HUMAN T-CELL LEUKEMIA-VIRUS TYPE-2 REX INHIBITS PRE-MESSENGER-RNA SPLICING IN-VITRO AT AN EARLY-STAGE OF SPLICEOSOME FORMATION

The Rex protein is an essential regulator of RNA expression in human T -cell leukemia virus types 1 and 2 (HTLV-1 and HTLV-2) that promotes t he accumulation of full-length and partially spliced viral transcripts in the cytoplasm. Rex-mediated regulation correlates with specific bi nding to a cognate RNA recognition element which overlaps the 5' splic e site in the viral long terminal repeat. It has been unclear whether Rex directly affects splicing or only nuclear-to-cytoplasmic transport of viral mRNA We demonstrate that HTLV-2 Rex is a potent inhibitor of splicing in vitro at an early step in spliceosome assembly. Inhibitio n requires phosphorylation of Rex and the ability of Rex to bind to th e Rex response element. Direct inhibition of early spliceosome assembl y by Rex may account for differential accumulation of unspliced transc ripts and represents a novel mechanism of retroviral gene regulation.