed leukemia when the cells in the chambers originated from leukemic spleens producing the virulent virus. On the contrary, when the cells in the chambers originated fromcultures producing '' attenuated" virus, the mice developed no disease but firm and
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