SPECIAL REVIEW
HIV reservoirs: pathogenesis and obstacles
to viral eradication and cure
Tae-Wook Chun and Anthony S. Fauci
Plasma HIV viremia can be suppressed and maintained below the limits of detection for
prolonged periods of time in the vast majority of HIV-infected individuals who receive
antiretroviral therapy (ART). Thus, the clinical outcome for HIV-infected individuals
who have access to these drugs is dramatically improved. However, ART alone cannot
eradicate HIV in infected individuals and this impediment is likely in part due to the
persistence of viral reservoirs in the peripheral blood and lymphoid tissues of infected
individuals despite the suppression of plasma viremia. In recent years, major research
efforts have been dedicated to a better understanding of the pathogenesis of persistent
HIV infection and to the development of therapeutic strategies aimed at eradicating
virus in infected individuals receiving ART. In this review, we discuss the pathophysiology of CD4þ T-cell HIV reservoirs, including recent advances in our understanding
of the mechanisms of persistent viral infection and perspectives for eradication of HIV in
ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
infected individuals.
AIDS 2012, 26:1261–1268
Keywords: antiretorviral therapy, cure, eradication, HIV, viral reservoirs
Introduction
Antiretroviral therapy (ART) dramatically suppresses HIV
replication in the vast majority of infected individuals,
resulting in a substantial decline in morbidity and
mortality in both developed and developing nations
where drugs are available [1–7]. Shortly after the wide
availability of combination ART involving at least three
drugs in 1996 and the demonstration that plasma viremia
could be rapidly and profoundly suppressed to below the
level of detection, optimism grew in the field that HIV
could potentially be eradicated in infected individuals
receiving ART for a few years [8]. However, the prospect
for eradication of HIV diminished considerably in 1997
following the publication of three independent studies in
which the persistence of a small but detectable pool of
latently infected, resting CD4þ T cells carrying replication-competent virus was documented in virtually all
study patients who had received clinically effective ART
for up to 3 years [9–11]. Moreover, a number of studies
demonstrated rapid viral rebound shortly after discontinuation of therapy in infected individuals in whom
profound and sustained suppression of plasma viremia had
been achieved for prolonged periods [12–17]. This
finding casts doubt on the feasibility of eradication of HIV
by ART alone. These sobering observations subsequently
led to the intensified pursuit of new avenues of research
with a focus on the cellular and molecular characterization of the latent HIV reservoir and the development of
strategies designed to eliminate persistently infected
CD4þ T cells in individuals receiving ART.
Following the initial observation over a decade ago that
latently infected, resting CD4þ T cells persist in infected
individuals receiving clinically effective ART [9–11,
18,19], considerable progress has been made regarding
our understanding of the pathogenesis of HIV reservoirs
in the era of successful ART (Fig. 1). However, the
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,
Maryland, USA.
Correspondence to Tae-Wook Chun, PhD, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Building 10, Room 6A32, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Tel: +1 301 496 0890; fax: +1 301 402 5920; e-mail: [email protected]
Received: 7 February 2012; revised: 6 March 2012; accepted: 21 March 2012.
DOI:10.1097/QAD.0b013e328353f3f1
ISSN 0269-9370 Q 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
1261
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1262
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2012, Vol 26 No 10
Presence of latent
viral reservoir in
infected individuals
receiving ART9,10,11
Characterization of
pre-integration
latency (in vitro)26
Identification of
resting CD4+ T
cells carrying
integrated HIV
DNA (ex vivo)20
Description
of HIV
latency in
cell lines23
1986
1987
Role of
transcription
factors in HIV
latency25
1990
1991
1995
Identification of
resting CD4+ T cells
carrying preintegration complex
(ex vivo)27
Quantitation of latent
tissue viral reservoir
and total HIV burden
in infected
individuals28
Development of
single copy
assay72
Establishment of latent
viral reservoir during
acute infection29
Rebound of plasma
viremia despite
treatment with IL-2
and/or anti-CD3
antibody30,85
Stability of
latent viral
reservoir18
1997
1998
Attempt to
purge latent
viral reservoir
and/or antiCD3
antibody83,84,85
1999
2000
2001
2002
Role of latent viral reservoir
in plasma viral rebound
after discontinuation of
ART16,17
Evidence for
decay of latent
viral reservoir in
acute treated
individuals32
Persistent plasma viremia
originating from unknown
viral reservoir74
Inability to
eliminate latent
viral reservoir
using
HDACi88,89,90
Evidence for on-going
HIV replication in
infected individuals
receiving ART57
2003
2004
2005
Case report on
eradication of
HIV95
2006
2007
2008
Attempt to purge
latent viral
reservoir using
HDACi97
Accelerated decay of latent
viral reservoir upon
intensification of ART52
Higher HIV burden in
GALT vs blood of
infected individuals
receiving ART66,67.68.69
Gene therapy
to achieve
eradication of
HIV93,94
Evidence for ongoing viral
replication upon
intensification of
ART80,81
2009
2010
2011
Inability of
intensified
antiretroviral
therapy to lower
residual plasma
viremia76,77,78,79
Homeostatic
proliferation of latent
viral reservoir as a
mechanism of HIV
persistence42
Fig. 1. Timeline. Highlights of research on basic and clinical aspects of HIV reservoirs conducted over the past two decades.
The latent HIV reservoir in resting CD4R
T cells: a major impediment to the
eradication of virus
integrated form of viral DNA in the genome of the host
cells [20]. This study was followed by a comprehensive
analysis of the frequency of resting CD4þ T cells carrying
integrated HIV DNA that were capable of producing
replication-competent virus upon cellular activation in
both the blood and lymphoid tissues of untreated infected
individuals [28]. This study estimated that the total body
burden of the latent viral reservoir was very small (fewer
than 10 million cells per infected person) and suggested at
least two reasons why such infected cells could persist for
extended periods in vivo. First, the latently infected, resting
CD4þ T cells exhibited primarily a memory phenotype
(CD45ROþ), implying that such infected cells could
be long-lived. Second, resting CD4þ T cells carrying
infectious HIV could do so without expressing viral
antigens on their cell surface, thereby enabling them to
escape recognition by the host immune system and to resist
virus-induced cytopathic effects. Indeed, several follow-up
studies demonstrated that the latent viral reservoir carrying
replication-competent HIV persists in virtually all infected
individuals receiving clinically effective ART. This
observation casts serious doubt on the feasibility of
eradicating virus by therapy alone [9–11,18,19].
The presence of latently infected, resting CD4þ T cells
carrying integrated HIV DNA in infected individuals was
first demonstrated in 1995 [20], 2 years prior to the report
of effective ART in the clinical setting [21,22]. However,
the concept of HIV latency had been previously
introduced on the basis of the studies involving the
establishment of HIV-infected cell lines expressing low
levels of virus [23] and the use of various cytokines [24]
and transcription factors [25] to reverse this state of viral
latency. Subsequently, primary resting CD4þ T cells
carrying unintegrated HIV DNA (preintegration latency)
were shown to generate infectious virus upon cellular
activation in vitro [26] and ex vivo [27]. Then, the concept
of postintegration latency was introduced in a report in
which a very small fraction of resting CD4þ T cells in
viremic HIV-infected individuals were shown to carry the
Having established that the latent viral reservoir persists in
infected individuals receiving ART despite profound and
sustained suppression of plasma viremia, a series of studies
was launched in the late 1990s and early 2000s with a goal
of better understanding the pathophysiologic mechanisms involved in the establishment and maintenance
of HIV latency. In particular, in anticipation of the
possibility that early initiation of ART may prevent the
generation of viral latency, studies were undertaken to
determine the approximate length of time required for
establishing a pool of latently infected, resting CD4þ
T cells. It became evident that the latent HIV reservoir
establishes itself very early during the course of infection.
This conclusion was based on the observation that
initiation of ARTas early as 10 days following the onset of
clinical symptoms associated with primary HIV infection
prospects for eradicating HIV in a sizable proportion of
infected individuals receiving ART remain unclear and
will likely remain so until the precise mechanisms by
which persistent HIV reservoirs are established and
maintained are fully understood. In addition, the sources
of persistent infection and rebounding plasma viremia
upon discontinuation of therapy need to be identified as
well as the mode of viral transmission/spread of infection
within lymphoid tissues. Finally, the development of
clinically relevant, novel therapeutic agents targeting
persistently infected cells must be assessed in infected
individuals receiving ART.
This article will review the state of our knowledge of
CD4þ T-cell-associated HIV reservoirs and discuss recent
therapeutic developments aimed at eradicating the virus
in infected individuals.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIV reservoirs: pathogenesis and viral eradication Chun and Fauci
did not prevent the establishment of a pool of latently
infected, resting CD4þ T cells carrying replicationcompetent virus [29]. In addition, the latent viral
reservoir was shown to expand rapidly following the
re-emergence of plasma viremia after discontinuation of
ART in HIV-infected individuals with undetectable
plasma viremia [30]. There are a number of challenges
associated with both identifying individuals during
primary HIV infection [31] and initiating ART prior to
the appearance of high levels of plasma viremia [29].
Nonetheless, several studies have attempted to determine
the half-life of latently infected, resting CD4þ T cells and
the duration of ART required to eliminate these infected
cells in early-treated individuals. Two longitudinal studies
demonstrated that the half-life of the latent viral reservoir
was approximately 4–6 months in HIV-infected individuals who initiated ART during the acute/early phase of
infection [32,33]. These studies projected that it would
require at least 7–8 years of continuous therapy to eradicate
HIV using the assumptions that ARTwas 100% effective at
suppressing viral replication and that no other viral
reservoirs existed in vivo [32,33]. These predictions were
in sharp contrast to other longitudinal studies that primarily
focused on infected individuals who initiated ART during
the chronic phase of infection and in which the half-life of
the latent viral reservoir exceeded 44 months. This
observation suggested that even 60 years of ART may not
be sufficient to completely eradicate HIV [18,19].
to date and is widely recognized as one of the major
obstacles to achieving eradication of virus [43,44], low
levels of HIV replication may persist in infected
individuals despite their treatment with clinically effective
ART [32,45–55]. In recent years, the lack of consensus
on the life span of the latent viral reservoir [19,32,33] has
sparked an intense debate regarding the possibility that
low levels of HIV replication in subsets of CD4þ T cells in
the lymphoid tissue may contribute to replenishment of a
pool of infected resting CD4þ T cells. By this mechanism,
the overall half-life of the viral reservoir could be
indefinitely extended. In this regard, previous mathematical models have suggested that productively infected
CD4þ T cells have a relatively short in-vivo half-life (<1
day) following initiation of ART [8,56]. The data indicate
that such cells should no longer be present in infected
individuals who had been receiving clinically effective
ART for extended periods. However, activated CD4þ T
cells, enriched at high purity from the blood of a viremic
individual receiving ART, carry HIV proviral DNA and
are capable of spontaneously producing virions in culture
[57]. Furthermore, in this study, phylogenetic analyses of
HIV env provided evidence for virologic cross-talk
between infected resting and activated CD4þ T cells in
the absence of detectable plasma viremia [57]. These
findings raise the possibility that ongoing HIV replication
may persist in nonresting CD4þ T-cell reservoirs in
aviremic individuals.
Assuming that the latent viral reservoir persists in virtually
all HIV-infected individuals receiving ART and that this
reservoir is considered to be one of the major impediments
to eradicating HIV [9–11,18,19], major efforts have been
directed towards elucidating the mechanism(s) by which
these infected cells persist in vivo. A number of cellular and
molecular mechanisms that could explain HIV persistence
have been proposed over the years. These include a paucity
of cellular factors required for robust HIV expression in
infected cells [34,35], modification of chromatin structure
that prevents viral replication [36,37], methylation of the 50
long terminal repeat region of HIV proviral DNA [38,39],
interference of HIV expression by the proximal host gene
promoters [40,41], homeostatic proliferation regenerating
latently infected cells in the absence of cell death [42], and
reversion of productively infected, activated CD4þ T cells
to the resting memory state without any specific
mechanisms [28]. Most likely, more than one of these,
or other yet to be identified mechanisms, may contribute to
the maintenance of the latent viral reservoir in vivo.
Without treatment, HIV replicates primarily in the
lymphoid tissues [58,59] with extremely high levels of
viral replication [60–62] and extensive destruction of
CD4þ T cells [63–65] in the gut-associated lymphoid
tissue (GALT) of infected animals and humans. Recent
studies have therefore shifted focus to the GALT as a
major viral reservoir in infected individuals receiving
ART. Such studies have demonstrated that the overall
HIV burden is substantially higher in the GALT than in
the blood of infected individuals receiving ART for long
time periods [66–69].
Persistence of HIV in infected individuals
receiving antiretroviral therapy: beyond
the latent viral reservoir
Although the pool of latently infected, resting CD4þ T
cells has been the most extensively studied HIV reservoir
1263
Collectively, these findings suggest that low levels of
ongoing viral replication, along with the persistence of
HIV in the latent viral reservoir in the blood, may occur
in the absence of detectable plasma viremia (<50 copies of
HIV RNA). Therefore, strategies targeting productively
infected cells in the tissue compartment must be
developed to further decrease the number of infected
cells. The recent introduction of newer classes of
antiretroviral drugs [70,71] ([72], this issue) combined
with the development of highly sensitive assays that are
capable of detecting plasma-associated HIV RNA at the
single copy level (below 50 copies of HIV RNA per ml of
plasma) [73–76] should play an important role in studying
and addressing the issue of persistent virus reservoirs. In
this regard, intensification of conventional ART with
newer classes of drugs was considered a possible approach
to further reduce the residual pool of virus if low levels of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1264
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2012, Vol 26 No 10
ongoing viral replication were indeed occurring in
treated infected individuals. Unfortunately, this line of
investigation has led to further disagreement. On the one
hand, several recent studies have demonstrated that
intensification of ART does not further reduce residual
plasma viremia [77–80]. Therefore, ongoing HIV
replication did not appear to occur and reactivation of
the latent viral reservoir seemed to be the main
mechanism by which residual plasma viremia is maintained in infected individuals receiving ART. On the
other hand, two studies taking a different approach have
demonstrated an accumulation of circularized HIV DNA
and a significant reduction in the level of cell-associated
RNA in the blood [81] and GALT [82], respectively,
upon intensification of ART in aviremic individuals.
Furthermore, evidence for cell-to-cell transmission of
HIV in the presence of antiretroviral drugs has been
recently demonstrated [83]. This finding implies that low
levels of ongoing HIV replication in the tissue compartment may not be detectable as plasma viremia. Given the
conflicting data regarding the virologic outcome of
intensification of ART, clinical studies involving comprehensive immunologic and virologic analyses of a large
number of study participants will be necessary to better
delineate the role of residual HIV replication in infected
individuals receiving ART. In addition, the precise origin
and clinical importance of residual plasma viremia need to
be further elucidated to better understand the dynamics of
HIV infection in the setting of effective ART.
Therapeutic strategies for the eradication
of persistent viral reservoirs in
HIV-infected individuals receiving
antiretroviral therapy: bench to bedside
A major thrust of HIV therapeutic research over the past
few years has been the development of clinical strategies
aimed at eradicating the virus in infected individuals who
receive ART. The pursuit of a cure for HIV disease began
in earnest over a decade ago with strategies that directly or
indirectly stimulated latently infected, resting CD4þ
T cells in vivo. These studies were based on the assumption
that activation of the latent viral reservoir would result in
rapid cell death due to HIV-induced cytopathic effects
and that the infectious virus released by these activated
cells would be contained by the administration of ART. In
this regard, it has been shown that a combination of
cytokines, namely IL-2, IL-6, and TNF-a, can induce
HIV replication from the latent viral reservoir ex vivo [35].
Indeed, several clinical studies have attempted to purge
the latent HIV reservoir in infected individuals receiving ART using immune-activating agents, such as IL-2
[84] and anti-CD3 antibody [85,86]. Among these
approaches, one nonrandomized study demonstrated a
marked diminution of the size of the pool of latently
infected, resting CD4þ T cells in infected individuals
receiving ART with repeated cycles of intermittent IL-2
compared with those who received ART alone [84].
Of note, no resting CD4þ T cells carrying replicationcompetent HIV could be detected in the blood and
lymphoid tissue of these patients [84]. Nonetheless, rapid
rebound of plasma viremia was observed following empiric
interruption of ART in these patients [30]; similar
rebounds of viremia following interruption of ART were
seen in patients treated with anti-CD3 antibody with ART
[86]. Taken together, these results strongly suggest that
strategies involving activation of the latent HIV reservoir
with potent T-cell stimulators may not be sufficient to
purge the virus from infected, resting CD4þ T cells and
thus achieve total eradication of HIV infection.
In recent years, molecular studies on the persistence of
HIV in latently infected cells have suggested that
repression of chromatin structure may play a role in
the inhibition of HIV transcription and that inhibitors of
histone deacetylases (HDACs) may allow expression of
viral RNA from the latent viral reservoir [87,88]
(Table 1). One of these HADC inhibitors, valproic acid
(VPA), has been tested extensively in vitro and ex vivo as a
potential candidate for purging the latent HIV reservoir.
One study demonstrated a diminution of the size of the
latent viral reservoir in a small number of infected
individuals receiving ART [98]. However, several subsequent studies have demonstrated no measurable effect of
VPA on the frequency of resting CD4þ T cells carrying
latent HIV in vivo [89–91]. These conflicting results may be
due in part to the fact that HDAC inhibitors are not potent
stimulators of HIV expression in latently infected, resting
CD4þ T cells and do not promote T-cell activation.
Currently, different HADC inhibitors are being tested in
clinical trials in order to investigate whether more potent
agents, such as suberoylanilide hydroxamic acid [99], are
better capable of purging the latent virus.
In addition to the aforementioned therapeutic agents that
target the latent HIV reservoir, the modification of host
genetics for the purpose of generating HIV-resistant
CD4þ T cells is under active investigation (Table 1). Such
an approach was inspired by a recent case report from
Germany describing an HIV-infected patient with acute
myeloid leukemia who underwent multiple rounds of
chemotherapy and stem cell transplants from a CCR5D32
homozygous donor. The virus appears to be completely
eliminated in this individual [96,97]. Remarkably, the
plasma viremia of this patient did not rebound following
discontinuation of ART and his viral load has remained
fully suppressed for several years in the absence of ART
[96,97]. On the basis of the initial success in a mouse
model [93,100], a number of clinical trials have been
recently launched in which autologous CD4þ T cells are
treated with a zinc-finger nuclease that is designed to
specifically eliminate or reduce the expression of HIV
coreceptors CCR5 or CXCR4 ex vivo [94,95]. These
genetically modified, HIV-resistant CD4þ T cells were
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
[92]
[93–95]
Ineffectiveness on the latent viral reservoir
Limited availability of human-tested
therapeutic vaccines
Low efficacy in infected individuals with
compromised immune systems
Unknown fate of viral reservoir after
transfusion with genetically modified cells
Cytolytic CD8þ T-cell-mediated
killing upon recognition
of viral antigen
Generation of HIV-resistant
CD4þ T cells
Generation of HIV-resistant
CD4þ T cells
Latently and/or productively
infected CD4þ T cells
CD4þ T cells
CD4þ T cells
Conclusion
HDACi, histone deacetylase inhibitor; SAHA, suberoylanilide hydroxamic acid; VPA, valproic acid.
Bone marrow transplantation
from CCR5D32
homozygous donor
Stem cell
transplantation
Difficulties in identifying HLA-matched donors
Need for chemotherapy and/or immunosuppressive
therapy prior to transplantation
Zinc finger nuclease-mediated
elimination of HIV
co-receptors
Gene therapy
Need for chemotherapy prior to transfusion
Therapeutic vaccine
Enhancement of
anti-HIV immunity
1265
then transfused back into the autologous donors.
Preliminary findings have demonstrated a repopulation
and steady increase in modified CD4þ T cells in the blood
and lymphoid tissues in some study participants [94,95].
However, the fate of preexisting HIV reservoirs in such
patients remains to be determined as does the question of
whether chemotherapy will be necessary to eliminate the
wild-type CCR5þ/CXCR4þ CD4þ T cells that may
harbor infectious virus prior to transfusion of genetically
modified cells. Future clinical trials involving long-term
follow-up and discontinuation of ART will shed light on
the feasibility of HIV eradication using these novel, more
targeted genetic approaches.
[96,97]
[89–91]
Induction of HIV may not lead to cell death
Minimal impact on productively
and recently infected CD4þ T cells
Induction of HIV expression
HDACi (VPA, SAHA)
Elimination of latent
HIV reservoir
Latently infected resting
CD4þ T cells
References
Challenges
Mode of action
Target cells
Agent/drug
Approach
Table 1. Current therapeutic strategies aimed at eradicating HIV in infected individuals receiving antiretroviral therapy.
HIV reservoirs: pathogenesis and viral eradication Chun and Fauci
Despite more than a decade of intense research and recent
therapeutic advances, achieving a true eradication of HIV
remains a daunting challenge for the HIV/AIDS scientific
community. The following key issues must be addressed
and implemented by the scientists in the field if the
eradication of HIV in infected individuals is to someday
become a realistic goal (Fig. 2). First, it is necessary to gain
a better understanding of the immunologic and virologic
factors/mechanisms that contribute to the persistence of
HIV in infected individuals receiving ART. In particular,
the following need to be fully delineated: the precise
mechanism by which the latent viral reservoir is
established and maintained; the role of tissue-derived
productively infected cells in the persistence of virus; the
origin of rebounding plasma viremia upon discontinuation of therapy; and the effect of immune activation on
viral burden in infected individuals receiving ART.
Second, the impact of the use of aggressive ARTregimens
administered as early as possible in the course of HIV
infection on the establishment and size of the HIV
reservoir and on our ability to ultimately eradicate this
reservoir needs to be addressed. Third, clinically relevant
and reproducible high-throughput virologic assays need
to be developed in order to measure the efficacy of agents
that are designed to target persistent HIV reservoirs.
Fourth, strategies aimed at targeting both latent (purging
agents) and nonlatent viral reservoirs (HIV-specific killing
agents such as immunotoxins) may need to be pursued
simultaneously in order to eradicate HIV. Given that
single cells carrying infectious HIVare potentially capable
of re-igniting viral replication in the absence of
antiretroviral drugs, a variety of cell types including cells
of monocyte/macrophage lineage in tissue compartments, such as the lymph nodes and other organs, need to
be examined and fully characterized as a potential
sanctuary for the virus. Finally, eradication strategies may
need to include immune-based therapies, such as
therapeutic vaccination [92] that are capable of boosting
the host immune responses against HIV and thus
contribute to the eradication process.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1266
AIDS
2012, Vol 26 No 10
Use of
aggressive drug
regimens
Use of virus
purging agents
Early
initiation of
antiretroviral
therapy
Enhancement
of anti-HIV
immunity
Use of HIVspecific killing
agents
Modification of
host genetics
Better understanding
of HIV basic science
Fig. 2. Potential strategies for eradicating HIV in infected
individuals receiving antiretroviral therapy.
Considering that a true sterilizing cure will be very
difficult to achieve in a large proportion of infected
individuals even in the best of circumstances involving
early access to therapy, the possibility of a ‘functional’ cure
should be pursued. In this case, the virus would not be
entirely eradicated, but HIV-specific immune responses
are boosted to prevent the rebound of plasma viremia
upon discontinuation of ART. The early initiation of
ART following acute infection would enhance the
possibility of such an immune-based functional cure by
minimizing the size of the viral reservoir. The
maintenance of this functional cure may likely require
multiple rounds of immune enhancement over several
years to ensure that the small amount of residual HIV is
not re-ignited in the absence of ART.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
References
1. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer
J, Satten GA, et al. Declining morbidity and mortality among
patients with advanced human immunodeficiency virus
infection. HIV Outpatient Study Investigators. N Engl J Med
1998; 338:853–860.
2. Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P,
d’Arminio Monforte A, et al. Decline in the AIDS and death
rates in the EuroSIDA study: an observational study. Lancet
2003; 362:22–29.
3. Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, et al. The survival benefits of AIDS treatment
in the United States. J Infect Dis 2006; 194:11–19.
4. The Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in
high-income countries: a collaborative analysis of 14 cohort
studies. Lancet 2008; 372:293–299.
5. van Sighem AI, Gras LA, Reiss P, Brinkman K, de Wolf F. Life
expectancy of recently diagnosed asymptomatic HIV-infected
patients approaches that of uninfected individuals. AIDS
2010; 24:1527–1535.
6. Donnell D, Baeten JM, Kiarie J, Thomas KK, Stevens W, Cohen
CR, et al. Heterosexual HIV-1 transmission after initiation of
antiretroviral therapy: a prospective cohort analysis. Lancet
2010; 375:2092–2098.
7. Koenig SP, Rodriguez LA, Bartholomew C, Edwards A,
Carmichael TE, Barrow G, et al. Long-term antiretroviral
treatment outcomes in seven countries in the Caribbean.
J Acquir Immune Defic Syndr 2012; 59:e60–e71.
8. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela
K, et al. Decay characteristics of HIV-1-infected compartments
during combination therapy. Nature 1997; 387:188–191.
9. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M,
et al. Presence of an inducible HIV-1 latent reservoir during
highly active antiretroviral therapy. Proc Natl Acad Sci U S A
1997; 94:13193–13197.
10. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC,
Spina CA, et al. Recovery of replication-competent HIV
despite prolonged suppression of plasma viremia. Science
1997; 278:1291–1295.
11. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C,
Chaisson RE, et al. Identification of a reservoir for HIV-1 in
patients on highly active antiretroviral therapy. Science 1997;
278:1295–1300.
12. Davey RT Jr, Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R,
et al. HIV-1 and T cell dynamics after interruption of highly
active antiretroviral therapy (HAART) in patients with a
history of sustained viral suppression. Proc Natl Acad Sci U
S A 1999; 96:15109–15114.
13. Neumann AU, Tubiana R, Calvez V, Robert C, Li TS, Agut H,
et al. HIV-1 rebound during interruption of highly active
antiretroviral therapy has no deleterious effect on reinitiated
treatment. Comet Study Group. AIDS 1999; 13:677–683.
14. Harrigan PR, Whaley M, Montaner JS. Rate of HIV-1 RNA
rebound upon stopping antiretroviral therapy. AIDS 1999;
13:F59–F62.
15. Garcia F, Plana M, Vidal C, Cruceta A, O’Brien WA, Pantaleo
G, et al. Dynamics of viral load rebound and immunological
changes after stopping effective antiretroviral therapy. AIDS
1999; 13:F79–F86.
16. Chun TW, Davey RT Jr, Ostrowski M, Shawn Justement J, Engel
D, Mullins JI, et al. Relationship between preexisting viral
reservoirs and the re-emergence of plasma viremia after
discontinuation of highly active antiretroviral therapy. Nat
Med 2000; 6:757–761.
17. Zhang L, Chung C, Hu BS, He T, Guo Y, Kim AJ, et al. Genetic
characterization of rebounding HIV-1 after cessation of highly
active antiretroviral therapy. J Clin Invest 2000; 106: 839–845.
18. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K,
Pierson T, et al. Latent infection of CD4R T cells provides a
mechanism for lifelong persistence of HIV-1, even in patients
on effective combination therapy. Nat Med 1999; 5:512–517.
19. Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K,
Margolick JB, et al. Long-term follow-up studies confirm
the stability of the latent reservoir for HIV-1 in resting
CD4R T cells. Nat Med 2003; 9:727–728.
20. Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D,
Siliciano RF. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med 1995;
1:1284–1290.
21. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C,
McMahon D, et al. Treatment with indinavir, zidovudine,
and lamivudine in adults with human immunodeficiency virus
infection and prior antiretroviral therapy. N Engl J Med 1997;
337:734–739.
22. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter
LM, Currier JS, et al. A controlled trial of two nucleoside
analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic
millimeter or less. AIDS Clinical Trials Group 320 Study
Team. N Engl J Med 1997; 337:725–733.
23. Folks T, Powell DM, Lightfoote MM, Benn S, Martin MA, Fauci
AS. Induction of HTLV-III/LAV from a nonvirus-producing
T-cell line: implications for latency. Science 1986; 231:600–
602.
24. Poli G, Kinter A, Justement JS, Kehrl JH, Bressler P, Stanley S,
et al. Tumor necrosis factor alpha functions in an autocrine
manner in the induction of human immunodeficiency virus
expression. Proc Natl Acad Sci U S A 1990; 87:782–785.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIV reservoirs: pathogenesis and viral eradication Chun and Fauci
25. Nabel G, Baltimore D. An inducible transcription factor
activates expression of human immunodeficiency virus in
T cells. Nature 1987; 326:711–713.
26. Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS.
HIV-1 entry into quiescent primary lymphocytes: molecular
analysis reveals a labile, latent viral structure. Cell 1990;
61:213–222.
27. Bukrinsky MI, Stanwick TL, Dempsey MP, Stevenson M.
Quiescent T lymphocytes as an inducible virus reservoir in
HIV-1 infection. Science 1991; 254:423–427.
28. Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor
H, et al. Quantification of latent tissue reservoirs and total
body viral load in HIV-1 infection. Nature 1997; 387:183–
188.
29. Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS.
Early establishment of a pool of latently infected, resting
CD4(R) T cells during primary HIV-1 infection. Proc Natl
Acad Sci U S A 1998; 95:8869–8873.
30. Chun TW, Davey RT Jr, Engel D, Lane HC, Fauci AS.
Re-emergence of HIV after stopping therapy. Nature 1999;
401:874–875.
31. Branson BM, Stekler JD. Detection of acute HIV infection: we
can’t close the window. J Infect Dis 2012; 205:521-524.
32. Zhang L, Ramratnam B, Tenner-Racz K, He Y, Vesanen M,
Lewin S, et al. Quantifying residual HIV-1 replication in
patients receiving combination antiretroviral therapy. N Engl
J Med 1999; 340:1605–1613.
33. Chun TW, Justement JS, Moir S, Hallahan CW, Maenza J,
Mullins JI, et al. Decay of the HIV reservoir in patients
receiving antiretroviral therapy for extended periods: implications for eradication of virus. J Infect Dis 2007; 195:1762–
1764.
34. Williams SA, Greene WC. Regulation of HIV-1 latency by
T-cell activation. Cytokine 2007; 39:63–74.
35. Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS. Induction of
HIV-1 replication in latently infected CD4R T cells using a
combination of cytokines. J Exp Med 1998; 188:83–91.
36. Coull JJ, Romerio F, Sun JM, Volker JL, Galvin KM, Davie JR, et al.
The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of
histone deacetylase 1. J Virol 2000; 74:6790–6799.
37. Ylisastigui L, Coull JJ, Rucker VC, Melander C, Bosch RJ, Brodie
SJ, et al. Polyamides reveal a role for repression in latency
within resting T cells of HIV-infected donors. J Infect Dis 2004;
190:1429–1437.
38. Blazkova J, Trejbalova K, Gondois-Rey F, Halfon P, Philibert P,
Guiguen A, et al. CpG methylation controls reactivation of
HIV from latency. PLoS Pathogens 2009; 5:e1000554.
39. Kauder SE, Bosque A, Lindqvist A, Planelles V, Verdin E.
Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathogens 2009; 5:e1000495.
40. Han Y, Lin YB, An W, Xu J, Yang HC, O’Connell K, et al.
Orientation-dependent regulation of integrated HIV-1
expression by host gene transcriptional readthrough. Cell
Host Microbe 2008; 4:134–146.
41. Lenasi T, Contreras X, Peterlin BM. Transcriptional interference antagonizes proviral gene expression to promote HIV
latency. Cell Host Microbe 2008; 4:123–133.
42. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA,
Yassine-Diab B, et al. HIV reservoir size and persistence are
driven by T cell survival and homeostatic proliferation. Nat
Med 2009; 15:893–900.
43. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda
D, Pomerantz RJ. The challenge of finding a cure for HIV
infection. Science 2009; 323:1304–1307.
44. Trono D, Van Lint C, Rouzioux C, Verdin E, Barre-Sinoussi F,
Chun TW, et al. HIV persistence and the prospect of long-term
drug-free remissions for HIV-infected individuals. Science
2010; 329:174–180.
45. Furtado MR, Callaway DS, Phair JP, Kunstman KJ, Stanton JL,
Macken CA, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent
antiretroviral therapy. N Engl J Med 1999; 340:1614–1622.
46. Gunthard HF, Havlir DV, Fiscus S, Zhang ZQ, Eron J, Mellors J,
et al. Residual human immunodeficiency virus (HIV) type 1
RNA and DNA in lymph nodes and HIV RNA in genital
secretions and in cerebrospinal fluid after suppression of
viremia for 2 years. J Infect Dis 2001; 183:1318–1327.
1267
47. Zhu T, Muthui D, Holte S, Nickle D, Feng F, Brodie S, et al.
Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(R) monocytes and its potential role as a
source of virus in patients on highly active antiretroviral
therapy. J Virol 2002; 76:707–716.
48. Izopet J, Cazabat M, Pasquier C, Sandres-Saune K, Bonnet E,
Marchou B, et al. Evolution of total and integrated HIV-1 DNA
and change in DNA sequences in patients with sustained
plasma virus suppression. Virology 2002; 302:393–404.
49. Sharkey ME, Teo I, Greenough T, Sharova N, Luzuriaga K,
Sullivan JL, et al. Persistence of episomal HIV-1 infection
intermediates in patients on highly active antiretroviral therapy. Nat Med 2000; 6:76–81.
50. Strain MC, Gunthard HF, Havlir DV, Ignacio CC, Smith DM,
Leigh-Brown AJ, et al. Heterogeneous clearance rates of longlived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence. Proc Natl Acad Sci U S A 2003;
100:4819–4824.
51. Natarajan V, Bosche M, Metcalf JA, Ward DJ, Lane HC, Kovacs
JA. HIV-1 replication in patients with undetectable plasma
virus receiving HAART. Highly active antiretroviral therapy.
Lancet 1999; 353:119–120.
52. Ramratnam B, Ribeiro R, He T, Chung C, Simon V, Vanderhoeven J, et al. Intensification of antiretroviral therapy accelerates the decay of the HIV-1 latent reservoir and decreases,
but does not eliminate, ongoing virus replication. J Acquir
Immune Defic Syndr 2004; 35:33–37.
53. Patterson BK, McCallister S, Schutz M, Siegel JN, Shults K,
Flener Z, et al. Persistence of intracellular HIV-1 mRNA
correlates with HIV-1-specific immune responses in infected
subjects on stable HAART. AIDS 2001; 15:1635–1641.
54. Delobel P, Sandres-Saune K, Cazabat M, Pasquier C, Marchou
B, Massip P, et al. R5 to X4 switch of the predominant HIV-1
population in cellular reservoirs during effective highly active
antiretroviral therapy. J Acquir Immune Defic Syndr 2005;
38:382–392.
55. Wightman F, Solomon A, Khoury G, Green JA, Gray L, Gorry
PR, et al. Both CD31(R) and CD31 naive CD4(R) T cells are
persistent HIV type 1-infected reservoirs in individuals receiving antiretroviral therapy. J Infect Dis 2010; 202:1738–
1748.
56. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho
DD. HIV-1 dynamics in vivo: virion clearance rate, infected
cell life-span, and viral generation time. Science 1996;
271:1582–1586.
57. Chun TW, Nickle DC, Justement JS, Large D, Semerjian A,
Curlin ME, et al. HIV-infected individuals receiving effective
antiviral therapy for extended periods of time continually
replenish their viral reservoir. J Clin Invest 2005; 115:3250–
3255.
58. Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox
CH, et al. HIV infection is active and progressive in lymphoid
tissue during the clinically latent stage of disease. Nature
1993; 362:355–358.
59. Embretson J, Zupancic M, Ribas JL, Burke A, Racz P, TennerRacz K, et al. Massive covert infection of helper T lymphocytes
and macrophages by HIV during the incubation period of
AIDS. Nature 1993; 362:359–362.
60. Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR,
Knight HL, et al. Gastrointestinal tract as a major site of CD4R
T cell depletion and viral replication in SIV infection. Science
1998; 280:427–431.
61. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M,
Roederer M. Massive infection and loss of memory CD4R
T cells in multiple tissues during acute SIV infection. Nature
2005; 434:1093–1097.
62. Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, et al. Peak
SIV replication in resting memory CD4R T cells depletes gut
lamina propria CD4R T cells. Nature 2005; 434:1148–1152.
63. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J,
McNeil A, et al. Severe CD4R T-cell depletion in gut lymphoid
tissue during primary human immunodeficiency virus type 1
infection and substantial delay in restoration following highly
active antiretroviral therapy. J Virol 2003; 77:11708–11717.
64. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH,
Beilman GJ, et al. CD4R T cell depletion during all stages of
HIV disease occurs predominantly in the gastrointestinal
tract. J Exp Med 2004; 200:749–759.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1268
AIDS
2012, Vol 26 No 10
65. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A,
Hogan C, et al. Primary HIV-1 infection is associated with
preferential depletion of CD4R T lymphocytes from effector
sites in the gastrointestinal tract. J Exp Med 2004; 200:761–770.
66. Yukl SA, Gianella S, Sinclair E, Epling L, Li Q, Duan L, et al.
Differences in HIV burden and immune activation within the
gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis 2010; 202:1553–1561.
67. Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G,
Hallahan CW, et al. Persistence of HIV in gut-associated
lymphoid tissue despite long-term antiretroviral therapy.
J Infect Dis 2008; 197:714–720.
68. Macal M, Sankaran S, Chun TW, Reay E, Flamm J, Prindiville
TJ, et al. Effective CD4R T-cell restoration in gut-associated
lymphoid tissue of HIV-infected patients is associated with
enhanced Th17 cells and polyfunctional HIV-specific T-cell
responses. Mucosal Immunol 2008; 1:475–488.
69. Sheth PM, Chege D, Shin LY, Huibner S, Yue FY, Loutfy M,
et al. Immune reconstitution in the sigmoid colon after longterm HIV therapy. Mucosal Immunol 2008; 1:382–388.
70. Havlir DV. HIV integrase inhibitors: out of the pipeline and
into the clinic. N Engl J Med 2008; 359:416–418.
71. Fatkenheuer G, Pozniak AL, Johnson MA, Plettenberg A,
Staszewski S, Hoepelman AI, et al. Efficacy of short-term
monotherapy with maraviroc, a new CCR5 antagonist, in
patients infected with HIV-1. Nat Med 2005; 11:1170–1172.
72. Vella S, Schwartländer B, Sow SP, Eholie SP, Murphy RL. The
history of antiretroviral therapy and of its implementation in
resource-limited areas of the world. AIDS 2012; 26:1231–
1241.
73. Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis
M, et al. New real-time reverse transcriptase-initiated PCR
assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 2003;
41:4531–4536.
74. Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ,
Brun SC, et al. Low-level viremia persists for at least 7 years in
patients on suppressive antiretroviral therapy. Proc Natl Acad
Sci U S A 2008; 105:3879–3884.
75. Bailey JR, Sedaghat AR, Kieffer T, Brennan T, Lee PK, WindRotolo M, et al. Residual human immunodeficiency virus type
1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in
circulating CD4R T cells. J Virol 2006; 80:6441–6457.
76. Chun TW, Murray D, Justement JS, Hallahan CW, Moir S,
Kovacs C, et al. Relationship between residual plasma viremia
and the size of HIV proviral DNA reservoirs in infected
individuals receiving effective antiretroviral therapy. J Infect
Dis 2011; 204:135–138.
77. Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ,
Cranmer L, et al. Treatment intensification does not reduce
residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 2009; 106:9403–9408.
78. Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S,
et al. The effect of raltegravir intensification on low-level
residual viremia in HIV-infected patients on antiretroviral
therapy: a randomized controlled trial. PLoS Med 2010;
7:e1000321.
79. Hatano H, Hayes TL, Dahl V, Sinclair E, Lee TH, Hoh R, et al. A
randomized, controlled trial of raltegravir intensification in
antiretroviral-treated, HIV-infected patients with a suboptimal CD4R T cell response. J Infect Dis 2011; 203:960–968.
80. McMahon D, Jones J, Wiegand A, Gange SJ, Kearney M,
Palmer S, et al. Short-course raltegravir intensification does
not reduce persistent low-level viremia in patients with HIV-1
suppression during receipt of combination antiretroviral therapy. Clin Infect Dis 2010; 50:912–919.
81. Buzon MJ, Massanella M, Llibre JM, Esteve A, Dahl V, Puertas
MC, et al. HIV-1 replication and immune dynamics are
affected by raltegravir intensification of HAART-suppressed
subjects. Nat Med 2010; 16:460–465.
82. Yukl SA, Shergill AK, McQuaid K, Gianella S, Lampiris H, Hare
CB, et al. Effect of raltegravir-containing intensification on
HIV burden and T-cell activation in multiple gut sites of HIVpositive adults on suppressive antiretroviral therapy. AIDS
2010; 24:2451–2460.
83. Sigal A, Kim JT, Balazs AB, Dekel E, Mayo A, Milo R, et al. Cellto-cell spread of HIV permits ongoing replication despite
antiretroviral therapy. Nature 2011; 477:95–98.
84. Chun TW, Engel D, Mizell SB, Hallahan CW, Fischette M, Park
S, et al. Effect of interleukin-2 on the pool of latently infected,
resting CD4R T cells in HIV-1-infected patients receiving
highly active antiretroviral therapy. Nat Med 1999; 5:651–
655.
85. Prins JM, Jurriaans S, van Praag RM, Blaak H, van Rij R,
Schellekens PT, et al. Immuno-activation with anti-CD3
and recombinant human IL-2 in HIV-1-infected patients on
potent antiretroviral therapy. AIDS 1999; 13:2405–2410.
86. Kulkosky J, Nunnari G, Otero M, Calarota S, Dornadula G,
Zhang H, et al. Intensification and stimulation therapy for
human immunodeficiency virus type 1 reservoirs in infected
persons receiving virally suppressive highly active antiretroviral therapy. J Infect Dis 2002; 186:1403–1411.
87. He G, Margolis DM. Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated
promoter of human immunodeficiency virus type 1 (HIV-1)
by the HIV-1 repressor YY1 and HIV-1 activator Tat. Mol Cell
Biol 2002; 22:2965–2973.
88. Williams SA, Chen LF, Kwon H, Ruiz-Jarabo CM, Verdin E,
Greene WC. NF-kappaB p50 promotes HIV latency through
HDAC recruitment and repression of transcriptional initiation. EMBO J 2006; 25:139–149.
89. Siliciano JD, Lai J, Callender M, Pitt E, Zhang H, Margolick JB,
et al. Stability of the latent reservoir for HIV-1 in patients
receiving valproic acid. J Infect Dis 2007; 195:833–836.
90. Sagot-Lerolle N, Lamine A, Chaix ML, Boufassa F, Aboulker JP,
Costagliola D, et al. Prolonged valproic acid treatment does
not reduce the size of latent HIV reservoir. AIDS 2008;
22:1125–1129.
91. Archin NM, Eron JJ, Palmer S, Hartmann-Duff A, Martinson JA,
Wiegand A, et al. Valproic acid without intensified antiviral
therapy has limited impact on persistent HIV infection of
resting CD4R T cells. AIDS 2008; 22:1131–1135.
92. Rosenberg ES, Graham BS, Chan ES, Bosch RJ, Stocker V,
Maenza J, et al. Safety and immunogenicity of therapeutic
DNA vaccination in individuals treated with antiretroviral
therapy during acute/early HIV-1 infection. PLoS One 2010;
5:e10555.
93. Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V, et al.
Human hematopoietic stem/progenitor cells modified by
zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo.
Nat Biotechnol 2010; 28:839–847.
94. Lalezari J, Mitsuyasu R, Deeks S, Wang S, Lee G, Holmes M,
et al. Successful and persistent engraftment of ZFN-M-R5-D
autologous CD4 T cells (SB-728-T) in aviremic HIV-infected
subjects on HAART. In: Proceedings of the 18th Conference on
Retroviruses and Opportunistic Infections; 2011; Boston, MA.
95. Tebas P, Levine B, Binder G, Hoxie J, Collman R, Gregory P,
et al. Disruption of CCR5 in zinc finger nuclease-treated CD4
T cells: phase I trials. In: Proceedings of the 18th Conference
on Retroviruses and Opportunistic Infections; 2011; Boston,
MA.
96. Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers
K, et al. Long-term control of HIV by CCR5Delta32/Delta32
stem-cell transplantation. N Engl J Med 2009; 360:692–
698.
97. Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K,
Thiel E, et al. Evidence for the cure of HIV infection by
CCR5Delta32/Delta32 stem cell transplantation. Blood
2011; 117:2791–2799.
98. Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA,
Wiegand A, et al. Depletion of latent HIV-1 infection in vivo:
a proof-of-concept study. Lancet 2005; 366:549–555.
99. Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D,
Margolis DM. Expression of latent HIV induced by the potent
HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res
Human Retroviruses 2009; 25:207–212.
100. Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O, et al.
Establishment of HIV-1 resistance in CD4R T cells by genome
editing using zinc-finger nucleases. Nat Biotechnol 2008;
26:808–816.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.