The mechanism by which a myeloblastosis associated virus induces osteopetrosis, a proliferative disorder of bone, will be investigated. The primary objective of the present study is to discover the molecular origin of the proliferative disease. The approach will be threefold. The first approach is to establish an explanation of the difference between two forms of osteopetrosis. We have observed that plaque-purification of a serum-passaged virus always results in an increase in the time required for osteopetrosis induction. We will determine whether the virus responsible for the rapid onset of osteopetrosis is a defective form of the virus or whether the plaque-purified form is a transformation-defective derivative of the rapid onset form. This analysis will be performed by examining the RNA of the two forms for differnces in size and oligonucleotide fragments. We will also examine the two viruses for differences revealed by heteroduplex mapping. Limb bud cells will be infected at low multiplicity, and clones of cells examined for nonproducers. Cells infected with the two forms of the virus will be examined for the presence of a gag-related polyprotein using antisera against p19. The second approach is to determine the basis for the lymphoid depletion observed in osteopetrotic chicks. Adoptive transfer experiments will be carried out to determine whether lymphoid cells from normal, immune, and bursectomized donors protect infected embryos. The effects of subfractionation of the lymphoid cells will be examined. We will also determine the nature of the immunosuppression present in the lymphoid cells from the osteopetrotic animal. The third approach is to determine the hematopoietic target cell responsible for the progressive anemia induced by the osteopetrotic virus. We will compare the hematopoietic target for the osteopetrosis virus with that of avian leukemia viruses AEV, AMV and MC29. We will also examine the nature of the protection against anemia obtained by the use of neutralizing antibody.
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