T-cell lymphotropic retroviruses (HTLV-I, II and III) have an affinity of human T lymphocytes and enter the cells by specific interaction with the T-4 receptor. All three types of HTLVs 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 human 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. We have also utilized the panel of Hut 102 X Chinese hamster hybrids to demonstrate that the novel Class I antigenic determinants expressed on HTLV-I-infected cells do 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. Two families of endogenous retroviral sequences were shown to be widely dispersed in the human genome using genetic analysis. The sequences are the consequence of an ancient evolutionary gene amplification which resulted in greater than 0.1% being homologous to retroviral sequences.
