NEGATIVE REGULATION OF GENE-EXPRESSION FROM THE HTLV TYPE-II LONG TERMINAL REPEAT BY REX - FUNCTIONAL AND STRUCTURAL DISSOCIATION FROM POSITIVE POSTTRANSCRIPTIONAL REGULATION

Regulation of human T cell leukemia virus type II (HTLV-II) gene expre ssion by Rex is mediated by cis-acting elements in the 5' viral long t erminal repeat (LTR). Rex acts posttranscriptionally to enhance cytopl asmic accumulation of incompletely spliced viral mRNAs encoding struct ural proteins. We report a distinct negative regulatory function media ted by Rex affecting expression from the viral 5' LTR, Using both LTR- driven CAT reporters and a full-length HTLV-II proviral construct, we demonstrate that Rex decreases total cellular levels of LTR-containing mRNA in a dose-dependent manner. Negative regulation is an independen t function as demonstrated by structural and functional dissociation f rom Rex positive posttranscriptional regulation. This negative regulat ory action was dependent on nuclear localization sequences, but did no t require the previously defined Rex-responsive element (RxRE). Negati ve regulation was observed in T cell lines but not in B cell lines, su ggesting the involvement of cell type-specific factors distinct from t hose involved in posttranscriptional regulation. An internal deletion mutant of Rex removing aa 38-80 retained the ability to repress, but d id not posttranscriptionally increase expression, while negative regul ation requires a previously uncharacterized carboxy-terminal region (a a 154-170). These findings suggest that Rex may serve two simultaneous functions: to decrease overall levels of transcribed viral mRNA, and to facilitate nuclear to cytoplasmic export of mRNAs encoding structur al proteins. The negative regulatory function of Rex may play a role i n viral latency.