HIV reservoirs and the possibility of a cure for HIV infection
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Symposium | doi: 10.1111/j.1365-2796.2011.02457.x
HIV reservoirs and the possibility of a cure for HIV infection
S. Palmer1,2, L. Josefsson1,2 & J. M. Coffin3
From the 1Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet; 2Department of Virology, Swedish Institute for Infectious
Disease Control, Solna, Sweden, and 3Department of Molecular Biology and Microbiology, Tufts University, Boston, MA, USA
Abstract. Palmer S, Josefsson L, Coffin JM (Karolinska suboptimal; and ⁄ or (iii) proliferation of latently in-
Institutet, Solna; Swedish Institute for Infectious Dis- fected cells with regeneration of a stable reservoir of
ease Control, Solna, Sweden; and Tufts University, slowly dividing infected cells. A well-defined latent
Boston, MA, USA). HIV reservoirs and the possibility reservoir of HIV is memory CD4+ T-cells where la-
of a cure for HIV infection (Symposium). J Intern Med tency is established when an activated CD4+ T-cell
2011; doi: 10.1111/j.1365-2796.2011.02457.x. becomes infected by HIV, but transitions to a termi-
nally differentiated memory cell before it is elimi-
Recent studies demonstrate that suppressive ther- nated. This review examines the dynamics and possi-
apy can drive HIV-1 RNA levels to less than 50 cop- ble reservoirs of persistent HIV in patients on
ies mL)1 in patient plasma. Yet, ultrasensitive assays suppressive therapy, the mechanisms promoting
show that most patients continue to harbour low- viral latency and strategies to purge latent viral reser-
level persistent viremia. Treatment intensification voirs. The promising research described here takes a
studies indicate that low-level viremia could arise number of steps forward to seriously address HIV
from several different sources. These sources in- remission and ⁄ or eradication.
clude: (i) long-lived HIV-infected cells that replicate
and produce virus; (ii) ongoing replication cycles in Keywords: HIV eradication, HIV latency, HIV persis-
cells located in sanctuary sites where drug levels are tence, HIV reservoirs.
development and many other related fields. In this
Introduction
article we review research into the source and dynam-
The development of combination antiretroviral ther- ics of persistent viremia. We will focus on studies
apy remains one of the great triumphs of modern describing the levels and genetic make-up of persis-
medicine. Despite its unquestioned success, current tent viremia during suppressive therapy and what
therapy for the treatment of human immunodefi- this research can tell us about viral reservoirs and
ciency virus (HIV) has a number of limitations. For mechanisms of HIV latency. In the final section we
example, although effective and life saving, it is not will discuss current strategies for reactivation of the
curative and does not eradicate infection. During latent HIV reservoir, a step likely to be crucial for its
combination antiretroviral therapy, reduction of HIV eradication.
RNA levels to less than 50 copies mL)1 is frequently
achieved; however, residual low-level viremia can be
Persistent HIV viremia
detected in most patients using ultrasensitive assays
[1–4]. Furthermore, interruption of treatment results Highly active antiretroviral therapy (HAART) effec-
in a rapid viral rebound arising from the persistent, tively suppresses HIV RNA levels from an average of
residual viremia. Notably, this persistent viremia is about 30 000 to below 50 copies mL)1 (the lower
evident even after seven years of therapy [5]. There- detection limit of most commercial assays used in
fore, effective therapy requires life-long adherence, clinical practice) in the plasma of infected patients.
which many patients find difficult to achieve. However, if treatment is interrupted, the virus will re-
bound and become detectable again, often within two
The eradication of human immunodeficiency virus weeks [6]. Therefore, HAART does not eliminate HIV
(HIV) from infected individuals is one of the major infection and residual low-level viremia has been de-
medical challenges of our time. For the past 25 years, tected using ultrasensitive assays [2, 3, 7–9] in 80%
this effort has attracted researchers in the fields of of treated patients. Notably, this viremia can persist
infectious disease, virology, molecular biology, drug for at least 7 years of suppressive therapy [5].
ª 2011 The Association for the Publication of the Journal of Internal Medicine 1S. Palmer et al.
| Symposium: HIV reservoirs and HIV infection
Owing to the fact that HAART prevents the transmis- ing viral replication is contributing to persistent vire-
sion of infection to new cells and the half-life of plas- mia in patients on effective HAART regimens. At least
ma virions is 6 h, the levels of HIV RNA in the plasma four studies, using a number of different treatment
are strongly correlated to the half-life of the cells pro- protocols, have shown no perceptible change in per-
ducing the virus [10, 11]. After introduction of HA- sistent viremia in patients receiving intensified treat-
ART, viremia declines rapidly and mathematical ment or statistical difference between the intensified
modelling has revealed at least four phases of viral de- and placebo arms of the study, implicating long-lived
cay corresponding to the half lives of different popula- cells as the probable source [14–17]. This conclusion
tions of HIV-infected cells (Fig. 1). As HAART prevents is supported by studies that demonstrate the lack of
new cycles of HIV infection, but has no effect on the further evolution in the persistent virus population.
death rate or viral production of already infected cells, Indeed, the emergence of genetically homogeneous
each phase of the decline in viremia reflects the death subpopulations can often be observed in patients un-
or elimination of a different population of virus-in- der long-term treatment, as well as in the viral popu-
fected cells. During the fourth phase, there is little or lation that rebounds during treatment interruption
no viral decay and the levels of plasma HIV RNA re- [18, 19]. The genetic homogeneity of these viral popu-
main stable ranging from £1–5 copies mL)1 with an lations suggests that persistent viremia arises from
overall median viral load of 3 copies mL)1 [1–3, 5]. long-lived latently infected cells rather than ongoing
cycles of replicating virus. Further support for this
There are two different views regarding the source an- comes from earlier studies which revealed that the le-
d ⁄ or dynamics of persistent viremia in patients on vel of persistent viremia is not related to treatment
long-term suppressive therapy. One view holds that regimen but to pretreatment viral RNA levels, sug-
persistent viremia is the result of ongoing cycles of vir- gesting that the pretreatment viral set-point is corre-
al replication [2, 12, 13]. The other view maintains lated to the number of long-lived HIV-infected cells
that this residual viremia is from long-lived cells that [3].
are infected prior to treatment initiation [3]. To settle
this debate, the source of persistent viremia was re- However, additional studies of treatment intensifica-
cently characterized by quantifying the levels of vire- tion with raltegravir, which blocks integration of HIV
mia in patients on suppressive regimens (viral DNA into chromosomal DNA, have produced appar-
load < 50 copies mL)1) who ‘intensify’ their standard ent conflicting results. In a minority (30%) of patients,
regimen of three drugs by adding a fourth drug such an increase in episomal (unintegrated) HIV DNA was
as raltegravir. If persistent viremia decreases during observed leading to the conclusion that active replica-
this treatment intensification, it would suggest ongo- tion persists in some infected individuals on suppres-
HAART
HIV-1 RNA
Fig. 1 The four phases of viral
decay after the initiation of
highly active antiretroviral ther-
< 50 copies/mL
apy and the virion producing cell
populations related to each
phase. The yellow cells represent
activated CD4+ T-cells, the green
cells represent partially acti-
Time vated CD4+ T-cells or other cell
Phase 1 2 3 4 types, the blue cells represent
Half time 1 – 2 days 2 weeks 39 weeks resting memory CD4+ T-cell sub-
Cell type Activated CD4+ T-cells Partially activated Resting memory Resting memory
sets or other cells and the red
CD4+ T-cells, CD4+ T-cells CD4+ T-cells
macrophages, - central - central cells represent long-lived HIV-in-
dendritic cells - transitional - transitional fected cells which could be rest-
- effector - effector
- terminally - terminally ing memory CD4+ T-cells, or sub-
differentiated differentiated sets of these cells.
2 ª 2011 The Association for the Publication of the Journal of Internal Medicine Journal of Internal MedicineS. Palmer et al.
| Symposium: HIV reservoirs and HIV infection
(a) (b)
Central nervous system/CSF
Activated CD4+ T-cell
Fig. 2 Possible reservoirs of
persistent HIV virus. HIV persis- Peripheral blood
tence in resting long-lived mem- Lymph node tissue
Becomes HIV infected
ory CD4+ T-cells: an activated
CD4+ T-cell becomes infected
and then subsequently transi- HIV integrates
tions to a resting memory pheno- into cellular genome Gut associated lymphoid tissue
type (a). A number of findings
suggest that the reservoir is lar- Bone marrow tissue
gely established and maintained Transition to
in human tissues (b). Determin- memory CD4+ T-cell
Antigen
ing the type of cells and reservoir
producing persistent HIV is cru-
cial for future efforts aimed at
HIV eradication as these cells Cellular activation and viral production
could be targeted by new thera-
pies.
sive therapy [20]. In addition, a recent raltegravir eral different types of HIV-infected cells may contrib-
intensification study with anatomic analysis of HIV ute to this viral decay including macrophages, par-
infection in the gastrointestinal tract revealed no de- tially activated CD4+ T-cells and different types of
creases in peripheral viremia but decreases were dendritic cells. Macrophages are less susceptible to
measured in unspliced HIV RNA in CD4+ T-cells ob- the viral cytopathic effects than activated CD4+
tained from the terminal ileum [21]. These results T-cells and the half-life of tissue macrophages can be
indicate that low-level viremia might arise from sev- several weeks [24, 25]. Partially activated HIV-
eral different sources. These sources may include: (i) infected CD4+ T-cells have been reported to have a
long-lived HIV-infected cells that produce virus; (ii) longer turnover time than fully activated CD4+ T-cells
ongoing replication cycles in cells located in sanctu- [9]. Although it is unknown how long dendritic cells
ary sites where drug levels are suboptimal such as a (DCs) can survive after HIV infection, in vitro studies
tissue-based foci of viral replication within CD4+ T- show that infected myeloid dendritic cells can survive
cells and ⁄ or myeloid cells; and ⁄ or (iii) proliferation of for more than 45 days [26]. Langerhans cells
latently infected cells with regeneration of a stable (dendritic cells in the skin) have been shown to have a
reservoir of slowly dividing infected cells [1, 4, 9–11]. half-life of about 15 days when infected [27, 28],
whilst DCs in the mucosa have a shorter half-life of
only 2–3 days [29]. However, HIV has not been found
Viral reservoirs and sanctuary sites
in DCs from the peripheral blood following 6 weeks of
During untreated infection, HIV predominantly repli- HAART which suggests that these cells do not con-
cates in activated CD4+ T-cells which die quickly tribute to long-term HIV persistence [30]. Follicular
either from viral cytopathic effect or from immune re- dendritic cells trap virions on their surface and these
sponse [9]. After suppressive HAART is initiated, virions can remain infectious for at least 9 months
infection of new cells is prevented. Cells that are al- [31] but it is unclear whether their slow release con-
ready infected produce virus and die as they would tributes to the different phases of decay. It has also
have without therapy. Measurement of decay of virus been observed that in HIV-infected patients treated
in plasma as a function of time since initiation of ther- with a raltegravir-containing regimen, the proportion
apy thus reveals the kinetics of death of infected cells. of virus attributable to the second phase is greatly
The bulk of the plasma virus – 90% or so – decays in reduced, suggesting that integration is delayed in the
the first phase with a half-life of 1–2 days, and almost cells that make-up this phase [32, 33].
certainly reflects infection and killing of activated
CD4+ T-cells (Fig. 1) [22, 23]. The cellular sources of the third and fourth phases of
decay have not been fully identified but these phases
The kinetics of the second phase of decay is slower most likely represent additional classes of long-lived
with a half-life of 12–14 days. The elimination of sev- virus-producing cells. One well-accepted latent
ª 2011 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 3S. Palmer et al.
| Symposium: HIV reservoirs and HIV infection
reservoir of HIV is the stable infection of resting long- fraction (perhaps 1% or so) of the total HIV DNA–
lived memory CD4+ T-cells. These cells may become positive cells in patients on long-term suppressive
infected directly or, more likely, when an activated therapy that is capable of being induced to make
CD4+ T-cell becomes infected and then subse- infectious virus in vitro. The large majority of provi-
quently transitions to a resting memory phenotype ruses are apparently incapable of activation, owing to
before HIV infection eliminates the cell (Fig. 2a). accumulation of inactivating mutations, unfavour-
Transition to a memory cell is associated with a able integration sites or some other cellular feature.
reduction in transcription factors required for HIV At the moment, there is no way to physically distin-
replication. Thus, switching to a memory cell allows guish amongst these populations.
this infected host cell to persist for years until it re-
ceives a stimulatory signal that activates the cell and Although the bulk of evidence favours the conclusion
concomitantly induces viral production. Resting that persistent viremia is owing to virus production
memory CD4+ T-cells isolated from infected individ- from cells infected prior to initiation of therapy, it re-
uals on suppressive therapy can be activated by mains possible that low-level viral replication may oc-
agents like anti-CD3 or by the combination of cyto- cur in anatomical compartments or tissues where
kines TNF-a, IL-2 and IL-6 to produce infectious drug levels are suboptimal (Fig. 2b) [21]. Only about
virus [34, 35]. During antiretroviral therapy, these 2% of lymphocytes are in the circulation, the remain-
inducible cells decay very slowly with an average der are spread throughout the body, especially in
half-life of 44 months, indicating that under current lymphoid organs such as the spleen, lymph nodes
treatment it will take over 60 years to deplete this and gut-associated lymphoid tissue (GALT) where
reservoir [36]. The frequency of infected resting the majority of viral replication takes place during un-
memory CD4+ T-cells is low, about one infected cells treated infection [41–44]. In fact, large numbers of
per 106 resting memory CD4+ T-cells (about 100-fold lymphocytes are sequestered in the gastrointestinal
less than total HIV DNA–positive cells), and this res- (GI) tract. During the acute phase of HIV infection,
ervoir is established during primary HIV infection CD4+ lymphocytes located in the GI tract are depleted
[37, 38]. and remain so throughout the course of the disease
[13–15]. During suppressive therapy, the CD4+ T-
Recently, Chomont et al. have shown that during cells in the GI tract are slowly but incompletely re-
HAART, integrated HIV DNA can be found in two stored [45]. Although antiretroviral therapy greatly
different subsets of CD4+ T-cells: central memory reduces HIV replication and immune activation, it is
T-cells (TCM) and transitional memory T-cells (TTM). unclear whether low-level ongoing HIV replication is
They found that TCM cells are the major viral reservoir continuing in the gut of treated patients.
for patients with relatively high CD4+ T-cell counts,
and the low proliferation rate of these cells allows Also of note, patients infected with HIV-1 present
them to persist at adequate levels for years. In hematopoietic abnormalities which are caused by
patients with low CD4+ counts, the major reservoir is HIV infection of the bone marrow [16]. A recent study
TTM cells and these cells persist by homoeostatic pro- has shown that HIV infects multipotent hematopoi-
liferation making them a very stable viral reservoir. etic progenitor cells (HPCs) and that latent HIV infec-
Furthermore, they observed that in individuals who tion was established in some of these HPCs [17]. The
have a lower CD4+ count the stability of the TTM reser- authors note in this study that further research is
voir is mediated through IL-7 induced proliferation now needed to test whether persistent circulating
and that in these individuals plasma levels of IL-7 virus in patients on suppressive therapy is partially
correlated inversely to the rate of decrease of the derived from HPCs as was shown for resting memory
reservoir. This study suggests that there are at least T-cells.
two mechanisms by which the reservoir of infected
resting memory CD4+ T-cells is maintained [39]. In addition to the lymphoid system, the central ner-
Recent studies indicate that the persistent viremia in vous system (CNS) is a target for HIV-1 infection; and
50% of patients is derived from memory CD4+ T-cells, during primary infection, viral RNA has been detected
which suggests that other virus-producing cellular in the cerebrospinal fluid (CSF) of patients [46, 47].
sources may be responsible for the persistent viremia This infection causes a local inflammatory response
during the fourth phase of decay during HAART [18, which is detectable in the CSF of some HIV-infected
40]. An important caveat in the interpretation of these individuals, although, in many, HIV-1 infection of the
studies is that they assume that the properties of the CNS is not clinically apparent [48]. In a subset of pa-
bulk proviral DNA are representative of the small tients during the late stages of disease, HIV-1 infec-
4 ª 2011 The Association for the Publication of the Journal of Internal Medicine Journal of Internal MedicineS. Palmer et al.
| Symposium: HIV reservoirs and HIV infection
tion of the CNS evolves to encephalitis and dementia. delve into mechanisms of latency have, for the most
In addition, opportunistic infections of the CNS in- part, been confined to cells infected and manipulated
crease during late stage HIV infection. Recent studies ex vivo.
suggest the CNS is a viral sanctuary site, as the HIV
genetic populations in plasma and CSF are nearly As the chromatin environment influences the expres-
identical during primary infection but as the disease sion of HIV, mechanisms which promote HIV latency
progresses, these populations diverge [49, 50]. More- in infected CD4+ T-cells include histone and DNA
over, patients with HIV-associated dementia have the modification in the viral long terminal repeat (LTR).
most divergent HIV populations between plasma and The recruitment of cellular histone deacetylases
CSF. The advent of HAART has reduced the levels of (HDACs) and CpG (CG-rich DNA) methylation, which
HIV RNA in the CSF and the incidence of dementia in closes the LTR chromatin structure, prevent HIV
HIV-infected patients has also greatly decreased [51, transcription and expression [60, 61]. The extent of
52]. However, many drugs have suboptimal penetra- DNA methylation has been studied in infected indi-
tion of the CNS owing to restrictions of these drugs in viduals and more hypermethylation was found in pa-
crossing the blood-brain and blood-CSF barriers tients with 50 copies mL)1, and a recent study
drugs allows the continual viral replication during demonstrated that CpG methylation is greater in la-
HAART not only resulting in HIV drug resistance but tently infected than in productively infected primary
is also the development of HIV-associated cognitive human T- cells [62]. Although CpG methylation once
impairments. It is unknown whether this persistent established is perhaps the major factor suppressing
virus in the CNS is contributing to the persistent vire- transcription of much of the genome, its establish-
mia found in plasma of patients on suppressive ther- ment may depend on other factors which block gene
apy, although the genetic similarity of both the persis- expression in the first place. Thus, in the case of HIV,
tent virus population and the virus that appears this modification is secondary to some other suppres-
following discontinuation of therapy to the prethera- sive mechanism, such as lack of an appropriate acti-
py plasma virus argues against this possibility. In vator. Furthermore, it is unclear whether reactivation
addition, a recent treatment intensification study re- of hypermethylated proviruses is a feasible mecha-
vealed no decreases in plasma or CSF HIV RNA levels nism to explain persistent viremia.
or changes in soluble inflammatory markers such as
neopterin [54]. These results suggest that persistent Several host transcription factors are maintained at
viremia may arise from sources other than the CNS low levels in resting CD4+ T-cells including nuclear
compartment. factor kappa B (NF-kB), nuclear factor of activated
T-cells (NFAT) and positive elongation factor b (P-
In untreated patients, there is compartmentalization TEFb). The up-regulation of these host factors may
of virus between genital secretions and plasma [55, activate latently HIV-infected cells and increase HIV
56]. During HAART, HIV can be found in the semen, expression. In addition, low concentrations or im-
both as free virus and integrated DNA [57]. Interest- paired activity of the viral activator protein Tat and
ingly, HIV has also been found in renal epithelium low levels of the cellular protein PTB, which causes
[58]. It remains to be determined to what extent a post-transcriptional block and degradation or
GALT, CNS and the genitourinary tract contributes to translational suppression of viral mRNA, have been
the production of virions and the persistence of HIV shown to be important mechanisms of HIV latency.
during HAART. (Reviewed in [63]).
The site of viral integration into the host genome can
Mechanism of HIV latency
affect the transcription rate of HIV. The integration of
The best-defined HIV reservoir is a small pool of la- HIV proviruses has been found to occur in both inac-
tently infected resting memory CD4+ T-cells carrying tively and actively transcribed genes [64, 65]. The
an integrated form of the viral genome [59]. The pre- reduction of viral transcription in actively transcribed
cise molecular mechanisms contributing to the gen- gene regions of resting memory CD4+ T-cells may be
eration and maintenance of this reservoir, however, owing to transcriptional interference [66]. Transcrip-
remain to be elucidated. As noted before, the scarcity tional interference takes place when cellular tran-
of such cells, even amongst those carrying integrated scripts initiated outside the integration site of HIV
HIV DNA, makes it virtually impossible to identify, read through the HIV genome and disrupt the tran-
isolate and study them directly. Therefore, studies to scription of HIV by displacing the viral transcription
ª 2011 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 5S. Palmer et al.
| Symposium: HIV reservoirs and HIV infection
factors assembled at the HIV promoter causing a de- Strategies for purging the latent HIV reservoir
crease in HIV expression.
The mechanisms behind HIV latency are extremely
complex; and to efficiently eliminate the viral reser-
Owing to difficulties in using primary human T-cells
voir, many different strategies have to be explored.
for investigation of HIV latency, most studies to date
Reactivation of these latently infected cells which
have utilized infected cell lines for modelling viral la-
would eliminate the HIV-infected cell either by viral
tency [65, 67, 68]. Studies based on these cell lines
cytopathic effect or natural immune response in com-
have revealed many important mechanisms of HIV la-
bination with antiretroviral therapy to prevent new
tency but an infected cell line may not truly reflect the
infections is currently considered the best strategy,
latent state in vivo. Therefore, new ex vivo models
but not the only, for eradication of HIV.
based on primary human CD4+ T-cells have been
developed by several researchers and most of these
Earlier studies have shown a nonspecific activation
promising ex vivo latency models use human primary
of resting memory T-cells and an increase in HIV
CD4+ T-cells infected with HIV [62, 69–72]. These
replication by CD3 monoclonal antibodies or by
new models have allowed for detailed studies of the
combination of cytokines TNF-a, IL-2 and IL-6 [34,
signalling pathways which can reactivate latent HIV.
35]. In addition, the cytokine IL-7 has been shown
They underline the importance of NFAT, the tyrosine
to reactivate HIV primary human T-cells and thy-
kinase Lck and cellular transcription factor binding
mocytes in vitro and is well tolerated in HIV-infected
sites such as Sp1 and kB ⁄ NFAT for optimal reactiva-
patients [76–79]. Patients infected with HIV are cur-
tion of latent HIV in memory CD4+ T-cells. In addi-
rently receiving IL-7 as part of an ongoing clinical
tion, these relatively new ex vivo models revealed that
trial to determine if IL-7 reduces their latent HIV
HIV was not reactivated after incubation with com-
reservoir (ERAMUNE, http://www.clinicaltrials.
pounds such as the HDAC inhibitor valproic acid; the
gov). The outcomes of this trial could help in the
NF-kB activating agent prostratin; PMA; and TNF-a.
development of new and important therapies for
These compounds had previously been shown to
HIV eradication. Upregulating cellular transcription
reactivate HIV in cell line-based models [70]. These
to induce HIV gene expression has been proposed
discrepancies further stress the importance of using
as another strategy for reducing latent HIV reser-
ex vivo models instead of models based on infected
voirs. This includes inhibiting class I HDACs be-
cell lines. Moreover, these ex vivo models did demon-
cause these HDACs promote latency by regulating
strate the importance of heterochromatic structures
genome structure and transcriptional activity. A re-
owing to histone deacetylation and DNA methylation
cent report has shown that synthetic class I HDAC
for promoting HIV latency.
inhibitors can reactivate latent HIV in a Jurkat cell
model of latency and in resting CD4+ T-cells iso-
A recent study revealed that HIV integration can hap-
lated from patients better than class II HDAC inhib-
pen in both active and resting primary human T-cells
itors by inducing LTR expression [67]. However, the
and that in both cell types, integration was favoured
coadministration of the HDAC inhibitor, valproic
in active transcription units [73]. A modest difference
acid and HAART gave mixed results [80, 81].
between resting and active cells was found and inte-
gration into actively transcribing genes was reduced
Similar to multiple-drug HIV therapy which interferes
in resting cells. The finding that latency can be estab-
with different stages in the viral life cycle, antilatency
lished in resting T-cells conflicts with commonly held
compounds have been combined to purge and reacti-
beliefs that HIV latency is established only in acti-
vate latent HIV. A recent study revealed that in
vated T-cells. Additional studies are needed to inves-
patients on suppressive therapy (HIV RNA < 50 cop-
tigate the contribution of resting T-cells to persistent
ies mL)1), a combination of prostratin with either
viremia.
valproic acid (long approved – at low doses – for the
treatment of epilepsy) or suberoylanilide hydroxamic
In addition, the role of myeloid cells in maintaining
acid (SAHA) (a recently approved HDAC inhibitor for
the latent reservoir should be investigated as it is gen-
clinical use as cancer therapy) was more efficient
erally assumed that HIV persists in both lymphoid
than each compound alone in reactivating latent HIV
and myeloid cells [74, 75]. For example, activated
in CD8 depleted PBMCs [82]. Synergistic reactivation
macrophages residing within tissues interact with
of latent HIV was also achieved by combining HDAC
CD4+ T-cells via cell-to-cell contact, and via release of
inhibitors and NF-kB activating agents [83]. This
inflammatory and regulatory cytokines. These inter-
study demonstrated that in PBMCs and Jurkat-cell-
actions may contribute to HIV persistence.
6 ª 2011 The Association for the Publication of the Journal of Internal Medicine Journal of Internal MedicineS. Palmer et al.
| Symposium: HIV reservoirs and HIV infection
based systems, a combination of SAHA and prostrat- HAART making this an attractive macaque model
in synergistically reactivates latent HIV. This SAHA for studying HIV latency [89, 90]. However, the
and prostratin combination targeted a wide range of macaque model has two major disadvantages:
latent integration sites, acted effectively against viral (i) rhesus macaques are expensive as they have to
variants that have acquired mutations in their pro- be maintained on therapy for a long time for studies
moter regions and functioned across five different of viral persistence, and (ii) there are important ge-
HIV-1 subtypes. These results emphasize the possi- netic differences between SIV and HIV. Therefore, a
bilities of using combination antilatency therapy and ‘humanized’ bone marrow ⁄ liver ⁄ thymus mouse
may explain earlier disappointing results from a clini- model populated with both human B- and T-cells
cal trial using valproic acid alone to treat patients on that can be infected with HIV is an interesting alter-
suppressive HAART [80]. Moreover, SAHA by itself native animal model for researching viral reservoirs
reactivated latent HIV in cell lines and CD4+ T-cells and compounds that purge these reservoirs [91].
isolated from patients on suppressive HAART. SAHA
is approved by the US Food and Drug Administration
Clinical approaches to HIV eradication
for clinical use, making it a promising candidate for
future clinical trials [84, 85]. Currently there are The observation that an increase in viral RNA was
large-scale screening efforts ongoing to find novel measured in HIV-infected individuals treated with
compounds to reactivate latent HIV using latently intravenous immunoglobulin (IVIGs) for Guillan-
HIV-1-infected reporter cell lines that allow for high Barrés syndrome resulted in a study of the possible
throughput drug screening [86]. In addition, resting use of IVIGs to eradicate HIV [92]. The administra-
memory CD4+ T-cells from patients on suppressive tion of high dosage of IVIGs to patients on HAART
HIV therapy are being used to screen potential reacti- decreased the latent reservoir, as measured by a
vating agents [67]. decrease in quantifiable HIV in resting memory
CD4+ T-cells, in about half of the patients revealing
NF-kB inducing agents such as prostratin have how bedside observations may point the way to
shown promise in reactivating HIV from latently in- new important anti-latency therapies. It is assumed
fected cells. However, NF-kB promotes global T-cell the mechanism for how IVIGs decrease the latent
activation running the risk of systemic inflammatory reservoir in HIV patients is related to the effects of
response in patients. Recently, two transcription fac- IVIGs have on the activation, differentiation and
tors Ets-1 and VII-Ets-I have been found which reac- effector functions of dendritic cells, and T- and
tivate latent HIV in a NF-kb-independent manner B-cells [93].
[87]. In addition, a compound, 5-hydroxynaphtha-
lene-1,4-dione (5HN), has been found which reacti- Also of note is the interesting case of a HIV-infected
vates latent HIV without causing global T-cell activa- patient in Germany, apparently now cured of the
tion[72]. In a related study, a protein secreted by the disease following a stem cell transplant from a
nonpathogenic bacterium, Massilia timonae, called donor, homozygous for the CCR5D32 mutation,
HIV-1-reactivating factor, efficiently reactivated which prevents expression of this HIV-1 coreceptor.
latent HIV-1 infection by producing a strong but short Despite receiving no antiretroviral therapy in the
burst of NF-jB activity. This NF-jB activity was suffi- 3.5 years since receiving the transplant, this pa-
cient to trigger initial HIV-1 Tat production, which tient has experienced no viral rebound [94]. Such
then induced HIV-1 expression [88]. procedures are not presently a viable solution for
tens of millions of HIV-infected individuals world-
To further elucidate where HIV persists during ther- wide. Nevertheless, it is an intriguing and promis-
apy and to test compounds for the eradication of ing result which informs efforts to develop a cure
HIV, an appropriate animal model is necessary. Ide- for HIV infection.
ally, this model should show similar patterns of viral
decay and CD4+ T-cell increase during therapy as The CCR5D32 phenotype is being replicated in HIV-
HIV-infected humans starting HAART. The therapy infected individuals through the use of gene modifi-
used in the animal model should also simulate HA- cation. The expression of the CCR5 coreceptor is
ART. A recent study revealed that SIV-infected ma- eliminated from CD4+ T-cells and hematopoietic
caques treated with a combination of four antiretro- stem or progenitor cells (HSC) by zinc-finger nucleas-
viral drugs revealed a similar pattern of viral decay es (ZFNs) which permanently disrupt the CCR5
and reduced frequencies of circulating resting CD4+ open-reading frame [95, 96]. The use of adenovirus
T-cells similar to HIV-infected humans starting vectors to deliver these CCR5-targeted ZFNs to pri-
ª 2011 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 7S. Palmer et al.
| Symposium: HIV reservoirs and HIV infection
mary human CD4+ T-cells resulted in HIV-resistant Conclusion
primary CD4+ T-cells that expanded stably in cul-
Under the most effective current antiretroviral ther-
ture [96]. The transplantation of these cells into
apy, HIV infection is well suppressed but not eradi-
immunodeficient mice and subsequent challenge
cated. During combination antiretroviral therapy,
with CCR5-tropic HIV-1 resulted in a statistically
reduction of HIV RNA levels to less than 50 cop-
significant reduction in plasma viral RNA in the mice
ies mL)1 is frequently achieved; however, ultrasensi-
receiving the ZFN-modified T-cells compared to the
tive assays detect the persistence of viremia in
mice which did not receive these cells. Additional
approximately 80% of patients on suppressive
studies of immunodeficient mice transplanted with
HAART for periods exceeding 7 years. The source
ZFN-modified HSC revealed that 6 weeks after infec-
and dynamics of this persistent viremia are currently
tion with a CCR5-tropic HIV-1, viral loads decreased
under investigation. The important conclusion that
and their transplanted human CD4+ T-cells in-
emerged from this work is that antiviral strategies
creased to preinfection levels. In fact, HIV-1 could
alone will never be adequate to eliminate HIV infec-
not be detected by PCR quantification 10–12 weeks
tion; to accomplish this goal, we must address HIV
postinfection at necropsy. In addition, the levels of
latency and its implications. A well-defined latent
CCR5-negative human cells had expanded indicat-
reservoir of HIV is resting memory CD4+ T-cells,
ing a selective advantage for these cells [95]. These
which might be infected directly at low frequency, or
CCR5-modified T-cells remain susceptible to
arise when an activated CD4+ T-cell becomes
CXCR4-tropic strains of HIV-1 and, therefore, phe-
infected by HIV, but transitions to a terminally differ-
nocopy the HIV-1 resistance in patients with the nat-
entiated memory T-cell before HIV infection elimi-
urally occurring CCR5D32 allele. Based on the
nates the cell. However, other cell types such as
positive results from these preclinical studies, the
hematopoietic stem cells or cells of the mono-
therapeutic value of CCR5-knockout T-cells is being
cyte ⁄ macrophage linage may also contribute to the
evaluated in a phase 1 clinical trial. Three different
latent reservoir. A number of mechanisms, such as
patient cohorts are being enrolled in this trial:
the chromatin environment, the viral integration
patients infected with multidrug resistant virus; pa-
site, down-regulated transcription factors, impaired
tients with controlled viral infection who have normal
activity of Tat and suppression of viral mRNA leading
CD4+ T-cell levels; and patients infected with drug-
to reduced viral protein translation, have been
sensitive virus but who have low CD4+ T-cell levels
shown to play a role in maintaining HIV latency.
(ClinicalTrials.govNCT00842634). CD4+ T-cells
Whilst further research is needed, recent studies
from these patients will be exposed to CCR5-targeted
have introduced new insights into the mechanisms
ZFNs ex vivo. The resulting CCR5-knockout cells will
of latency and persistent HIV reservoirs. Consider-
be expanded for 10 days and then transferred to the
able effort is now underway to apply the findings of
patient. The overall aim of this trial is to replicate the
these mechanistic studies to the clinical problem.
CCR5D32 phenotype in HIV-infected individuals and
The problem of HIV remission and ⁄ or eradication
it will be completed in 2011.
from an infected patient is an extremely difficult one,
but well worth the effort.
Obviously, caution in approaching therapies that
meddle with control of immune activation is war-
ranted. The very nature of the virus-host relation- Conflict of interest statement
ship means that seeking to purge the latent HIV res-
No conflict of interest was declared.
ervoir runs the risk of triggering a systemic patient
immune reaction. In addition, any future clinical ap-
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