HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jeang, K.-T. Articles by Rich, E. A. Search for Related Content PubMed PubMed Citation Articles by Jeang, K.-T. Articles by Rich, E. A. Social Bookmarking                      What's this?

J Biol Chem, Vol. 274, Issue 41, 28837-28840, October 8, 1999

MINIREVIEW
Multifaceted Activities of the HIV-1 Transactivator of Transcription, Tat^*

Kuan-Teh Jeang, Hua Xiao, and Elizabeth A. Rich

From the Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892

	INTRODUCTION

TOP INTRODUCTION Domains of the 101-Amino... Role of Tat in... Additional Activities of the... Concluding Remarks REFERENCES

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 (1). Over the past decade, the transcriptional function(s) of Tat (reviewed in detail several years ago (2)) 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 (3-5) and a potentiator of reverse transcription (6). Here we review recent insights into the multifaceted activities of Tat.

View larger version (28K): [in this window] [in a new window]   Fig. 1.   Physical domains of the 101-amino acid HIV-1 Tat protein. Tat can be broadly viewed as containing five physical domains. Overlying the line representation are several examples of cellular factors that have been shown to associate with various regions of Tat. An underlying illustration highlights that the popularly considered full-length Tat protein (86 amino acids) based on the open reading frames from laboratory-passaged viruses (LAI, HXB2, and NL4-3) is likely missing for the carboxyl-terminal 87-101 amino acid residues, which are conserved in natural isolates of HIV-1s (1) that replicate in vivo. Thus it has been shown that a single nucleotide change in the stop codon of tat from laboratory isolates, LAI, HXB2, and NL4-3, converts these open reading frames to the 101-amino acid sequence (e.g. SF2) found in Tat from natural viral isolates (12). The possibility that the 86-amino acid form of Tat has an artifactually premature termination generated as a consequence of tissue culture passaging is discussed in the text. PKR, protein kinase R; DNA-PK, DNA protein kinase; HAT, histone acetyltransferase.

	Domains of the 101-Amino Acid RNA-binding Tat Protein

TOP INTRODUCTION Domains of the 101-Amino... Role of Tat in... Additional Activities of the... Concluding Remarks REFERENCES

Tat is a transcriptional activator that binds to a short nascent stem-bulge-loop leader RNA, TAR (trans-activation responsive (7-10)), 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" (11) (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 (12). 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 (1) 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 vivo provides 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 (13-19).

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 (11, 12, 20-29). 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, domain 2) 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 (30, 31).

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 (32-35) and is important for nuclear localization of the protein (22, 23) and uptake of Tat by cells (3). For association with TAR, the short basic motif contributes importantly to affinity but dictates insufficiently specificity of binding. Flanking amino acids outside this basic domain influence significantly the specificity of Tat-TAR interaction (36, 37). A recent detailed review of Tat-TAR RNA interaction is available elsewhere (38).

	Role of Tat in HIV-1 LTR-directed Transcription

TOP INTRODUCTION Domains of the 101-Amino... Role of Tat in... Additional Activities of the... Concluding Remarks REFERENCES

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) (39) (Fig. 2). Recent experimental findings have added to our understanding of the mechanism(s) through which Tat acts through these elements.

View larger version (28K): [in this window] [in a new window]   Fig. 2.   Schematic models of Tat transactivation. A simplified representation of the HIV-1 promoter containing two (small yellow rectangles) NF-B-binding sites and three (small yellow ovals) Sp1-binding sites. Large ovals represent RNAP II complexes that overlie the TATAA box and transcribe a promoter-proximal stem-bulge-loop TAR RNA. Tat (gray) binds the bulge of TAR, whereas TAK (purple) binds the loop of TAR. In A, loop-bound TAK is shown to phosphorylate RNAP II in its CTD domain converting a non-processive (red) to a processively elongating (green) polymerase. Here, it is suggested that TAK acts on a paused RNAP II molecule which has cleared the promoter. B diagrams an alternate view whereby protein(s) bound to the TAR loop of an early elongating RNAP II affects the activity of a subsequent RNAP II that is yet docked at the promoter, converting a non-productive (red) to a productive (green) complex. In this perspective, an activity of TAR-bound proteins serves to facilitate promoter clearance (46). The activities in A and B need not be mutually exclusive. C illustrates a speculative model in which Tat (gray) either dissociated from TAR RNA or in a free form entered a promoter-upstream locale by direct contact with DNA-bound Sp1 (blue). Through protein-protein interaction with Sp1 (67), it is envisioned that some Tat protein could form an early promoter-DNA-associated preinitiation complex (76, 78). It remains to be determined if upstream promoter-bound Tat could influence RNAP II (re-)initiation events (cluster of green ovals) at the TATAA box.

In considering Tat action, one understands that two operationally defined events occur for each round of transcription at virtually all promoters. These are: (i) recruitment of an RNA polymerase II (RNAP II) complex to the promoter and (ii) the escape of that complex from the promoter into productive elongation. A typicalrole proposed for transcriptional activator proteins is that of facilitating a rate-limiting step in the recruitment of TBP-bound RNAP II to the promoter (40, 41). Although Tat is not a typical activator protein, it does possess the capacity to bind directly several general transcription factors including TFIID (42), TFIIB (43), TFIIH (44), and RNAP II (45). Thus, an attractively simple mechanism of how Tat might accelerate the rate of transcription from the HIV-1 LTR would be if it increased the recruitment of TBP/RNAP II to the viral promoter. This hypothesis was directly examined; and in such a study, it was found that Tat unlikely functions at recruiting TBP/RNAP II to the LTR promoter. Indeed, the rate-limiting event(s) resolved by Tat occurs at a step(s) post-TBP recruitment to the HIV-1 TATAA promoter (46).

What might be the "post-recruitment" step(s) influenced by Tat? Events that ensue after the docking of TBP/RNAP II at the promoter range, among others, from the consummation of a competent initiation complex to the clearance of such a complex from the promoter to the transit of cleared RNAP IIs into productive elongation. Because Tat function requires the presynthesis of at least the first 44 nascent nucleotides of TAR RNA (7), activation cannot occur until the initiated RNAP II has proceeded beyond this position (47). This scenario, which is very much compatible with Tat overcoming a "block" to transcription (44, 48, 49) at a point after nucleotide +44, suggests that Tat might interact with factors that regulate the processivity of RNAP II elongation.

General control of early RNAP II elongation at eukaryotic promoters is dictated by the actions of the negative (N-TEF) and positive (P-TEF) transcription elongation factor (50). A recent breakthrough in understanding Tat function came with the integration of positive transcription elongation factor, P-TEFb, into HIV-1 LTR-directed transcription. This recognition culminated from several preceding observations. First, it was found that a Tat-associated kinase (TAK (51)) could phosphorylate the carboxyl-terminal domain (CTD) of the large subunit of RNAP II. Next, phosphorylation of the RNAP II-CTD was correlated with Tat activation of transcription (52, 53). Subsequently, TAK was elucidated to be the P-TEFb complex of proteins, which included the cyclin-dependent kinase, cdk9 (54-57). In the P-TEFb complex, cdk9 was shown to be bound to one of several forms of cyclin T (T1, T2a, T2b (58, 59)). The cdk9-cyclin T complex (P-TEFb) was found to associate directly with Tat. This association with P-TEFb facilitates a high affinity binding of Tat for TAR RNA (57, 58). P-TEFb can also bind to a previously demonstrated Tat co-factor, Tat-SF1, resulting in its phosphorylation (57). This phosphorylation of Tat-SF1 has been suggested as an additional contributory event to the role of P-TEFb in HIV-1 LTR transcription (57).

Schematically, a simplified view of Tat/P-TEFb/TAR/RNAP II interaction can be represented by the illustration in Fig. 2A. Association of Tat and P-TEFb (TAK) with TAR leads to phosphorylation of the RNAP II-CTD. Phosphorylation of RNAP II-CTD renders otherwise non-processive RNAP IIs into productively elongating molecules (60, 61).

If P-TEFb explains Tat transactivation, then are there roles to be played by other Tat-associated cellular factors (49, 62-68)? In considering this question, one notes that although the requirement for presynthesized TAR RNA is consistent with a Tat effect on RNAP II elongation, it is equally compatible with a mechanism affecting reinitiation of transcription (Fig. 2B). Intracellularly, the ability to achieve continuous and rapid reinitiations, rather than simple initiations, represents the major determinant of the strength (defined by the amount of transcripts produced over time) of a eukaryotic promoter (69). Hence, although extant cell-free transcription studies (70-74) have analyzed well the effect of Tat on the processivity of initiated polymerases, they do not address potential contributions to reinitiations. If Tat does contribute significantly to reinitiations, this could possibly explain the rather large discrepancies in the magnitudes measured for its cell-free elongation effects (reported variously as inductions of 3-fold (75) to 10-fold (54)) versus its intracellular effect on steady state transcription, which has been quantified as several hundred-fold. Indeed, recent biochemical evidence that Tat can exist in a TAR-RNA independent complex at the promoter (76, 77) and findings that this TAR-independent complex may directly contact DNA-bound Sp1 (78, 79) suggest that some Tat moieties might not necessarily be tethered to an elongating RNAP II and migrate away from the promoter (71, 75). In principle, TAR-RNA independent protein-protein contact of Tat with Sp1 (67, 79) implies that some Tat protein could be stably docked at a promoter proximal locale. If so, promoter-associated Tat (Fig. 2C) could influence transcriptional reinitiations in a fashion similar to promoter-bound TBPs/TAFs/TFIIA (80). It remains to be directly tested whether such a mechanistic function could exist for Tat.

HIV-1 has an additional transcriptional complexity that is not found for non-integrating viruses. For large portions of its life cycle, HIV-1, like other retroviruses, exists as chromosomally integrated proviral DNA (81) in infected cells. In its integrated form, the HIV-1 LTR is bound with histone proteins in a nucleosomally organized format. In this regard, access by RNAP II to these histone-packaged LTRs is a step that is not well reflected by the existing cell-free transcription assays for Tat function. Four recent reports, however, have addressed this issue from an intracellular context. Collectively, these reports firmly demonstrate a role for a Tat-associate histone acetyltransferase (TAH) in transcriptional access of RNAP II to integrated proviral LTRs. TAH activity was shown to be redundantly provided by the p300/CBP, PCAF, and/or TAF250 (82-85) proteins.

	Additional Activities of the Tat Protein

TOP INTRODUCTION Domains of the 101-Amino... Role of Tat in... Additional Activities of the... Concluding Remarks REFERENCES

Large viruses, such as those from the herpes family, have genome sizes of 200 or more kilobase pairs. By contrast, the HIV-1 genome is less than one-twentieth in size. For purposes of viral replication, the smaller HIV-1 genome must provide functions similar to those encoded within the genomes of larger viruses. A possible consequence of genome size constraint is that each HIV-1 open reading frame might have been selected to evolve multiple functions. Indeed, based on genetic inferences, Tat was shown to have activities in addition to its transcriptional function for the viral LTR (86). Some of these additional functions have been described from several independent laboratories and include the activation of quiescent T-lymphocytes (19), the induction of cellular apoptosis (87), and the modulation of cellular gene expression such as that for manganese-dependent superoxide dismutase (88). Tat also has functions consistent with an extracellular chemokine (5) and/or growth factor (4). There is evidence that Tat might additionally affect gene expression through post-transcriptional (18) and/or reverse transcription (20) steps. Many of these non-transcriptional activities for Tat have not been studied in sufficient detail; their physiological relevance remains to be verified in future investigations.

	Concluding Remarks

TOP INTRODUCTION Domains of the 101-Amino... Role of Tat in... Additional Activities of the... Concluding Remarks REFERENCES

Studies on Tat over the last decade have yielded important biological and virological insights. Early work established Tat as a lead example of an RNA-binding protein that functions in eukaryotic transcription. Later, in studying the transcriptional activity of Tat, new understandings of general controls of transcriptional elongation and processivity and activation of chromosomally integrated promoters were gained. From the latter arena we have learned how this RNA-binding protein can cooperate with RNAP II CTD kinases and histone acetylases in modulating expression from the LTR promoter. In studies unrelated to transcription, Tat has provided an important paradigm for how highly charged proteins can be specifically taken up into cells (89); and in aspects related to AIDS pathogenesis, there is emerging evidence that HIV-1 virulence (90) and a potentially useful approach for a viral vaccine (91) are impacted by the biological functions of the Tat protein. Indeed, although we have elucidated much of the transcriptional properties of Tat, much more remains to be learned.

	FOOTNOTES

^* This minireview will be reprinted in the 1999 Minireview Compendium, which will be available in December, 1999. 

To whom correspondence should be addressed: Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892. Tel.: 301-496-6680; Fax: 301-480-3686; E-mail: kj7e@nih.gov.

Deceased.

	ABBREVIATIONS

The abbreviations used are: HIV-1, human immunodeficiency virus, type 1; LTR, long terminal repeat; RNAP II, RNA polymerase II; TBP, TATA-binding protein; TAK, Tat-associated kinase; CTD, carboxyl-terminal domain; TAH, Tat-associated histone acetyltransferase; TAF, TBP-associated factor.

	REFERENCES

TOP INTRODUCTION Domains of the 101-Amino... Role of Tat in... Additional Activities of the... Concluding Remarks REFERENCES

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				W. Li, Y. Huang, R. Reid, J. Steiner, T. Malpica-Llanos, T. A. Darden, S. K. Shankar, A. Mahadevan, P. Satishchandra, and A. Nath NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent J. Neurosci., November 19, 2008; 28(47): 12190 - 12198. [Abstract] [Full Text] [PDF]

				O. R. Faridani, G. M. McInerney, K. Gradin, and L. Good Specific ligation to double-stranded RNA for analysis of cellular RNA::RNA interactions Nucleic Acids Res., September 1, 2008; 36(16): e99 - e99. [Abstract] [Full Text] [PDF]

				M. Kuciak, C. Gabus, R. Ivanyi-Nagy, K. Semrad, R. Storchak, O. Chaloin, S. Muller, Y. Mely, and J.-L. Darlix The HIV-1 transcriptional activator Tat has potent nucleic acid chaperoning activities in vitro Nucleic Acids Res., June 1, 2008; 36(10): 3389 - 3400. [Abstract] [Full Text] [PDF]

				I. Montanuy, R. Torremocha, C. Hernandez-Munain, and C. Sune Promoter Influences Transcription Elongation: TATA-BOX ELEMENT MEDIATES THE ASSEMBLY OF PROCESSIVE TRANSCRIPTION COMPLEXES RESPONSIVE TO CYCLIN-DEPENDENT KINASE 9 J. Biol. Chem., March 21, 2008; 283(12): 7368 - 7378. [Abstract] [Full Text] [PDF]

				U. Mahlknecht, I. Dichamp, A. Varin, C. Van Lint, and G. Herbein NF-{kappa}B-dependent control of HIV-1 transcription by the second coding exon of Tat in T cells J. Leukoc. Biol., March 1, 2008; 83(3): 718 - 727. [Abstract] [Full Text] [PDF]

				S. Boireau, P. Maiuri, E. Basyuk, M. de la Mata, A. Knezevich, B. Pradet-Balade, V. Backer, A. Kornblihtt, A. Marcello, and E. Bertrand The transcriptional cycle of HIV-1 in real-time and live cells J. Cell Biol., October 22, 2007; 179(2): 291 - 304. [Abstract] [Full Text] [PDF]

				B. Poon, M. A. Chang, and I. S. Y. Chen Vpr Is Required for Efficient Nef Expression from Unintegrated Human Immunodeficiency Virus Type 1 DNA J. Virol., October 1, 2007; 81(19): 10515 - 10523. [Abstract] [Full Text] [PDF]

				Z. Zhang, A. Klatt, D. S. Gilmour, and A. J. Henderson Negative Elongation Factor NELF Represses Human Immunodeficiency Virus Transcription by Pausing the RNA Polymerase II Complex J. Biol. Chem., June 8, 2007; 282(23): 16981 - 16988. [Abstract] [Full Text] [PDF]

				G. R. Campbell, J. D. Watkins, K. K. Singh, E. P. Loret, and S. A. Spector Human Immunodeficiency Virus Type 1 Subtype C Tat Fails To Induce Intracellular Calcium Flux and Induces Reduced Tumor Necrosis Factor Production from Monocytes J. Virol., June 1, 2007; 81(11): 5919 - 5928. [Abstract] [Full Text] [PDF]

				S. P. O'Hara, A. J. Small, J. B. Nelson, A. D. Badley, X.-M. Chen, G. J. Gores, and N. F. LaRusso The Human Immunodeficiency Virus Type 1 Tat Protein Enhances Cryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism Infect. Immun., February 1, 2007; 75(2): 684 - 696. [Abstract] [Full Text] [PDF]

				K.-T. Jeang and V. Yedavalli Role of RNA helicases in HIV-1 replication Nucleic Acids Res., September 10, 2006; 34(15): 4198 - 4205. [Abstract] [Full Text] [PDF]

				A. M. Hidalgo-Estevez, E. Gonzalez, C. Punzon, and M. Fresno Human immunodeficiency virus type 1 Tat increases cooperation between AP-1 and NFAT transcription factors in T cells J. Gen. Virol., June 1, 2006; 87(6): 1603 - 1612. [Abstract] [Full Text] [PDF]

				S. Shojania and J. D. O'Neil HIV-1 Tat Is a Natively Unfolded Protein: THE SOLUTION CONFORMATION AND DYNAMICS OF REDUCED HIV-1 Tat-(1-72) BY NMR SPECTROSCOPY J. Biol. Chem., March 31, 2006; 281(13): 8347 - 8356. [Abstract] [Full Text] [PDF]

				V. W. Gautier, N. Sheehy, M. Duffy, K. Hashimoto, and W. W. Hall Direct interaction of the human I-mfa domain-containing protein, HIC, with HIV-1 Tat results in cytoplasmic sequestration and control of Tat activity PNAS, November 8, 2005; 102(45): 16362 - 16367. [Abstract] [Full Text] [PDF]

				D. Mondal, C. A. Williams, M. Ali, M. Eilers, and K. C. Agrawal The HIV-1 Tat Protein Selectively Enhances CXCR4 and Inhibits CCR5 Expression in Megakaryocytic K562 Cells Experimental Biology and Medicine, October 1, 2005; 230(9): 631 - 644. [Abstract] [Full Text] [PDF]

				S. Amini, G. Mameli, L. Del Valle, A. Skowronska, K. Reiss, B. B. Gelman, M. K. White, K. Khalili, and B. E. Sawaya p73 Interacts with Human Immunodeficiency Virus Type 1 Tat in Astrocytic Cells and Prevents Its Acetylation on Lysine 28 Mol. Cell. Biol., September 15, 2005; 25(18): 8126 - 8138. [Abstract] [Full Text] [PDF]

				Y. Desfosses, M. Solis, Q. Sun, N. Grandvaux, C. Van Lint, A. Burny, A. Gatignol, M. A. Wainberg, R. Lin, and J. Hiscott Regulation of Human Immunodeficiency Virus Type 1 Gene Expression by Clade-Specific Tat Proteins J. Virol., July 15, 2005; 79(14): 9180 - 9191. [Abstract] [Full Text] [PDF]

				Y.-S. Kim, J.-M. Kim, D.-L. Jung, J.-E. Kang, S. Lee, J. S. Kim, W. Seol, H.-C. Shin, H. S. Kwon, C. Van Lint, et al. Artificial Zinc Finger Fusions Targeting Sp1-binding Sites and the trans-Activator-responsive Element Potently Repress Transcription and Replication of HIV-1 J. Biol. Chem., June 3, 2005; 280(22): 21545 - 21552. [Abstract] [Full Text] [PDF]

				P. P. Kumar, P. K. Purbey, D. S. Ravi, D. Mitra, and S. Galande Displacement of SATB1-Bound Histone Deacetylase 1 Corepressor by the Human Immunodeficiency Virus Type 1 Transactivator Induces Expression of Interleukin-2 and Its Receptor in T Cells Mol. Cell. Biol., March 1, 2005; 25(5): 1620 - 1633. [Abstract] [Full Text] [PDF]

				G. R. Campbell, E. Pasquier, J. Watkins, V. Bourgarel-Rey, V. Peyrot, D. Esquieu, P. Barbier, J. de Mareuil, D. Braguer, P. Kaleebu, et al. The Glutamine-rich Region of the HIV-1 Tat Protein Is Involved in T-cell Apoptosis J. Biol. Chem., November 12, 2004; 279(46): 48197 - 48204. [Abstract] [Full Text] [PDF]

				J.-M. Peloponese Jr., H. Iha, V. R. K. Yedavalli, A. Miyazato, Y. Li, K. Haller, M. Benkirane, and K.-T. Jeang Ubiquitination of Human T-Cell Leukemia Virus Type 1 Tax Modulates Its Activity J. Virol., November 1, 2004; 78(21): 11686 - 11695. [Abstract] [Full Text] [PDF]

				F. Rayne, A. Vendeville, A. Bonhoure, and B. Beaumelle The Ability of Chloroquine To Prevent Tat-Induced Cytokine Secretion by Monocytes Is Implicated in Its In Vivo Anti-Human Immunodeficiency Virus Type 1 Activity J. Virol., November 1, 2004; 78(21): 12054 - 12057. [Abstract] [Full Text] [PDF]

				L. Ramakrishna, K. K. Anand, K. M. Mohankumar, and U. Ranga Codon Optimization of the Tat Antigen of Human Immunodeficiency Virus Type 1 Generates Strong Immune Responses in Mice following Genetic Immunization J. Virol., September 1, 2004; 78(17): 9174 - 9189. [Abstract] [Full Text] [PDF]

				T. de Oliveira, M. Salemi, M. Gordon, A.-M. Vandamme, E. J. van Rensburg, S. Engelbrecht, H. M. Coovadia, and S. Cassol Mapping Sites of Positive Selection and Amino Acid Diversification in the HIV Genome: An Alternative Approach to Vaccine Design? Genetics, July 1, 2004; 167(3): 1047 - 1058. [Abstract] [Full Text] [PDF]

				O. Kutsch, D. N. Levy, P. J. Bates, J. Decker, B. R. Kosloff, G. M. Shaw, W. Priebe, and E. N. Benveniste Bis-Anthracycline Antibiotics Inhibit Human Immunodeficiency Virus Type 1 Transcription Antimicrob. Agents Chemother., May 1, 2004; 48(5): 1652 - 1663. [Abstract] [Full Text] [PDF]

				A. T. Das, X. Zhou, M. Vink, B. Klaver, K. Verhoef, G. Marzio, and B. Berkhout Viral Evolution as a Tool to Improve the Tetracycline-regulated Gene Expression System J. Biol. Chem., April 30, 2004; 279(18): 18776 - 18782. [Abstract] [Full Text] [PDF]

				D. J. Segal, J. Goncalves, S. Eberhardy, C. H. Swan, B. E. Torbett, X. Li, and C. F. Barbas III Attenuation of HIV-1 Replication in Primary Human Cells with a Designed Zinc Finger Transcription Factor J. Biol. Chem., April 9, 2004; 279(15): 14509 - 14519. [Abstract] [Full Text] [PDF]

				A. Roisin, J.-P. Robin, N. Dereuddre-Bosquet, A.-L. Vitte, D. Dormont, P. Clayette, and P. Jalinot Inhibition of HIV-1 Replication by Cell-penetrating Peptides Binding Rev J. Biol. Chem., March 5, 2004; 279(10): 9208 - 9214. [Abstract] [Full Text] [PDF]

				Y.-L. Chiu, H. Cao, J.-M. Jacque, M. Stevenson, and T. M. Rana Inhibition of Human Immunodeficiency Virus Type 1 Replication by RNA Interference Directed against Human Transcription Elongation Factor P-TEFb (CDK9/CyclinT1) J. Virol., March 1, 2004; 78(5): 2517 - 2529. [Abstract] [Full Text] [PDF]

				U. Ranga, R. Shankarappa, N. B. Siddappa, L. Ramakrishna, R. Nagendran, M. Mahalingam, A. Mahadevan, N. Jayasuryan, P. Satishchandra, S. K. Shankar, et al. Tat Protein of Human Immunodeficiency Virus Type 1 Subtype C Strains Is a Defective Chemokine J. Virol., March 1, 2004; 78(5): 2586 - 2590. [Abstract] [Full Text] [PDF]

				D. H. Dandekar, K. N. Ganesh, and D. Mitra HIV-1 Tat directly binds to NF{kappa}B enhancer sequence: role in viral and cellular gene expression Nucleic Acids Res., February 23, 2004; 32(4): 1270 - 1278. [Abstract] [Full Text] [PDF]

				R. Chen, Z. Yang, and Q. Zhou Phosphorylated Positive Transcription Elongation Factor b (P-TEFb) Is Tagged for Inhibition through Association with 7SK snRNA J. Biol. Chem., February 6, 2004; 279(6): 4153 - 4160. [Abstract] [Full Text] [PDF]

				I. Quinto, A. Puca, J. Greenhouse, P. Silvera, J. Yalley-Ogunro, M. G. Lewis, C. Palmieri, F. Trimboli, R. Byrum, J. Adelsberger, et al. High Attenuation and Immunogenicity of a Simian Immunodeficiency Virus Expressing a Proteolysis-resistant Inhibitor of NF-{kappa}B J. Biol. Chem., January 16, 2004; 279(3): 1720 - 1728. [Abstract] [Full Text] [PDF]

				S. M. Smith, S. Pentlicky, Z. Klase, M. Singh, C. Neuveut, C.-y. Lu, M. S. Reitz Jr., R. Yarchoan, P. A. Marx, and K.-T. Jeang An in Vivo Replication-important Function in the Second Coding Exon of Tat Is Constrained against Mutation despite Cytotoxic T Lymphocyte Selection J. Biol. Chem., November 7, 2003; 278(45): 44816 - 44825. [Abstract] [Full Text] [PDF]

				O. Rohr, C. Marban, D. Aunis, and E. Schaeffer Regulation of HIV-1 gene transcription: from lymphocytes to microglial cells J. Leukoc. Biol., November 1, 2003; 74(5): 736 - 749. [Abstract] [Full Text] [PDF]

				I. A. Ignatovich, E. B. Dizhe, A. V. Pavlotskaya, B. N. Akifiev, S. V. Burov, S. V. Orlov, and A. P. Perevozchikov Complexes of Plasmid DNA with Basic Domain 47-57 of the HIV-1 Tat Protein Are Transferred to Mammalian Cells by Endocytosis-mediated Pathways J. Biol. Chem., October 24, 2003; 278(43): 42625 - 42636. [Abstract] [Full Text] [PDF]

				S. Hwang, N. Tamilarasu, K. Kibler, H. Cao, A. Ali, Y.-H. Ping, K.-T. Jeang, and T. M. Rana Discovery of a Small Molecule Tat-trans-Activation-responsive RNA Antagonist That Potently Inhibits Human Immunodeficiency Virus-1 Replication J. Biol. Chem., October 3, 2003; 278(40): 39092 - 39103. [Abstract] [Full Text] [PDF]

				A. Fittipaldi, A. Ferrari, M. Zoppe, C. Arcangeli, V. Pellegrini, F. Beltram, and M. Giacca Cell Membrane Lipid Rafts Mediate Caveolar Endocytosis of HIV-1 Tat Fusion Proteins J. Biol. Chem., September 5, 2003; 278(36): 34141 - 34149. [Abstract] [Full Text] [PDF]

				O. Rohr, D. Lecestre, S. Chasserot-Golaz, C. Marban, D. Avram, D. Aunis, M. Leid, and E. Schaeffer Recruitment of Tat to Heterochromatin Protein HP1 via Interaction with CTIP2 Inhibits Human Immunodeficiency Virus Type 1 Replication in Microglial Cells J. Virol., May 1, 2003; 77(9): 5415 - 5427. [Abstract] [Full Text] [PDF]

				C. Rudolph, C. Plank, J. Lausier, U. Schillinger, R. H. Muller, and J. Rosenecker Oligomers of the Arginine-rich Motif of the HIV-1 TAT Protein Are Capable of Transferring Plasmid DNA into Cells J. Biol. Chem., March 21, 2003; 278(13): 11411 - 11418. [Abstract] [Full Text] [PDF]

				I. Tikhonov, T. J. Ruckwardt, G. S. Hatfield, and C. D. Pauza Tat-Neutralizing Antibodies in Vaccinated Macaques J. Virol., March 1, 2003; 77(5): 3157 - 3166. [Abstract] [Full Text] [PDF]

				R. M. Surabhi and R. B. Gaynor RNA Interference Directed against Viral and Cellular Targets Inhibits Human Immunodeficiency Virus Type 1 Replication J. Virol., November 13, 2002; 76(24): 12963 - 12973. [Abstract] [Full Text] [PDF]

				A. Michienzi, S. Li, J. A. Zaia, and J. J. Rossi A nucleolar TAR decoy inhibitor of HIV-1 replication PNAS, October 29, 2002; 99(22): 14047 - 14052. [Abstract] [Full Text] [PDF]

				S. Opi, J.-M. Peloponese Jr., D. Esquieu, G. Campbell, J. de Mareuil, A. Walburger, M. Solomiac, C. Gregoire, E. Bouveret, D. L. Yirrell, et al. Tat HIV-1 Primary and Tertiary Structures Critical to Immune Response Against Non-homologous Variants J. Biol. Chem., September 20, 2002; 277(39): 35915 - 35919. [Abstract] [Full Text] [PDF]

				C. Ambrosino, C. Palmieri, A. Puca, F. Trimboli, M. Schiavone, F. Olimpico, M. R. Ruocco, F. di Leva, M. Toriello, I. Quinto, et al. Physical and Functional Interaction of HIV-1 Tat with E2F-4, a Transcriptional Regulator of Mammalian Cell Cycle J. Biol. Chem., August 23, 2002; 277(35): 31448 - 31458. [Abstract] [Full Text] [PDF]

				F. Darfeuille, A. Arzumanov, S. Gryaznov, M. J. Gait, C. Di Primo, and J.-J. Toulme Loop-loop interaction of HIV-1 TAR RNA with N3' right-arrow P5' deoxyphosphoramidate aptamers inhibits in vitro Tat-mediated transcription PNAS, July 23, 2002; 99(15): 9709 - 9714. [Abstract] [Full Text] [PDF]

				P. G. Conaldi, A. Bottelli, A. Baj, C. Serra, L. Fiore, G. Federico, B. Bussolati, and G. Camussi Human Immunodeficiency Virus-1 Tat Induces Hyperproliferation and Dysregulation of Renal Glomerular Epithelial Cells Am. J. Pathol., July 1, 2002; 161(1): 53 - 61. [Abstract] [Full Text] [PDF]

				N. Srinivasakumar, M. Zaboikin, T. Zaboikina, and F. Schuening Evaluation of Tat-Encoding Bicistronic Human Immunodeficiency Virus Type 1 Gene Transfer Vectors in Primary Canine Bone Marrow Mononuclear Cells J. Virol., June 14, 2002; 76(14): 7334 - 7342. [Abstract] [Full Text] [PDF]

				V. Bres, R. Kiernan, S. Emiliani, and M. Benkirane Tat Acetyl-acceptor Lysines Are Important for Human Immunodeficiency Virus Type-1 Replication J. Biol. Chem., June 14, 2002; 277(25): 22215 - 22221. [Abstract] [Full Text] [PDF]

				N. N. Zheng, C. Vella, P. J. Easterbrook, and R. S. Daniels Selection following isolation of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and herpesvirus saimiri-transformed T cells is comparable J. Gen. Virol., June 1, 2002; 83(6): 1343 - 1352. [Abstract] [Full Text] [PDF]

				Y. Yang, B. Dong, P. R. Mittelstadt, H. Xiao, and J. D. Ashwell HIV Tat Binds Egr Proteins and Enhances Egr-dependent Transactivation of the Fas Ligand Promoter J. Biol. Chem., May 24, 2002; 277(22): 19482 - 19487. [Abstract] [Full Text] [PDF]

				A. Cota-Gomez, N. C. Flores, C. Cruz, A. Casullo, T. Y. Aw, H. Ichikawa, J. Schaack, R. Scheinman, and S. C. Flores The Human Immunodeficiency Virus-1 Tat Protein Activates Human Umbilical Vein Endothelial Cell E-selectin Expression via an NF-kappa B-dependent Mechanism J. Biol. Chem., April 19, 2002; 277(17): 14390 - 14399. [Abstract] [Full Text] [PDF]

				M. Kameoka, M. Morgan, M. Binette, R. S. Russell, L. Rong, X. Guo, A. Mouland, L. Kleiman, C. Liang, and M. A. Wainberg The Tat Protein of Human Immunodeficiency Virus Type 1 (HIV-1) Can Promote Placement of tRNA Primer onto Viral RNA and Suppress Later DNA Polymerization in HIV-1 Reverse Transcription J. Virol., March 19, 2002; 76(8): 3637 - 3645. [Abstract] [Full Text] [PDF]

				N. Kaushik, A. Basu, P. Palumbo, R. L. Myers, and V. N. Pandey Anti-TAR Polyamide Nucleotide Analog Conjugated with a Membrane-Permeating Peptide Inhibits Human Immunodeficiency Virus Type 1 Production J. Virol., March 19, 2002; 76(8): 3881 - 3891. [Abstract] [Full Text] [PDF]

				G. Marzio, M. Vink, K. Verhoef, A. de Ronde, and B. Berkhout Efficient Human Immunodeficiency Virus Replication Requires a Fine-Tuned Level of Transcription J. Virol., February 22, 2002; 76(6): 3084 - 3088. [Abstract] [Full Text] [PDF]

				T. Ishizuka, T. Satoh, T. Monden, N. Shibusawa, T. Hashida, M. Yamada, and M. Mori Human Immunodeficiency Virus Type 1 Tat Binding Protein-1 Is a Transcriptional Coactivator Specific for TR Mol. Endocrinol., August 1, 2001; 15(8): 1329 - 1343. [Abstract] [Full Text] [PDF]

				M. Kameoka, L. Rong, M. Götte, C. Liang, R. S. Russell, and M. A. Wainberg Role for Human Immunodeficiency Virus Type 1 Tat Protein in Suppression of Viral Reverse Transcriptase Activity during Late Stages of Viral Replication J. Virol., March 15, 2001; 75(6): 2675 - 2683. [Abstract] [Full Text]

				P. A. Wender, D. J. Mitchell, K. Pattabiraman, E. T. Pelkey, L. Steinman, and J. B. Rothbard The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: Peptoid molecular transporters PNAS, November 21, 2000; 97(24): 13003 - 13008. [Abstract] [Full Text] [PDF]

				H. Xiao, C. Neuveut, H. L. Tiffany, M. Benkirane, E. A. Rich, P. M. Murphy, and K.-T. Jeang Selective CXCR4 antagonism by Tat: Implications for in vivo expansion of coreceptor use by HIV-1 PNAS, October 10, 2000; 97(21): 11466 - 11471. [Abstract] [Full Text] [PDF]

				C. Mischiati, G. Feriotto, M. Borgatti, P. Giacomini, and R. Gambari Characterization of a Major Histocompatibility Complex Class II X-Box-Binding Protein Enhancing Tat-Induced Transcription Directed by the Human Immunodeficiency Virus Type 1 Long Terminal Repeat J. Virol., October 1, 2000; 74(19): 8989 - 9001. [Abstract] [Full Text]

				Y. W. Fong and Q. Zhou Relief of Two Built-In Autoinhibitory Mechanisms in P-TEFb Is Required for Assembly of a Multicomponent Transcription Elongation Complex at the Human Immunodeficiency Virus Type 1 Promoter Mol. Cell. Biol., August 15, 2000; 20(16): 5897 - 5907. [Abstract] [Full Text]

				N. Srinivasakumar and F. Schuening Novel Tat-Encoding Bicistronic Human Immunodeficiency Virus Type 1-Based Gene Transfer Vectors for High-Level Transgene Expression J. Virol., July 15, 2000; 74(14): 6659 - 6668. [Abstract] [Full Text]

				D. Harrich, C. W. Hooker, and E. Parry The Human Immunodeficiency Virus Type 1 TAR RNA Upper Stem-Loop Plays Distinct Roles in Reverse Transcription and RNA Packaging J. Virol., June 15, 2000; 74(12): 5639 - 5646. [Abstract] [Full Text]

				S. K. Manna and B. B. Aggarwal Differential Requirement for p56lck in HIV-tat Versus TNF-Induced Cellular Responses: Effects on NF-{kappa}B, Activator Protein-1, c-Jun N-Terminal Kinase, and Apoptosis J. Immunol., May 15, 2000; 164(10): 5156 - 5166. [Abstract] [Full Text] [PDF]

				X. Li, M.-C. Multon, Y. Henin, F. Schweighoffer, C. Venot, J. Josef, C. Zhou, J. LaVecchio, P. Stuckert, M. Raab, et al. Grb3-3 Is Up-regulated in HIV-1-infected T-cells and Can Potentiate Cell Activation through NFATc J. Biol. Chem., September 29, 2000; 275(40): 30925 - 30933. [Abstract] [Full Text] [PDF]

				Y.-H. Ping and T. M. Rana DSIF and NELF Interact with RNA Polymerase II Elongation Complex and HIV-1 Tat Stimulates P-TEFb-mediated Phosphorylation of RNA Polymerase II and DSIF during Transcription Elongation J. Biol. Chem., April 13, 2001; 276(16): 12951 - 12958. [Abstract] [Full Text] [PDF]

				R. Fujii, M. Okamoto, S. Aratani, T. Oishi, T. Ohshima, K. Taira, M. Baba, A. Fukamizu, and T. Nakajima A Role of RNA Helicase A in cis-Acting Transactivation Response Element-mediated Transcriptional Regulation of Human Immunodeficiency Virus Type 1 J. Biol. Chem., February 16, 2001; 276(8): 5445 - 5451. [Abstract] [Full Text] [PDF]

				L.-M. Huang, M.-F. Chao, M.-Y. Chen, H.-m. Shih, Y.-P. Chiang, C.-Y. Chuang, and C.-Y. Lee Reciprocal Regulatory Interaction between Human Herpesvirus 8 and Human Immunodeficiency Virus Type 1 J. Biol. Chem., April 13, 2001; 276(16): 13427 - 13432. [Abstract] [Full Text] [PDF]

				S. M. Smith, M. Khoroshev, P. A. Marx, J. Orenstein, and K.-T. Jeang Constitutively Dead, Conditionally Live HIV-1 Genomes. EX VIVO IMPLICATIONS FOR A LIVE VIRUS VACCINE J. Biol. Chem., August 17, 2001; 276(34): 32184 - 32190. [Abstract] [Full Text] [PDF]

				M. Gomez-Gonzalo, M. Carretero, J. Rullas, E. Lara-Pezzi, J. Aramburu, B. Berkhout, J. Alcami, and M. Lopez-Cabrera The Hepatitis B Virus X Protein Induces HIV-1 Replication and Transcription in Synergy with T-cell Activation Signals. FUNCTIONAL ROLES OF NF-kappa B/NF-AT AND SP1-BINDING SITES IN THE HIV-1 LONG TERMINAL REPEAT PROMOTER J. Biol. Chem., September 14, 2001; 276(38): 35435 - 35443. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jeang, K.-T. Articles by Rich, E. A. Search for Related Content PubMed PubMed Citation Articles by Jeang, K.-T. Articles by Rich, E. A. Social Bookmarking                      What's this?