Multifaceted Activities of the HIV-1 Transactivator of Transcription, Tat

Abstract

human immunodeficiency virus, type 1 long terminal repeat RNA polymerase II TATA-binding protein Tat-associated kinase carboxyl-terminal domain Tat-associated histone acetyltransferase TBP-associated factor Human immunodeficiency virus, type 1 (HIV-1)1 is the etiological agent for the acquired immunodeficiency syndrome (AIDS). HIV-1 is a retrovirus that encodes a small nuclear transcriptional activator protein, Tat (Fig. 1). In vivo, Tat is required for virus replication and is conserved in the genomes of all primate lentiviruses (1Myers G. Korber B.T. Foley B.T. Jeang K-T. Mellors J.W. Wain-Hobson S. Human Retroviruses and AIDS: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM1996: III-11-III-26Google Scholar). Over the past decade, the transcriptional function(s) of Tat (reviewed in detail several years ago (2Jones K.A. Peterlin B.M. Annu. Rev. Biochem. 1994; 63: 717-743Crossref PubMed Scopus (559) Google Scholar)) has been intensely investigated. It has become clear that a primary role for Tat is in regulating productive and processive transcription from the HIV-1 long terminal repeat (LTR). Tat also has other activities; some are consistent with that of a secreted growth factor (3Chang H.K. Gallo R.C. Ensoli B.J. J. Biomed. Sci. 1995; 2: 189-202Crossref PubMed Scopus (91) Google Scholar, 4Trinh D.P. Brown K.M. Jeang K.T. Biochem. Biophys. Res. Commun. 1999; 256: 299-306Crossref PubMed Scopus (29) Google Scholar, 5Albini A. Ferrini S. Benelli R. Sforzini S. Giunciuglio D. Aluigi M.G. Proudfoot A.E. Alouani S. Wells T.N. Mariani G. Rabin R.L. Farber J.M. Noonan D.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13153-13158Crossref PubMed Scopus (245) Google Scholar) and a potentiator of reverse transcription (6Harrich D. Ulich C. Garcia-Martinez L.F. Gaynor R. EMBO J. 1997; 16: 1224-1235Crossref PubMed Scopus (124) Google Scholar). Here we review recent insights into the multifaceted activities of Tat. Tat is a transcriptional activator that binds to a short nascent stem-bulge-loop leader RNA, TAR (trans-activation responsive (7Berkhout B. Silverman R.H. Jeang K.T. Cell. 1989; 59: 273-282Abstract Full Text PDF PubMed Scopus (513) Google Scholar, 8Dingwall C. Ernberg I. Gait M.J. Green S.M. Heaphy S. Karn J. Lowe A.D. Singh M. Skinner M.A. EMBO J. 1990; 9: 4145-4153Crossref PubMed Scopus (340) Google Scholar, 9Cordingley M.G. La Femina R.L. Callahan P.L. Condra J.H. Sardana V.V. Graham D.J. Nguyen T.M. Le Grow K. Gotlib L. Schlabach A.J. Colonno R.J. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 8985-8989Crossref PubMed Scopus (176) Google Scholar, 10Calnan B.J. Biancalana S. Hudson D. Frankel A.D. Genes Dev. 1991; 5: 201-210Crossref PubMed Scopus (292) Google Scholar)), for its activity. The 101-amino acid Tat protein, with residues 1–72 encoded by a first exon and residues 73–101 encoded by a second exon, can be arbitrarily considered as containing several “domains” (11Kuppuswamy M. Subramanian T. Srinivasan A. Chinnadurai G. Nucleic Acids Res. 1989; 17: 3551-3561Crossref PubMed Scopus (208) Google Scholar) (Fig. 1). Of interest, it should be noted that whereas an 86-amino acid form of Tat, which exists for a few laboratory-passaged virus strains (e.g. LAI, HXB2, pNL4–3) (Fig. 1), has been frequently used; this version represents a truncated and not naturally full-length protein. Indeed, a single nucleotide change in LAI, HXB2, and/or pNL4–3 at putative residue 87 unmasks in these respective genomes the conserved 101 amino acids (Fig. 1) of Tat that are found in most in vivo isolates of virus. This suggests that the premature termination codon that exists in laboratory isolates at position 87 conceivably arose artifactually during tissue culture passaging (12Neuveut C. Jeang K.T. J. Virol. 1996; 70: 5572-5581Crossref PubMed Google Scholar). Thus, that more than 90% of the more than 100 extant independently characterized HIV-1 Tat proteins maintain the 101 (and not the 86) amino acid configuration (1Myers G. Korber B.T. Foley B.T. Jeang K-T. Mellors J.W. Wain-Hobson S. Human Retroviruses and AIDS: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM1996: III-11-III-26Google Scholar) is consistent with this interpretation. Hence, although residues 87–101 of Tat might not contribute greatly to the ex vivo propagation of HIV-1, their conservation in viruses that replicate in vivoprovides a good indication of their biological importance. In this regard, the second coding exon of Tat, which in many studies has been frequently not considered, has been shown to be significant in several biological assays (13Viglianti G. Mullins J.I. J. Virol. 1988; 62: 4523-4532Crossref PubMed Google Scholar, 14Tong-Starksen S. Baur A. Lu X.B. Peck E. Peterlin B.M. Virology. 1993; 195: 826-830Crossref PubMed Scopus (23) Google