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J Biol Chem, Vol. 274, Issue 41, 28837-28840, October 8, 1999
From the Laboratory of Molecular Microbiology, NIAID, National
Institutes of Health, Bethesda, Maryland 20892
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.
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).
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.
MINIREVIEW
Multifaceted Activities of the HIV-1 Transactivator of
Transcription, Tat*
,
![]()
INTRODUCTION
TOP
INTRODUCTION
Domains of the 101-Amino...
Role of Tat in...
Additional Activities of the...
Concluding Remarks
REFERENCES

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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
Point mutations in Tat
![]()
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

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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.
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Additional Activities of the Tat Protein |
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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.
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Concluding Remarks |
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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.
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FOOTNOTES |
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* 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.
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ABBREVIATIONS |
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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.
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