Hindawi Publishing Corporation
Molecular Biology International
Volume 2012, Article ID 614120, 11 pages
Mechanismsof HIVTranscriptional Regulationand
Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
Correspondence should be addressed to Andrew J. Henderson, email@example.com
Received 15 February 2012; Accepted 9 April 2012
Academic Editor: Rahm Gummuluru
Copyright © 2012 G. M. Schiralli Lester and A. J. Henderson. This is an open access article distributed under the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Long-lived latent HIV-infected cells lead to the rebound of virus replication following antiretroviral treatment interruption and
present a major barrier to eliminating HIV infection. These latent reservoirs, which include quiescent memory T cells and tissue-
resident macrophages, represent a subset of cells with decreased or inactive proviral transcription. HIV proviral transcription is
regulated at multiple levels including transcription initiation, polymerase recruitment, transcription elongation, and chromatin
organization. How these biochemical processes are coordinated and their potential role in repressing HIV transcription along with
establishing and maintaining latency are reviewed.
A critical step in the HIV life cycle is transcriptional regula-
tion of the integrated provirus. Robust transcription assures
that sufficient mRNA and genomic RNA are produced for
efficient virus assembly and infectivity. Repression of HIV
transcription leads to the establishment of HIV latency,
which creates repositories for infectious and drug-resistant
viruses that reemerge upon treatment failure or interruption
[1–4]. The existence of long-lived stable HIV reservoirs was
demonstrated by the rebound of virus replication following
highly active antiretroviral therapy (HAART) interruption
[5–8]. These latent reservoirs, which include quiescent
memory T cells, tissue-resident macrophages [9, 10], and
potentially hematopoietic stem cells , although this is
still controversial , represent long-lived subsets of cells
with decreased or inactive proviral transcription. In general,
studies with chronically and acutely infected cells show that
mutations in Tat [13, 14], absence of cellular transcription
factors [15–18], miRNA machinery [19, 20], and proviral in-
integration latency [21, 22]. Although there may not be a
common mechanism that promotes HIV latency, it is critical
to understand the molecular events that establish and main-
tain latency if strategies to reduce or purge HIV from latent
reservoirs are to be devised [9, 23, 24]. HIV transcription is
polymerase recruitment, transcriptional elongation, and
chromatin organization. How these events are coordinated
and their role in HIV latency will be reviewed. In particular,
mechanisms that contribute to repressing HIV transcription
will be highlighted.
2.LTR and TranscriptionFactors
Although viral accessory proteins, such as Vpr, and putative
elements within the HIV provirus genome may influence
HIV transcription [25, 26], the dominant HIV transcrip-
tional regulatory element is the 5?long terminal repeat
(LTR). The HIV LTR is often divided into four functional
elements: the Tat activating region (TAR), which in the
context of the nascent RNA forms an RNA stem loop struc-
ture that binds the virus-encoded transactivator Tat; the
promoter, the enhancer, and the negative/modulatory reg-
ulatory element (Figure 1(a)). The promoter, enhancer and
modulatory elements recruit a plethora of tissue specific and
ubiquitously expressed host-transcription factors that func-
tion as activators, repressors, or adapter proteins (see refe-
rences for detailed reviews [27–29]). AP-1, Sp1, and NF-κB
2 Molecular Biology International
p50 p50 p65p65
nuc 0 nuc 1
Figure 1: Regulation of HIV transcription initiation and elongation. (a) HIV LTR organization. This only represents a small subset of cis-
elements and transcription factors, which bind these sites. (b) Cellular transcription factors are recruited to LTR elements and initiation
complex forms at the transcriptional start site. Nucleosomes are posttranslationally modified favoring a condensed chromatin structure that
impedes RNAP II transcriptional elongation. (c) RNAP II processes a short distance downstream from the transcriptional start site when
DSIF and NELF induce a pause in transcription. Pcf11 reinforces this block in elongation by prematurely terminating the transcription of
the short nascent RNA product. HDAC recruitment to the paused complex reinforces a transcriptionally repressed chromatin state. The red
asterisk depicts phosphorylation of RNAP II CTD at serine 5 position. (d) RNAP II elongation complex is released from the transcriptional
pause by the recruitment of P-TEFb, which mediates hyperphosphorylation of the CTD at serine 2 position and phosphorylation of DSIF,
which induces NELF disassociation from the complex (red asterisks indicate key phosphorylation events). The recruitment of chromatin
remodeling machinery such as HATs and PBAF SWI/SNF facilitates acetylation of nucleosomes, which displaces the blocking nucleosome
and supports transcription elongation.
are required for efficient basal and induced HIV transcrip-
tion and replication [27–32]. One major check-point in the
control of HIV transcription is the availability of critical
transcription factors. Several inducible transcription factors
have been identified in T cell and monocytic cell lines that
transactivate the HIV LTR, including AP-1 [30, 33, 34],
C/EBPb [35, 36], NFAT [37–39], Ets/PU.1 [40, 41], and
TCF/LEF-1 [42, 43] to cite a select few. A classic example of
Molecular Biology International3
transcription factor availability regulating function is the
binding of NF-κB to sites within the HIV LTR . Upon
cell activation, the p65 subunit is released from the IκB inhi-
bitory complex, dimerizes with the p50 NF-κB subunit, and
translocates from the cytoplasm to the nucleus, where it
binds the NF-κB sites in HIV LTR to mediate efficient tran-
scription . However, sequestering p65 in the cytoplasm
through its interaction with IκB limits the availability of
active NF-κB in the nucleus and HIV provirus transcription.
Furthermore, this transcriptional repression is reinforced by
p50-p50 homodimers binding theNF-κB sitesand recruiting
histone deacetylase complexes (HDACs), which promote a
repressive chromatin state . In addition, there have been
reports of several cellular transcription factors that repress
transcription in the context of HIV latency. They include but
are not limited to, the ubiquitous factors LSF-1, YY-1 [45,
46]; Sp1 and the bHLH-zipper proto-oncogene c-Myc ;
the central nervous system that interacts with Sp1 [48, 49];
FBI-1, a POZ domain, Kruppel-type zinc finger . Which
specific cellular subsets is a critical question that needs to be
One function of transcription factors is to recruit complexes
that influence chromatin organization. For example, tran-
scriptional activators such as NF-κB, NFAT, and C/EBPβ
recruit histone acetyltransferases (HATs) that modify key
lysines on histone 3 and histone 4 [10, 24, 44, 53–56]. His-
tone acetylation, which is associated with active transcrip-
tion, results in an open or accessible DNA conformation that
activators, initiation factors, and RNA polymerase II (RNAP
II). SWI/SNF complexes and demethylases are recruited to
promoters and enhancers by transcription factors and co-
activators to remodel nucleosomes, especially around the
promoter and transcriptional start sites of genes, resulting in
the induction of transcription. The chromatin organization
of the HIV LTR has been studied in detail (reviewed in [55–
57]). The HIV LTR is flanked by two positioned nucleo-
somes, nuc-0 at the 5?end of the LTR and nuc-1 that
is juxtaposed to the transcriptional start site (Figure 1(b)).
lation, recruitment of HATs [53, 58–60], PBAF containing
61, 63–67]. These posttranscriptional modifications to the
chromatin state are associated with HIV transcription.
Reversing the posttranslational modifications associated
with transcriptional activation is accomplished by recruit-
which catalyze histone trimethylation. These inhibitory
modifications are proposed to contribute to a more conden-
at least two distinctive complexes that have been described,
PBAF which has been associated with transcriptional activa-
and maintenance of HIV latency [62, 64]. Class I and II
HDACs [54, 70], the methyltransferases Suv39H1, Zeste 2,
and heterochromatin protein 1 (hp-1) [71, 72] have been
of nuc-1 and the repression of HIV transcriptional elonga-
tion. Long term repression of transcription can be reinforced
[55, 73]. In summary, posttranslational modifications of
Although epigenetic events, such as restrictive positioned
nucleosomes or DNA methylation, limit HIV transcription
lighted the need to consider additional models to explain
repression of HIV transcription. Initial experiments by the
Bushman laboratory [74–77] in which proviral integration
sites in cells that were latently infected with HIV were sequ-
enced indicated that silenced HIV preferentially integrated
into transcriptionally active host genes. Similar findings were
obtained in infection models with cell lines [77–80] and pri-
mary cells, as well as resting CD4 cells from patients either
untreated or undergoing HAART [79, 81]. These findings
indicate that active neighboring promoters are directly rep-
80, 82]. Transcriptional interference is defined as the sup-
pression of one transcription unit by another neighboring
cis-element . Suggested mechanisms that lead to inter-
ference of the HIV LTR include the adjacent promoters com-
peting for or displacing the components of transcription
initiation complexes, or collisions between transcription
elongation complexes moving in opposite directions [83–
88]. Although there may be a potential role for chromatin-
, other reports from the literature would predict that
there are additional critical repressive checkpoints that con-
tribute to HIV latency [78, 82].
Transcription factors assist with the recruitment of the
general basal factors, which include the RNAP II itself,
TFIID (TATA binding protein or TBP), and the TBP-
associated factors (TAFs), TFIIA, TFIIB, TFIIE, TFIIF, and
TFIIH, to assemble the core promoter complex and assure
proper positioning of the RNAP II at the transcriptional
start site (Figure 1(b)). General transcription factors, such
as TFIIH, have been implicated as playing a critical role
in HIV transcription at times of low Tat expression .
However, recently, the concept of a “core” promoter has
been challenged by the dis-covery of tissue-specific TAFs
and unique preinitiation com-plexes  favoring models
in which the factors found at core promoters and the
4 Molecular Biology International
RNAP II are diverse and dynamic. For example, RNAP II
associated protein, Gdown1, competes with TFIIF for RNAP
II, therefore inhibiting transcription and promoting the
complexity associated with RNAP II recruitment and assem-
bly reflects cell type and cell-cycle-specific requirements for
it has been shown that Tat can influence the recruitment
of TBP and associated TAFs  suggesting that these early
transcriptional complexes are regulated by HIV infection.
Control of transcription elongation is a critical check-
c-fms, hsp-70, Jun B, and HIV [95–99] and is dependent
on the coordination of RNAP II activity, premature tran-
scription termination, and chromatin structure . Fur-
thermore, several genome-wide studies with multiple organ-
isms mapping RNAP II location have shown that 20–30% of
with both detectable or undetectable transcription [101–
104] suggesting that post-RNAP II recruitment and tran-
scriptional elongation represents a key rate-limiting tran-
scriptional checkpoint for gene expression . The inter-
play between the negative elongation factors, negative elon-
gation factor (NELF) and DRB sensitivity-inducing factor
(DSIF), and positive elongation factors, such as P-TEFb
early elongation complex and inhibit RNAP II processivity,
script from the elongation complex . P-TEFb, which is
composed of a regulatory Cyclin T1 (CycT1) subunit and an
enzymatic Cyclin-dependent kinase 9 (Cdk9) subunit, alle-
viates transcriptional repression by phosphorylating one or
more of the components in this complex as well as the
carboxy terminal domain (CTD) of RNAP II at serine 2
leading to the active engagement of RNAP II in transcription
elongation [108–112]. Phosphorylation of DSIF converts
DSIF from a negative to a positive elongation factor ,
whereas phosphorylation of NELF by P-TEFb reduces the
ability of NELF to associate with RNA . Notably, NELF
transcribing the DNA in vivo suggesting that NELF primarily
functions as an inhibitor of elongation  (Figure 1).
P-TEFb is a general transcription factor, which is re-
quired for efficient expression of the majority of cellular
genes, and its availability and activity is carefully regulated
to allow for changes in global transcriptional demand [115–
impact HIV transcription as well as overall cellular gene
expression. One mechanism that limits P-TEFb is its asso-
ciation with the 7SK complex, which includes 7SK RNA,
HEXIM1, HEXIM2, MePCE, and LARP7 [55, 115–117]. Re-
lease of P-TEFb from this complex during T cell activation
chemical profiling has indicated that there are multiple P-
TEFb complexes that include association with other coacti-
vators including Brd4 [118–120], SKIP [121, 122], and com-
ponents of the super elongation complex [116, 123, 124].
Although the significance of these different complexes with
regard to HIV latency is still being explored, it is tempting to
speculate that these additional cofactors could couple tran-
scription elongation with other processes that influence gene
expression including chromatin organization and splic-
ing. P-TEFb activity is also regulated by phosphorylation
and dephosyphorylation in the T-loop domain of Cdk9.
Although the kinase responsible for Cdk9 posttranslational
modification has not been reported, several phosphatases,
PPM1, PP1, PP2A, PP2B have been implicated in regulating
P-TEFb and HIV transcription [125–129]. Finally, P-TEFb
activity is in part regulated by expression of CycT1, which is
T cells .
Recruitment of P-TEFb to the HIV LTR is a critical step
of the viral transcriptional activator Tat. Furthermore, NELF
and DSIF, which are necessary for pausing RNAP II, are both
bound to the HIV LTR after initiation of viral transcription
[110, 113, 131]. The NELF E subunit, which has an RNA
binding domain, has been shown to bind the HIV-TAR
element and inhibit Tat transactivation [113, 132]. Dimin-
ishing the Spt5 subunit of DSIF decreases HIV replication
, whereas decreasing NELF expression releases paused
polymerases on the HIV LTR and induces HIV transcription
elongation in cell line models for transcriptional latency. In
addition, depleting NELF induced histone acetylation and
displacement of the positioned nucleosome, hinting that
transcription elongation and chromatin remodeling maybe
coupled processes .
In the context of HIV, RNAP II processivity and trans-
by the accumulation of short transcripts in the cytoplasm
in HIV-infected cells [96–98, 133]. Under conditions that
inhibit transcription elongation, RNAP II is prone to prema-
ture termination which reenforces the block in RNAP II pro-
cessivity and the accumulation of short transcripts observed
in cells that have repressed HIV provirus. One possibility
for this is that a termination complex is recruited to RNAP
II, which destabilizes the nonprocessive RNAP II complex
similar to 3?end processing of mRNA and transcription
termination. Only two proteins are known that have the
capa-city to dissociate RNAP II from the DNA template:
TTF2, which dissociates the elongation complex in an ATP-
dependent manner during chromosome condensation of the
M-phase of the cell cycle  and Pcf11, which is in-
volved in 3?end processing of mRNA and transcription ter-
mination of protein-encoding genes [135, 136]. Pcf11 has
been demonstrated to dissociate transcriptionally engaged
RNAP II from DNA, indicating a pivotal role in termination
[137–139]. Recent reports show that Pcf11 binds to the HIV
LTR and represses HIV transcription in cell line models for
HIV latency . Pcf11 may be recruited to the LTR by the
paused RNAP II complex. In summary, HIV transcriptional
elongation is limited by multiple mechanisms that include
the availability of P-TEFb, processiveness of the RNAP II
complex, and premature termination (Figure 1(c)).
Molecular Biology International5
The presence of a blocking nucleosome and the role of paus-
ing and premature termination would indicate that tran-
scriptional elongation presents a major checkpoint to HIV
transcription. HIV overcomes this limitation through the
function of the virally encoded transcriptional activator Tat.
Tat potently activates HIV gene expression by facilitating the
recruitment of P-TEFb to the HIV LTR. Tat binds the
RNA stem loop structure formed by the TAR element and
recruits P-TEFb through its interaction with the CycT1
subunit . The Tat-P-TEFb interaction brings active
Cdk9 into the proximity of the paused RNAP II complex.
P-TEFb phosphorylates the CTD domain of RNAP II as
well as NELF and DSIF, inducing RNAP II processivity and
transcriptional elongation. In addition to directly target-
ing the paused RNAP II complex Tat recruits chromatin
remodeling factors such as SWI/SNF complexes Brm and/or
Brg-1 [63, 64, 142] as well as HATs, p300/CBP, P/CAF
and GCN5 that can promote transcriptional activation
through post-translational modification of histones and
the remodeling of the positioned nuc-1 [59, 63]. Thus,
Tat is positioned to play a cri-tical role in coordinating
transcriptional elongation and chromatin remodeling to
assure efficient HIV transcription. The transactivation of
Tat couples HIV transcriptional elon-gation along with
chromatin remodeling [21, 67] (Figure 1(d)).
Tat activity is regulated at multiple levels including tran-
scription and posttranslational modification . Tat tran-
scription is regulated by the HIV LTR and if repressed,
limited Tat will be expressed. Minimal Tat function, either
favors repression of HIV transcription and latency [55,
143]. In addition, stochastic fluctuations in Tat transcription
have been shown to overcome initial repression and induce
efficient transcription elongation . Post-translational
modifications of Tat have been demonstrated to modulate
its interactions with TAR, P-TEFb, and chromatin-remo-
deling complexes to assure the transactivation of Tat even
under limiting conditions . In particular, Tat is subject
to a dynamic sequential methylation/demethylation and
acetylation/deacetylation cycles. Monomethylation of lysine
51 (K51) by Set7/9/KMT7 enhances Tat binding to the TAR,
whereas demethylation by LSD1/KDM1/CoREST and acety-
lation of neighboring lysine 50 (K50) mediated by p300/
KAT3B favor the dissociation of Tat from TAR and P-TEFb
[146–150]. SIRT1, the class III nicotinamide adenine dinuc-
leotide-dependent class III protein, deacetylates Tat and rep-
resses its activity . The methyltransferase, demethylase
HDACs and HATS that control HIV Tat function are at-
tractive therapeutic targets .
Studies using a variety of cell lines [16, 22, 151] and primary
cell systems [37, 152, 153] have provided insights into the
complexity of HIV transcription and the appreciation that
multiple mechanisms contribute to latency . Further-
more, these studies have suggested that therapeutic strategies
targeting transcription may be used to purge HIV from dif-
ferent cellular reservoirs. Attempts to activate repressed pro-
viral transcription present several unique challenges includ-
that target RNAP II, P-TEFb, and chromatin remodeling fac-
tors will likely be toxic, lack specificity, and have a global
lating our general understanding of HIV transcription into
a viable therapeutic approach are highlighted by the recent
clinical trials with HDAC inhibitors. Based on the strong
evidence from cell line models of HIV latency, which showed
that overcoming the repressive effects of chromatin induces
could be a useful tool in purging HIV from latently infected
cells . Initial experiments using the HDAC inhibitor
valproic acid with primary cells from HIV-positive patients
a recent clinical trial have shown that valproic acid had a
minimal impact on the low level of virema in the peripheral
blood of ART patients [159–163]. Although these results
might be viewed as discouraging, next-generation HDAC
inhibitors [164, 165] in combination with other potential
treatments such as methyltransferase inhibitors  as well
as newly identified compounds discovered in recent screens
[89, 153], which target HIV transcription but only partially
activate T cells, may be efficacious. As we screen and develop
new compounds, it will be critical to assure that they are
active in multiple in vitro and in vivo models of latency to
assure that the broad range of potential mechanisms that
influence HIV transcription and latency are targeted .
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