RECOGNITION OF HIV-1 TAR RNA BY TAT PROTEIN AND TAT-DERIVED PEPTIDES

The human immunodeficiency virus (HIV-1) Tat protein stimulates transc riptional elongation by binding the trans-activation response region ( TAR) RNA encoded by all HIV-1 transcripts. RNA residues critical for T ar recognition have been mapped to the region surrounding a three pyri midine bulge in TAR. In vitro binding studies and in vivo trans-activa tion assays have identified two regions of Tat necessary for specific RNA binding. The first region contains an arginine-rich sequence that is the signature of this class of RNA-binding proteins. The second, hi ghly conserved 'core' sequence contains a number of important hydropho bic residues. Although regions N-terminal to these two sequences are r equired for in vivo activity, model peptides comprising the core and a rginine-rich region adequately reproduce the binding specificity of th e full protein. In the presence of peptides comprising these conserved sequences TAR RNA undergoes a conformational change. The rearrangemen t can also be reproduced by peptides limited to the Tar basic region a nd even by a single amino acid arginine at very high concentration. Th e conformations of the free and peptide-bound TAR RNA have been determ ined to very high precision by NMR and are discussed here. The data in dicate that the basic region of Tat interacts with the major groove of TAR RNA without forming a canonical secondary structure. The implicat ions of these results for other lentiviral proteins an discussed, toge ther with implications for the discovery of novel antivirals that inte rfere with the essential function of Tar protein. (C) 1998 Elsevier Sc ience B.V.