Year: 1999
Type: review
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 Scholar, 15Jeang K.-T. Berkhout B. Dropulic B. J. Biol. Chem. 1993; 268: 24940-24949Abstract Full Text PDF PubMed Google Scholar, 16Howcroft T.K. Strebel K. Martin M.A. Singer D.S. Science. 1993; 260: 1320-1323Crossref PubMed Scopus (200) Google Scholar, 17Verhoef K. Bauer M. Meyerhans A. Berkhout B. AIDS Res. Hum. Retroviruses. 1998; 14: 1553-1559Crossref PubMed Scopus (40) Google Scholar, 18Xiao H. Neuveut C. Benkirane M. Jeang K.T. Biochem. Biophys. Res. Commun. 1998; 244: 384-389Crossref PubMed Scopus (43) Google Scholar, 19Ott M. Emiliani S. Van Lint C. Herbein G. Lovett J. Chirmule N. McCloskey T. Pahwa S. Verdin E. Science. 1997; 275: 1481-1485Crossref PubMed Scopus (187) Google Scholar). Over the past decade, a detailed structure-function analysis of Tat has emerged, in part through the generation of an extensive collection of point mutants (Table I) produced from 11 laboratories (11Kuppuswamy M. Subramanian T. Srinivasan A. Chinnadurai G. Nucleic Acids Res. 1989; 17: 3551-3561Crossref PubMed Scopus (208) Google Scholar, 12Neuveut C. Jeang K.T. J. Virol. 1996; 70: 5572-5581Crossref PubMed Google Scholar, 20Garcia J.A. Harrich D. Pearson L. Misuyasu R. Gaynor R. EMBO J. 1988; 7: 3143-3147Crossref PubMed Scopus (139) Google Scholar, 21Sadaie M.R. Rappaport J. Benter T. Josephs S.F. Willis R. Wong-Staal F. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 9224-9228Crossref PubMed Scopus (62) Google Scholar, 22Ruben S. Perkins A. Purcell R. Joung K. Sia R. Burghoff R. Haseltine W.A. Rosen C.A. J. Virol. 1989; 63: 1-8Crossref PubMed Google Scholar, 23Hauber J. Malim M.H. Cullen B.R. J. Virol. 1989; 63: 1181-1187Crossref PubMed Google Scholar, 24Meyerhans A. Cheynier R. Albert J. Seth M. Kwok S. Sninsky J. Morfeldt-Manson L. Asjo B. Wain-Hobson S. Cell. 1989; 58: 901-910Abstract Full Text PDF PubMed Scopus (512) Google Scholar, 25Rice A.P. Carlotti F. J. Virol. 1990; 64: 1864-1868Crossref PubMed Google Scholar, 26Rice A.P. Carlotti F. J. Virol. 1990; 64: 6018-6026Crossref PubMed Google Scholar, 27Siderovski D.P. Matsuyama T. Frigerio E. Chui S. Min X. Erfle H. Sumner-Smith M. Barnett R.W. Mak T.W. Nucleic Acids Res. 1992; 20: 5311-5320Crossref PubMed Scopus (12) Google Scholar, 28Verhoef K. Berkhout B. J. Virol. 1999; 73: 2781-2789Crossref PubMed Google Scholar, 29Ulich C. Dunne A. Parry E. Hooker C.W. Gaynor R.B. Harrich D. J. Virol. 1999; 73: 2499-2508Crossref PubMed Google Scholar). From these mutants, one notes that single residue changes in domain 1 of Tat (amino acids 1–20) are well tolerated. By contrast, changes in six of the seven highly conserved cysteines in amino acids 21–40 (Fig. 1, domain2) abolish function (see Table I). Domain 3 (amino acids 41–48) contains a common RKGLGI motif found in HIV-1, HIV-2, and SIV Tat. Amino acids 1–48 together circumscribe a minimal activation domain for HIV-1 Tat (30Carroll R. Martarano L. Derse D. J. Virol. 1991; 65: 3460-3467Crossref PubMed Google Scholar, 31Derse D. Carvalho M. Carroll R. Peterlin B.M. J. Virol. 1991; 65: 7012-7015Crossref PubMed Google Scholar).Table IPoint mutations in TatAmino acid changesAmino acid changesFromaLetter(s) indicates original amino acid(s). Number indicates position of amino acid in Tat.TobLetter(s) indicates the resulting amino acid(s).Activitiesc++, >50% wild type; +, >10% wild type activity; +/− or −, ∼10% or <10% wild type activity.FromaLetter(s) indicates original amino acid(s). Number indicates position of amino acid in Tat.TobLetter(s) indicates the resulting amino acid(s).Activitiesc++, >50% wild type; +, >10% wild type activity; +/− or −, ∼10% or <10% wild type activity.Q2A++F32A+E2D5E9GGG(−)dMeasurement of contribution by Tat to reverse transcription (29).H33A−P3A++C34G−P3Q++C34S−P3L(+/−)dMeasurement of contribution by Tat to reverse transcription (29).G35A+V4A++C37G−D5A+C37S−D5N−eMeasurement is based not upon trans-activation of a reporter plasmid but on delayed replication of an HIV-1 molecular clone in T-cell lines (12, 28).F38A−P6A++F38L++P6S++F38R40LK−eMeasurement is based not upon trans-activation of a reporter plasmid but on delayed replication of an HIV-1 molecular clone in T-cell lines (12, 28).Δ3–6+K40D−P6P10LL++ (−)dMeasurement of contribution by Tat to reverse transcription (29).K40T++R7A++K41A−(+)dMeasurement of contribution by Tat to reverse transcription (29).L8A++K41fDifferent results reported for the same mutation from Refs.11 and 24.T−E9A++K41fDifferent results reported for the same mutation from Refs.11 and 24.T++P10A++L43F+P10P14LL++ (+/−)dMeasurement of contribution by Tat to reverse transcription (29).L43F−eMeasurement is based not upon trans-activation of a reporter plasmid but on delayed replication of an HIV-1 molecular clone in T-cell lines (12, 28).W11A++G44S++K12A++G44D−eMeasurement is based not upon trans-activation of a reporter plasmid but on delayed replication of an HIV-1 molecular clone in T-cell lines (12, 28).K12N++S46A++P18A++S46P−K19R++Y47H++A21D++Y47A++A21T23VA+G48S++T23A++G48R49gAmino acids beyond position 59 completely changed.SG++C22S−R49T++C22G−K50Stop−N23T++K50K51YY+N24A++K50K51SG+/(+/−)N24K++K50E++C25R−K50T++C25G−R52E++Y26A+R53I++Y26F++Q54N++C27S− (+)dMeasurement of contribution by Tat to reverse transcription (29).R55N+C27G−R55R56LT+K28K29AA+R56E++K28K29EA−R57Q63SE++C30G−L69I++C31S++Q72Stop+/−eMeasurement is based not upon trans-activation of a reporter plasmid but on delayed replication of an HIV-1 molecular clone in T-cell lines (12, 28).C31E−P81fshFrameshift of amino acids beyond position 81.+/−eMeasurement is based not upon trans-activation of a reporter plasmid but on delayed replication of an HIV-1 molecular clone in T-cell lines (12, 28).C31G++K90R+/−eMeasurement is based not upon trans-activation of a reporter plasmid but on delayed replication of an HIV-1 molecular clone in T-cell lines (12, 28).a Letter(s) indicates original amino acid(s). Number indicates position of amino acid in Tat.b Letter(s) indicates the resulting amino acid(s).c ++, >50% wild type; +, >10% wild type activity; +/− or −, ∼10% or <10% wild type activity.d Measurement of contribution by Tat to reverse transcription (29Ulich C. Dunne A. Parry E. Hooker C.W. Gaynor R.B. Harrich D. J. Virol. 1999; 73: 2499-2508Crossref PubMed Google Scholar).e Measurement is based not upon trans-activation of a reporter plasmid but on delayed replication of an HIV-1 molecular clone in T-cell lines (12Neuveut C. Jeang K.T. J. Virol. 1996; 70: 5572-5581Crossref PubMed Google Scholar, 28Verhoef K. Berkhout B. J. Virol. 1999; 73: 2781-2789Crossref PubMed Google Scholar).f Different results reported for the same mutation from Refs.11Kuppuswamy M. Subramanian T. Srinivasan A. Chinnadurai G. Nucleic Acids Res. 1989; 17: 3551-3561Crossref PubMed Scopus (208) Google Scholar and 24Meyerhans A. Cheynier R. Albert J. Seth M. Kwok S. Sninsky J. Morfeldt-Manson L. Asjo B. Wain-Hobson S. Cell. 1989; 58: 901-910Abstract Full Text PDF PubMed Scopus (512) Google Scholar.g Amino acids beyond position 59 completely changed.h Frameshift of amino acids beyond position 81. Open table in a new tab Perhaps the best studied region of Tat resides in amino acids 49–72 (domain 4), which contain a basic RKKRRQRRR motif. This peptide motif confers TAR RNA binding properties to Tat (32Dingwall C. Ernberg I. Gait M.J. Green S.M. Heaphy S. Karn J. Lowe A.D. Singh M. Skinner M.A. Vallerio R. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 6925-6929Crossref PubMed Scopus (402) Google Scholar, 33Roy S. Delling U. Chen C.-H. Rosen C.A. Sonenberg N. Genes Dev. 1990; 4: 1365-1373Crossref PubMed Scopus (326) Google Scholar, 34Weeks K.M. Crothers D.M. Cell. 1991; 66: 577-588Abstract Full Text PDF PubMed Scopus (302) Google Scholar, 35Chang Y.N. Jeang K.T. 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Virol. 1993; 67: 3441-3445Crossref PubMed Google Scholar). A recent detailed review of Tat-TAR RNA interaction is available elsewhere (38Rana T.M. Jeang K.-T. Arch. Biochem. Biophys. 1999; 365: 175-185Crossref PubMed Scopus (162) Google Scholar). Transcription from the HIV-1 LTR is several hundred-fold higher in the presence of Tat than in its absence. Thus, Tat must resolve a rate-limiting step at this promoter. Optimal Tat action requires, in addition to TAR RNA, basal (TATA and initiator sequence) and upstream promoter elements (i.e. Sp1) (39Berkhout B. Jeang K.T. J. Virol. 1992; 66: 139-149Crossref PubMed Google Scholar) (Fig.2). Recent experimental findings have added to our understanding of the mechanism(s) through which Tat acts through these elements. In considering Tat action, one understands that two operationally defined events occur for each round of transcription at virtually all promoters. 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Source: Journal of Biological Chemistry
Authors: Kuan-Teh Jeang, Hua Xiao, Elizabeth A. Rich
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1971592398