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Review article
Immune reconstitution under antiretroviral therapy: the new challenge
in HIV-1 infection
Pierre Corbeau1-3 and Jacques Reynes3-5
1Unité
Fonctionnelle d’Immunologie, CHU de Nîmes, Nîmes, France; 2Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France; 3Université
Montpellier I, Montpellier, France; 4Département des Maladies Infectieuses et Tropicales, CHU de Montpellier, Montpellier, France; and 5UMI 233, Montpellier,
France
Although highly active antiretroviral
therapy has enabled constant progress in
reducing HIV-1 replication, in some patients who are “aviremic” during treatment, the problem of insufficient immune
restoration remains, and this exposes
them to the risk of immune deficiency–
associated pathologies. Various mechanisms may combine and account for this
impaired immunologic response to treatment. A first possible mechanism is immune activation, which may be because
of residual HIV production, microbial
translocation, co-infections, immunosenescence, or lymphopenia per se. A
second mechanism is ongoing HIV replication. Finally, deficient thymus output,
sex, and genetic polymorphism influenc-
ing apoptosis may impair immune reconstitution. In this review we will discuss
the tools at our disposal to identify the
various mechanisms at work in a given
patient and the specific therapeutic strategies we could propose based on this
etiologic diagnosis. (Blood. 2011;117(21):
5582-5590)
Introduction
Highly active antiretroviral therapy (HAART) is increasingly
efficient at reducing HIV-1 load. Currently, even with salvage
therapy, up to 90% of treated HIV-1–infected adults are “aviremic,”
that is, have viral RNA plasma levels under the level of detection of
commercially available tests.1 Consequently, most of these patients
reconstitute their immunity under treatment. Yet, in some patients,
CD4⫹ T-cell recovery is abnormally low despite their full virologic
response to HAART. An impaired immunologic response is linked
to increased risk of disease progression and death,2-6 but we
currently have no efficient therapeutic strategy in these situations.
It is therefore becoming more and more important to understand the
pathophysiologic mechanisms responsible for this lack of immune
reconstitution, to design assays capable of diagnosing these
mechanisms, and to propose therapies adapted to each situation.
Immunologic responses to HAART: both
quality and quantity matter
Peripheral CD4⫹ T-cell increase under treatment is a 3-phase
process, whatever the regimen is (Figure 1). During the first 1 to
6 months of HAART, the average rate of reconstitution is of 20 to
30 cells/␮L monthly.7-10 Bosch et al have estimated this first phase
to last for exactly 10 weeks.11 Most of this initial reconstitution
seems to be the consequence of a redistribution of memory CD4⫹
T cells12 from the lymphoid tissues toward the blood compartment.
The decrease in immune activation induced by the inhibition of
viral replication results in a down-regulation of adhesion molecules
at the surface of CD4⫹ T cells, including vascular cell adhesion
molecule-1 (VCAM-1) and intercellular adhesion molecule-1
(ICAM-1). As these adhesion molecules are responsible for the
trapping of CD4⫹ T cells into the secondary lymphoid organs, their
Submitted December 5, 2010; accepted February 18, 2011. Prepublished
online as Blood First Edition paper, March 14, 2011; DOI 10.1182/blood-201012-322453.
5582
down-regulation provokes the release of these CD4⫹ T cells into
the periphery.13 The second phase of CD4⫹ T-cell increase, of about
5 to 10 cells/␮L monthly, lasts until the end of the second year of
therapy, and the third phase, of about 2 to 5 cells/␮L monthly,
extends beyond this second year for at least 7 years.10,12,14-16
Various mechanisms account for the rise in mostly naive CD4⫹
T cells12,17 during these 2 phases: first, de novo production of
T lymphocytes by the thymus; second, the homeostatic proliferation of the residual CD4⫹ T cells, and third, the extension of CD4⫹
T-cell half life, a mechanism responsible for sustaining the number
of naive CD4⫹ T cells in older individuals in whom thymic
production is impaired.18 From a qualitative point of view, these
3 mechanisms of reconstitution are not equivalent. A healthy
individual harbors a panel of T cells able to recognize a large set of
antigens, his T-cell repertoire. HIV-induced CD4⫹ T-cell loss
results in the shrinkage of this repertoire. If CD4⫹ T-cell recovery
under therapy is based on the production of new CD4⫹ T cells, this
repertoire may be at least partially restored. In contrast, if the
increase in CD4 count stems mainly from CD4⫹ T-cell proliferation and survival, the T-cell repertoire will remain truncated, even
though the total number of CD4⫹ T cells is normalized (Figure 2).
What is an impaired CD4⫹ T-cell restoration on HAART?
Unfortunately there is no consensus on the definition. Some authors
have called nonimmunologic responders patients whose CD4⫹
T-cell count remained below a threshold (eg, 350 to 500 cells/␮L)
after a variable period of time of treatment (eg, 4 to 7 years). For
instance, Kelley et al showed that 24% of individuals with a CD4⫹
T-cell count ⬍ 500 cells/␮L at year 4 of HAART had evidence of a
CD4⫹ T-cell count plateau between years 4 and 7.5.19 It seems
preferable to take into account the pretherapeutic CD4⫹ T-cell
count and to define nonimmunologic responders after their CD4⫹
T-cell slope. A reasonable definition could be a rise in CD4⫹ T-cell
© 2011 by The American Society of Hematology
BLOOD, 26 MAY 2011 䡠 VOLUME 117, NUMBER 21
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BLOOD, 26 MAY 2011 䡠 VOLUME 117, NUMBER 21
IMMUNOLOGIC RESPONSE TO ANTIRETROVIRAL THERAPY
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Figure 1. Average CD4ⴙ T-cell recovery under HAART. The increase in CD4⫹ T-cell count and the mechanisms responsible for this increase are represented at various time
points.
count lower than 100 cells/␮L after 2 years of treatment, that is,
less than half of the expected recovery.
Because of the thus far lack of consensus on this definition, and
because of the variability of the patient populations studied, the
estimation of the frequency of virologic responder only varied from
6% to 24%.3-5,12,14,19-23
Of note, not only CD4⫹ T-cell number and quality are impaired
in HIV infection, but many functions of many immune cells may be
impaired, and not fully recovered under HAART. For instance,
plasmacytoid dendritic cell and natural killer cell activities have
been reported to remain incompletely reconstituted after 1 year of
effective antiretroviral therapy.24 Thus, by routinely monitoring
only CD4⫹ T-cell count, we overlook not only CD4⫹ T-cell
functionality but also the functionality of the other immune cells.
The observation that in vivo immune response to immunization
may remain impaired in treated patients with more than 450 CD4⫹
T cells/␮L25 emphasizes this notion that CD4 count is an imperfect
surrogate marker of immune restoration. The failure of IL-2
Figure 2. T-cell repertoire reduction under HIV-1 infection, and reconstitution under HAART. The quality of the reconstitution is represented depending on the various
mechanisms accounting for the increase in CD4⫹ T-cell count.
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CORBEAU and REYNES
BLOOD, 26 MAY 2011 䡠 VOLUME 117, NUMBER 21
Figure 3. Causes of impaired CD4ⴙ T-cell recovery under HAART.
therapy to protect from disease progression despite a robust effect
on CD4 counts26 is in keeping with this idea. This means that we
will need to define better indicators, for instance, subpopulations of
CD4⫹ T cells, expression of specific CD4⫹ T-cell surface antigens,
in vitro functional assays, or in vivo tests to monitor immune
reconstitution.
The many determinants of impaired immune
reconstitution in virologic responders
The reason why the drastic reduction in viral load does not always
result in the normalization of the CD4⫹ T-cell count may be
multifactorial. It is of major importance to understand these various
factors at work if we want to establish an etiologic diagnosis and
propose an appropriate therapy. Two main mechanisms may result
in a suboptimal rise in CD4 count: insufficient production of CD4⫹
T cells and excessive CD4⫹ T-cell destruction. Excessive CD4⫹
T-cell destruction may be the consequence of HIV pathogenesis,
immune activation, and/or genetically determined increase in the
programmed cell death of lymphocytes (Figure 3).
that is a by-product of the rearrangement, called a TCR excision
circle (TREC). TRECs have been therefore used as a surrogate
marker of thymus output, although cell division may dilute their
content. Some,27,33 but not all,31 groups have reported low levels of
TRECs in T lymphocytes in subjects with low CD4⫹ T-cell
response. This might be the consequence of an impaired bone
marrow30 and/or thymic34 production. It could also account for the
frequent observation that older individuals, in whom thymic
activity has declined,35 are at higher risk for persistently reduced
CD4⫹ T-cell count during HAART than younger persons.5,36,37
Another factor that may hinder thymocyte production is HIV-1
infection per se, as it impairs hematopoietic stem cell metabolism38
and thymic function.39 As some of this impairment may be partially
irreversible, T-cell maturation may remain suboptimal in some
patients even though the viral replication is inhibited.
In final support of the importance of thymus output, polymorphisms in genes coding for the cytokines IL-2 and IL-15 and the
receptor for IL-15, involved in the maturation and development of
T-cells, have been associated with nonimmunologic response to
HAART.40
Persistent viral replication
Thymic output
The level of de novo T-cell production is a determining factor for
CD4⫹ T-cell recovery. Many studies have shown that poor CD4⫹
T-cell regeneration is linked to a low proportion of naive cells
among CD4⫹ T lymphocytes.27-31 Smith et al have reported a link
between the importance of the naive CD4⫹ T-cell gain during the
first 4 weeks of therapy and the abundance of thymic tissue.32
Freshly matured T cells, also called recent thymus emigrants
(RTEs), are characterized by their harboring a scar that is a
consequence of the rearrangement of the genes coding for the T-cell
receptor (TCR). This scar is an extra-chromosomic circular DNA
In aviremic patients under HAART, some cells may still produce
virions, so that ultra-sensitive techniques can detect HIV RNA
in the blood41,42 and in tissues.43 The question thus arises as to
whether these residual virions stem from reservoir cells that
continuously release noninfecting particles (residual production) or from recently infected cells that produce infectious
particles that permanently infect new cells (ongoing replication). Whereas most authors agree that residual production
persists in some patients, the possibility of ongoing replication
is controversial. Various observations argue for the existence of
ongoing replication. First, some authors,41,43,44 but not all,45
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BLOOD, 26 MAY 2011 䡠 VOLUME 117, NUMBER 21
have observed the diversification of HIV sequences in aviremic
patients, a phenomenon consecutive to mutations occurring
during reverse transcription and therefore necessitating viral life
cycles. Second, extra-chromosomic HIV DNA, including circular DNA containing 2 “long terminal repeat” sequences (LTR), a
putative marker of recent infection, has been evidenced in
virologic responders.46 Third, Petitjean et al have shown that
under in vitro activation, the production of virions by peripheral
blood CD4⫹ T cells from virologic responders may be prevented
by an integrase inhibitor.47 These results indicate that some of
these cells had preintegrated forms of viral genome, that is, had
been recently infected. Likewise, recent reports of an increase in
the amount of 2 LTR forms of HIV DNA in the peripheral blood
mononuclear cells (PBMCs) of aviremic patients under treatment intensification with integrase inhibitor48 are in line with
the same hypothesis. On the other hand, some others who
observed that treatment intensifications have not reduced residual HIV-1 viremia in virologic responders argue against the
hypothesis of ongoing replication.49-51 Finally, the finding that
monocytes from subjects aviremic under HAART may harbor
HIV proviral DNA52 is an additional argument for ongoing
replication because these cells transit very rapidly in the blood.
Thus, if ongoing replication occurs in some aviremic patients,
in lymphoid organs for instance, the cytopathogenicity of the virus
may still be at work, particularly if it uses CXCR4 as a coreceptor,31 and this could hamper the reconstitution of the CD4⫹ T-cell
count. Moreover, Doitsh et al have recently shown that the HIV
replicative cycle does not need to be complete to induce CD4⫹
T-cell death.53
Immune activation
Many authors have linked immune activation to impaired rise in
peripheral blood CD4⫹ T-cell count under treatment.28-30,54-56 This
link may have at least 2 causes. On one hand, as discussed above,
activated CD4⫹ T cells may be trapped in secondary lymphoid
organs. And on the other hand, most CD4⫹ T cells die by apoptosis
once they have been stimulated. Various phenomena, listed in the
following sections, may be responsible for immune activation in
the course of HIV-1 disease (Figure 3).
Residual viral production. Persistent production of viral
particles by reservoir cells in aviremic treated patients even in
absence of ongoing replication may induce an immune activation. This is because of the anti-HIV immune response and of
the fact that various HIV components are able to stimulate the
immune system. HIV RNA for instance induces immune cell
activation via TLR7,57 the gp120 envelope through the CD4
receptor and the coreceptors58 and the accessory protein nef
through lipid rafts.59 All the more so, any ongoing replication
should induce immune activation. In line with this, HAART
intensification has been reported to decrease immune activation
in some patients.60
Age. Older persons have a higher background of immune
activation than younger ones.61 This might contribute, in addition
to their reduced thymic output, to the link between age and
suboptimal CD4⫹ T-cell progression. From a general point of view,
immunosenescence might be a cause and a consequence of immune
activation, leading to a vicious circle.
High level of CCR5-induced activation. As the main HIV-1
coreceptor, C-C chemokine receptor type 5 (CCR5) is now
recognized as a co-activation molecule at the surface of CD4⫹
T cells,62 it could be involved in immune activation and thereby
in the rise in CD4 count. This could explain why the administra-
IMMUNOLOGIC RESPONSE TO ANTIRETROVIRAL THERAPY
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tion of a CCR5 antagonist resulted in a decrease in T-cell
activation.63,64 Accordingly, a high efficiency of CCR5-induced
activation, as a consequence of genetic polymorphism65 or of a
high CD4⫹ T-cell surface CCR5 density (P.C. and J.R., unpublished data, November 2010) may favor the persistence of
immune activation under HAART. In support of this notion,
Ahuja’s group has established a correlation between CD4⫹
T-cell recovery and the genetic polymorphism of the gene
encoding CCR5, and the number of copies of the gene encoding
one of the natural ligand of this coreceptor, C-C chemokine
ligand 3-like 1 (CCL3L1).65 In this study, the authors observed
that this polymorphism was predictive of the intensity of CD4
count increase in virologic responders. This raises the interesting hypothesis that CCR5, in addition to its virologic roles as an
HIV-1 coreceptor, might play a role in immune reconstitution.
This hypothesis is in line with the fact that CD4⫹ T-cell
restoration is linked to CD4⫹ T-cell surface CCR5 density.66
Co-infections. Another possible source of CD4⫹ T-cell stimulation comes from infectious agents other than HIV. Hepatitis C
virus (HCV) co-infection is known to result in a higher level of
immune activation.67 Most but not all authors have linked HCV
infection with incomplete CD4⫹ T-cell regeneration.68-70 Likewise,
cytomegalovirus has been identified as a cause of CD8⫹ T-cell
activation in HIV-infected subjects under HAART.71 Immune
activation might also explain why CD4⫹ T-cell restoration after
initiation of HAART is impaired in subjects who are co-infected
with Mycobacterium avium complex.72
Microbial translocation. It is now established that HIV-1
destroys the CD4⫹ T cells highly expressing CCR5 that are
abundantly present in the gut-associated lymphoid tissues (GALT)
early in the infection and that this destruction is partly irreversible,
even after years of HAART.73 One of the consequences of this
destruction is that the immune barrier becomes leaky, leaving the
way for microbia coming from the gut lumen to invade the
organism, a phenomenon called microbial translocation. Microbial
translocation has been linked to the proportion of CD8⫹ T cells
overexpressing CD38, and IFN␣ concentration in the blood.73
Therefore, microbial translocation might be one of the driver of
immune activation, and thereby of CD4⫹ T-cell loss. In keeping
with this notion, high levels of microbial translocation during
therapy have been linked to reduced increases in the CD4⫹ T-cell
count.74
Treg. Interestingly, a low level of regulatory T-cell activity,
which could account for immune activation, has been linked to
failure in CD4⫹ T-cell reconstitution.29 Yet the opposite observation has been also reported.54
Predisposition to immune activation. Genetics may predispose individuals to a high background of immune activation that
might be deleterious for immune response under HAART. In
keeping with this model, polymorphisms in genes encoding the
cytokines IL-6, tumor necrosis factor-␣ (TNF-␣), and interferon-␣
(IFN-␣)40 have been involved in HAART-induced CD4⫹ T-cell
count gain.75
Other genetic factors
Genes involved in apoptosis. Apoptosis is a form of cell death
responsible for CD4⫹ T-cell loss during HIV infection. The
intensity of spontaneous,27 Fas-induced,27 and HIV-induced54 ex
vivo apoptosis of CD4⫹ T cells has been inversely correlated with
CD4⫹ T-cell progression after HAART. Therefore, it is not
surprising that polymorphisms in genes involved in apoptosis such
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BLOOD, 26 MAY 2011 䡠 VOLUME 117, NUMBER 21
Table 1. Causes, markers, and therapeutic possibilities in absence of immune restoration under HAART
HAART indicates highly active antiretroviral therapy; TREC, T-cell receptor excision circle; GH, growth hormone; KGF, keratinocyte growth factor; LHRH, luteinizing
hormone-releasing hormone; LPS, lipopolysaccharide; and CCR5, C-C chemokine receptor type 5.
as TRAIL,40 Bim,40 Fas,76 and FasL76 have been linked to the rise in
CD4⫹ T-cell count through therapy.
Sex. Men have been reported to be at higher risk of non-CD4⫹
T-cell response under HAART than women.28,37 The reasons for
that are unclear. One explanation might be that thymic output is
higher in females than in males.35 Another could be an antiapoptotic effect of female sex steroids on CD4⫹ T cells as observed for
instance on neutrophils.77 Moreover, the level of expression of
CCR5 at the surface of CD4⫹ T cells, linked to CD4⫹ T-cell
recovery66 as mentioned in “Immune activation,” is lower in
women than in men.78
Other genes. Genetic polymorphisms in the genes coding for
the CXCR4-binding chemokine CXCL12 or SDF-1,79 for the
chemokine receptor CX3CR1,79 and in genes located in the major
histocompatibility complex75,80 have also been linked to treatmentinduced CD4⫹ T-cell restoration.
at week 48 for the CCR5 antagonist maraviroc, which persisted at
week 96.86
CD4ⴙ T-cell nadir. Low nadir CD4⫹ T-cell count36,54,87 and
low pretherapeutic CD4 count37,88 have been identified as predictive factors of persistently reduced CD4⫹ T-cell count. Obviously,
if the definition of immune response is based exclusively on the
CD4 count reached, rather than on the CD4 slope, the baseline CD4
count will definitely influence the level of immune response.
Moreover, low nadir CD4⫹ T-cell count and low pretherapeutic
CD4 count may cause emergence of X4 strains,89 intense microbial
translocation,55 development of co-infections, and immunosenescence, all factors hindering CD4⫹ T-cell regeneration as discussed
previously.
HIV RNA plasma level. CD4⫹ T-cell response has been
reported to be low when the pretherapeutic viremia is low.28 The
reasons for this correlation remain to be unveiled.
Other causes
HAART. Some antiretroviral agents such as AZT may be toxic for
hematopoietic progenitor cells,81 and could thereby hamper CD4⫹
T-cell count reconstitution. Likewise, the combination of tenofovir
with high doses of ddI has been involved in poor recovery of CD4⫹
T cells eventually induced by a deleterious effect of ddI on T-cell
maturation and differentiation.82 On the contrary, a better immunologic response has initially been reported with protease inhibitor.83
Yet other studies have shown that CD4⫹ T-cell gain was independent of the antiretroviral regimen.28,84 Recently, the integrase
inhibitor raltegravir has been shown to induce a greater increase in
CD4 count in treatment-naive patients at week 48 but not at
week 96 compared with efavirenz.85 The same result was reported
How to identify the causes of an impaired
CD4ⴙ T-cell recovery in a given individual?
Now that we have reviewed the potential causes of poor CD4⫹
T-cell progression, failure of thymic activity, ongoing viral replication, and residual immune activation, it is important from a
practical point of view to review the tools we have at our disposal
to identify the main causes at work in a given patient (Table 1).
Insufficient thymic activity
A weak synthesis of new T cells will result in a low naive
T-cell/memory T-cell ratio in peripheral blood. But, as other causes
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BLOOD, 26 MAY 2011 䡠 VOLUME 117, NUMBER 21
may have the same outcome, we need other tools to more
specifically evaluate thymic activity. Various TRECs may be
numerated, and the best indicator of thymic activity is the ratio
between two of them, the signal-junction (sj)TREC and the
␤TREC, because this ratio is not modified by cell proliferation.39
However, determining the sj/␤TREC ratio is not a routine assay,
and we need more convenient markers. One of them could be
CD31, as the CD31-expressing T-cell subpopulation contains the
RTEs.90
Ongoing viral replication
We also need to design routine assays to identify the potential
virologic responders in whom the virus still replicates. The
relevance of the 2-LTR HIV DNA circles as a marker of recent
infection is controversial, because the duration of their lifespan is
discussed.91 The analysis of molecular variance of HIV sequences
in patients who are aviremic under HAART as an indicator of
continuous reinfection is protracted and requires a follow-up.44 The
study of the effect of an integrase inhibitor on HIV-1 production
induced by ex vivo stimulation of CD4⫹ T cells from patients under
HAART to evidence the presence of unintegrated HIV DNA, a
marker of recent infection, is also not a routine assay.47 Other
strategies need to be tested, such as, for instance, the detection of
HIV DNA in peripheral blood monocytes.52
IMMUNOLOGIC RESPONSE TO ANTIRETROVIRAL THERAPY
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and a potential drawback is that by inducing CXCR4 expression,
IL-7 might favor the emergence of X4 strains.97 IL-15 has also been
considered to boost immune recovery.98
Another option might be to inhibit the production of sex
steroids. As estrogens, progesterone, and testosterone induce
thymic atrophy, probably mainly through their effect on thymic
stroma, castration has been tested with success to boost thymic
activity in animals.99 Accordingly, in humans the administration of
luteinizing hormone-releasing hormone (LHRH) agonist has resulted in transient enhancement of thymic function,100 particularly
after hematopoietic stem cell transplantation.101 Obviously, although chemical castration is temporary, the gain in thymic output
will have to be balanced with the side effects.
An alternative way to sustain thymic activity is to induce thymic
epithelial cell proliferation by using keratinocyte growth factor
(KGF). In mice, KGF administration reverses age-induced thymic
and T-cell dysfunction.102 The effect of KGF after hematopoietic
stem cell transplantation is currently being tested.
Finally, growth hormone (GH) is supposed to enhance hematopoiesis and immune function both directly and via insulin-like
growth factor 1.103 GH treatment has been shown to improve
thymic function in HIV-1–infected subjects.104 Yet, here again the
risk of adverse events, such as carpal tunnel syndrome, hyperglycemia, or cancer progression, will have to be carefully considered.
Immune activation
Ongoing viral replication
The marker of immune activation that is the best predictor of
disease progression might be the percentage of CD8⫹ T cells that
overexpress CD38.92 But we also need to discriminate between the
different causes of immune activation. Residual production of
virions may be detected by quantitating the viremia with ultrasensitive techniques.41 Alternatively, the quantification of unspliced HIV
RNA in PBMCs might be used to track persistent synthesis of viral
particles.93 Active co-infection may be diagnosed by assays that are
specific for the various infectious agents participating in the
residual immune activation. High levels of CCR5 activation could
be detected by genotyping the CCR5 gene and by determining the
CCL3L1 gene copy number65 or by measuring CD4⫹ T-cell surface
CCR5 density.66 Finally, microbial translocation has been initially
measured by quantifying lipopolysaccharide (LPS) plasma level,94
but the quantification of bacterial ribosomal 16S DNA (16S rDNA)
plasma level is more sensitive, more specific, and more
comprehensive.74
If there is evidence for continuous reinfection of target cells in
tissues, the challenge will be to intensify antiretroviral therapy with
the aim of stopping this process. Attention should be paid to
ensuring that the chosen therapeutic agents reach inhibiting concentrations in the organs where this replication persists.
Therapeutic possibilities
According to the etiology, various therapies may be considered
(Table 1).
Insufficient thymic activity
Several options for increasing CD4⫹ T-cell restoration might be
developed in the near future.
IL-7 is a good candidate because it promotes the maturation of
thymocytes, the survival and function of T cells, as well as the
homeostatic expansion of all T-cell subpopulations.95 A phase 1/2a
trial has recently shown that administration of IL-7 enhanced T-cell
recovery in HAART-treated subjects.96 The limitations might be
that lymphopenic patients already produce high amounts of IL-7,
Immune activation
Two strategies may be adopted: on one hand, a symptomatic
therapy aimed at reducing the global level of polyclonal immune
activation, and on the other hand, etiologic therapies targeting the
mechanisms responsible for this activation.
Symptomatic therapy. In the past, various attempts to downregulate the polyclonal immune activation observed in HIV-1–
infected patients have been made. These attempts included the use
of hydroxyurea, thalidomide, mycophenolate, corticosteroids, IL10, anti–TNF-␣ agents, cyclosporin A, FK506, and rapamycin.105
Most of these attempts have been disappointing. If CCR5 is
actually involved, as a co-activation molecule, into this immune
activation, CCR5 antagonists could exert some inhibitory effect on
it. Of note, HAART intensification with the CCR5 antagonist
maraviroc has resulted in a decrease in the proportion of activated
peripheral blood CD4⫹64 and CD8⫹63 T cells, and in an increase in
CD4⫹ T-cell slopes that tended to achieve significance63 in
nonimmunologic responders. Thus, agents targeting CCR5 could
have an immunologic effect, sparing CD4⫹ T cells in addition to
their antiviral effects.
Residual viral production. In this case, the way to stop
HIV-induced immune activation will be to get rid of the reservoir
cells that continue to release virions even though these virions do
not cause de novo infection. This goal is presently pursued by some
groups with different approaches including the brief induction of
viral overexpression with the aim of inducing a cytopathic effect.
For this purpose, cytokines as IL-2 or IL-7, activation of protein
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CORBEAU and REYNES
kinase C, agents remodeling the chromatin, intravenous immunoglobulin injection, and microRNA manipulation have been
proposed.100-108
Co-infections. If active co-infections reinforce the global
immune activation, the infectious agents responsible for these
co-infections might be targeted. Thus, therapeutic clearance of
HCV RNA in HIV/HCV co-infected adults has been shown by
some authors to decrease immune activation67 and to improve
immune reconstitution under HAART.68 In the same way, 8 weeks
of treatment with valganciclovir of CMV-seropositive HIVinfected patients with CD4⫹ T-cell counts ⬍ 350 cells/␮L after
more than 1 year of HAART resulted in a decrease in the
proportion of activated CD8⫹ T cells.109
Microbial translocation. The treatment of microbial translocation may be considered in at least 2 ways. First, if a persisting
viral replication in the GALT prevents the reconstitution of the
gut-associated immune barrier, intensification of HAART using
a regimen of drugs with an efficient gut tissue penetration may
be a solution. Second, therapeutic intervention, such as per os
administration of probiotics, aimed at modifying the commensal
microbiota to reduce the presence of proinflammatory bacteria
and to increase that of anti-inflammatory bacteria,110 might be
considered.
High level of CCR5 activation. If co-activation signals
delivered via CCR5 participate in the maintenance of a high level
of immune activation, the administration of CCR5 antagonists
might be beneficial.
Finally, the fact that some of the causes of incomplete immune
response we have reviewed might be prevented by HAART argues
for an early initiation of antiretroviral therapy.
Conclusions
Various mechanisms may be responsible in a given patient for an
impaired immune recovery under HAART despite a control of viral
replication. To correctly address this issue, we need to design convenient
tools to identify which of these mechanisms are at work in each
nonimmunologic responder. On the basis of this personalized etiologic
diagnosis we then will be able to propose specific therapeutic strategies.
Beyond the challenge of restoring immunity to prevent AIDS-associated
events, the measurement of immune hyperactivation, the identification
of the causes of this hyperactivation, and the fight against it will also
decrease the risk of non–AIDS-linked pathologies.
Authorship
Contribution: P.C. wrote the manuscript; and J.R. reviewed and
edited the manuscript.
Conflict-of-interest disclosure: P.C. has received honoraria for
lectures or advisory boards from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Pfizer, Gilead, and ViiV
Healthcare, and a research grant from Pfizer. J.R. has received
honoraria for lectures or advisory boards and/or research support
from Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead,
GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Pfizer, Roche,
Schering-Plough, and Tibotec.
Correspondence: Pierre Corbeau, Laboratoire d’Immunologie,
Hôpital Saint Eloi, 80 avenue A. Fliche, 34295, Montpellier cedex
5, France; e-mail: [email protected].
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2011 117: 5582-5590
doi:10.1182/blood-2010-12-322453 originally published
online March 14, 2011
Immune reconstitution under antiretroviral therapy: the new challenge in
HIV-1 infection
Pierre Corbeau and Jacques Reynes
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