Recognition of HIV-1 TAR RNA by Tat protein and Tat-derived peptides

The human immunodeficiency virus (HIV-1) Tat protein stimulates transcriptional elongation by binding the trans-activation response region (TAR) RNA encoded by all HIV-1 transcripts. RNA residues critical for Tar recognition have been mapped to the region surrounding a three pyrimidine bulge in TAR. In vitro binding studies and in vivo trans-activation 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, highly conserved 'core' sequence contains a number of important hydrophobic residues. Although regions N-terminal to these two sequences are required for in vivo activity, model peptides comprising the core and arginine-rich region adequately reproduce the binding specificity of the full protein. In the presence of peptides comprising these conserved sequences TAR RNA undergoes a conformational change. The rearrangement can also be reproduced by peptides limited to the Tar basic region and even by a single amino acid arginine at very high concentration. The conformations of the free and peptide-bound TAR RNA have been determined to very high precision by NMR and are discussed here. The data indicate that the basic region of Tat interacts with the major groove of TAR RNA without forming a canonical secondary structure. The implications of these results for other lentiviral proteins an discussed, together with implications for the discovery of novel antivirals that interfere with the essential function of Tar protein. (C) 1998 Elsevier Science B.V.