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ABSTRACT: Helper-independent virus from a molecularly cloned stock of Friend murine leukemia virus (F-MuLV) induces an erythroproliferative disease characterized by splenomegaly and severe anemia in newborn mice of certain susceptible strains, such as NIH Swiss. With age, NIH Swiss mice become resistant to this F-MuLV-induced erythroleukemia. Resistance is not correlated with the replication of the input Friend MuLV but is correlated related with the replication of Friend MCF viruses in the spleens of infected mice. Treatment of adult NIH Swiss mice with X-irradiation, phenylhydrazine, or silica before injection of F-MuLV increases the replication of MCF viruses in the spleens of these mice and renders them significantly more susceptible to erythroleukemia. In contrast to mice infected with F-MuLV as newborns or as X-irradiated adults, untreated 6-week-old NIH Swiss mice develop a good humoral immune response to MCF gp70. These results suggest that the resistance of adult NIH Swiss mice to erythroleukemia induced by F-MuLV is due to the lack of replication of Friend MCF viruses in these mice because of (1) a good immune response to the virus, (2) the lack of a suitable number of susceptible target cells, or (3) both.