BASIC MECHANISMS IN HTLV-INDUCED LEUKEMIA AND AIDS

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The family of retroviruses known as human T-cell lymphotropic retroviruses (HTLV-I, II, and III) has an affinity for infecting T lymphocytes and a similar genomic structure. All 3 types of HTLV have been transmitted in vitro, molecularly cloned and sequenced. Despite these advances, the mechanism by which infection with these viruses results in malignant transformation or immunosuppression remains unknown. We are focusing on basic mechanisms both on a cellular and molecular level by which these viruses transform or immunosuppress. In order to address whether HTLV-I may induce transformation through an insertional mutagenesis mechanism, we have utilized somatic cell hybrids constructed between rodent cells and HTLV-I infected cell lines to study the processes and consequences of HTLV chromosomal integration. Integration in vitro was shown to be a dynamic process and proviral integration apparently occurs at random in the genome. Studies are in progress to determine whether common integration sites are present in fresh tumor material. Since HTLV-I infected cells often lose their dependence for interleukin-2 (IL-2) this gene may play a role in transformation induced by HTLV-I. The gene was first mapped to chromosome 4 and sublocalized to 4q26-28 in normal lymphocytes. We next demonstrated that the IL-2 gene was not rearranged in several HTLV-I infected cell lines and mapped to chromosome 4 in Hut 102, suggesting that this gene is not operative in HTLV-I induced malignant transformation. We have also utilized the panel of Hut 102X Chinese hamster hybrids to demonstrate that the novel Class I antigenic determinants expressed on HTLV-I infected cells does not result from induction of Class I genes encoded by the cellular MHC locus, but are probably encoded by integrated HTLV-I. The activities of the promoter unit contained within the LTR of both HTLV-I and HTLV-III were examined by transfecting various cells with recombinant plasmids containing the LTR of HTLV-I or HTLV-III linked to the bacterial gene for chloramphenicol acetyltransferase (CAT). We have demonstrated that infected cells contain factors that act in trans on the LTRs of the infecting virus to activate transcription.