CHARACTERIZATION OF REPLICATION-COMPETENT RETROVIRUSES FROM NONHUMAN-PRIMATES WITH VIRUS-INDUCED T-CELL LYMPHOMAS AND OBSERVATIONS REGARDING THE MECHANISM OF ONCOGENESIS

Rapidly progressive T-cell lymphomas were observed in 3 of 10 rhesus m onkeys several months after autologous transplantation of enriched bon e marrow stem cells that had been transduced with a retroviral vector preparation containing replication-competent virus (R. E. Donahue, S. W. Kessler, D. Bodice, K. McDonagh, C. Dunbar, S. Goodman, B. Agricola , E. Byrne, M. Raffeld, R. Moen, J. Bacher, K. M. Zsebo, and A. W. Nie nhuis, J. Exp. Med. 176:1124-1135, 1992). The animals with lymphoma ap peared to be tolerant to retroviral antigens in that their sera lacked antibodies reactive with viral proteins and contained 10(4) to 10(5) infectious virus particles per mi. By molecular cloning and DNA sequen cing, we have now demonstrated that the serum from one of the monkeys contained a replication-competent retrovirus that arose by recombinati on between vector and packaging encoding sequences (vector/helper [V/H ] recombinant) in the producer clone used for transduction of bone mar row stem cells. Southern blot analysis demonstrated 14 or 25 copies of this genome per cell where present in two animals. The genome of a se cond replication-competent virus was also recovered by molecular cloni ng; it arose by recombination involving the genome of the V/H recombin ant and endogenous murine retroviral genomes in the producer clone. Tw elve copies of this amphotropic virus/mink cell focus-forming virus ge nome were present in tumor DNA of one animal, but it was not found in tumor DNA of the other two animals with lymphoma. Southern blot analys is of DNA from various tissues demonstrated common insertion site band s in several samples of tumor DNA from one animal, suggesting clonal o rigin of the lymphoma. Our data are most consistent with a pathogenic mechanism in which chronic productive retroviral infection allowed ins ertional mutagenesis of critical growth control genes, leading to cell transformation and clonal tumor evolution.