immune reconstitution under anti retro viral therapy - the new challenge in hiv-1 infection
TRANSCRIPT
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Immune reconstitution under antiretroviral therapy:
the new challenge in HIV-1 infection
Pierre Corbeau1,2,3
and Jacques Reynes3,4,5
1Unit Fonctionnelle d'Immunologie, CHU de Nmes, 2Institut de Gntique Humaine, CNRS
UPR1142, Montpellier,3Universit Montpellier I, 4Dpartement des Maladies Infectieuses et
Tropicales, CHU de Montpellier,5UMI 233, Montpellier, France
Running head: Immunologic response to antiretroviral therapy
Blood First Edition Paper, prepublished online March 14, 2011; DOI 10.1182/blood-2010-12-322453
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Abstract
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 due to residual HIV production, microbial translocation, co-
infections, immunosenescence or lymphopenia per se. A second mechanism is ongoing HIV
replication. Finally, deficient thymus output, gender and genetic polymorphism influencing
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.
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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 , i.e. have viral RNA plasma levels under the level of detection of commercially
available tests1. Consequently, most of these patients reconstitute their immunity under
treatment. Yet, in some patients CD4+ T cell recovery is abnormally low in spite of their full
virologic response to HAART. An impaired immunologic response is linked to increased risk
of disease progression and death2-6
, but we currently have no efficient therapeutic strategy in
these situations. It is therefore becoming more and more important to understand the
pathophysiological mechanisms responsible for this lack of immune reconstitution, to design
assays capable of diagnosing these mechanisms, and to propose therapies adaptated 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 1 to 6 first 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
weeks11
. Most of this initial reconstitution seems to be the consequence of a redistribution of
memory CD4+ T cells12
from the lymphoid tissues towards the blood compartment. The
decrease in immune activation induced by the inhibition of viral replication results in a
downregulation of adhesion molecules at the surface of CD4+ T cells, including vascular cell
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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 years10,12,14-16
. Various mechanisms
account for the rise in mostly naive CD4+ T cells12,17
during these two 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 impaired18
. From a qualitative point of view, these three mechanisms of
reconstitution are not equivalent. A healthy individual harbours a pannel 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 mainly stems from CD4+ T cell proliferation and survival, the T-
cell repertoire will remain truncated, eventhough 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 non immunologic responders patients
whose CD4+ T cell count remained below a threshold (e.g., 350 to 500 cells/l) after a
variable period of time of treatment (e.g., 4 to 7 years). For instance, Kelley et al. showed that
24% of individuals with a CD4+ T cell count
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Because of the so far lack of consensus on this definition, and because of the variability of the
patients 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 incompletly reconstituted after one year of effective antiretroviral therapy24
. Thus, by
routinely monitoring only CD4+ T cell count, we not only overlook 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 over 450 CD4+ T
cells/l25
emphasizes this notion that CD4 count is an imperfect surrogate marker of immune
restoration. The failure of IL-2 therapy to protect from disease progression in spite of 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
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and/or genetically determined increase in the programmed cell death of lymphocytes (figure
3).
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 lymphocytes27-31
. 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 tissue32
. Freshly matured T cells, also called recent thymus emigrants
(RTE), are characterized by the fact that they harbour 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 that is a by-product of the rearrangement, called TCR excision
circle (TREC). TREC have been therefore used as a surrogate marker of thymus output,
although cell division may dilute their content. Some27,33
, but not all31
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
declined35
, are at higher risk of persistently reduced CD4+ T cell count during HAART than
younger ones 5,36,37.
Another factor that may hinder thymocyte production is HIV-1 infection per se, as it impairs
haematopietic stem cell metabolism38
and thymic function39
. As some of this impairment
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In final support of the importance of thymus output, polymorphisms in genes coding for the
cytokines interleukin (IL)-2, IL-15 and the receptor for IL-15, involved in the maturation and
development of T-cells, have been associated with non immunologic response to HAART40
.
Persistent viral replication
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 tissues43
. The question thus
arises as to whether these residual virions stem from reservoir cells that continuously release
non-infecting 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 authors41,43,44
, but not all45
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 LTR, a putative marker of recent infection,
has been evidenced in virologic responders46
. 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. These results indicate that some of
these cells had pre-integrated forms of viral genome i.e. had been recently infected47
.
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HIV-1 viremia in virologic responders argue against the hypothesis of ongoing replication49-
51. Finally, the finding that monocytes from subjects aviremic under HAART may harbour
HIV proviral DNA52
is an additional argument for ongoing replication since 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 coreceptor31
, and this could hamper the reconstitution of the CD4+ T cell count.
Moreover, Doitsh et al. have recently shown that HIV replicative cycle does not need to be
complete to induce CD4+ T cell death53
.
Immune activation
Many authors have linked immune activation to impaired rise in peripheral blood CD4+ T
cell count under treatment28-30,54-56
. This link may have at least two causes. On one hand, as
above-discussed, 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 below, 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 due to the anti-
HIV immune response and to the fact that various HIV components are able to stimulate the
57
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activation. In line with this, HAART intensification has been reported to decrease immune
activation in some patients60
.
Age
Older persons have a higher background of immune activation than younger ones61
. 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 cells62
, it could be involved in immune
activation and thereby in the rise in CD4 count. This could explain why the administration of
a CCR5 antagonist resulted in a decrease in T cell activation63,64
. Accordingly, a high
efficiency of CCR5-induced activation, as a consequence of genetic polymorphism65
or of a
high CD4+ T cell-surface CCR5 density (personal data) may favour the persistence of
immune activation under HAART. In support of this notion, Ahujas 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
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polymorphisms in genes encoding the cytokines IL-6, tumour 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 spontaneous27
, Fas-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 as TRAIL40
, Bim40
, Fas
76, and FasL
76have been linked to the rise in CD4+ T cell count through therapy.
Gender
Men have been reported to be at higher risk of non CD4+ T cell response under HAART than
women28,37
. The reasons for that are unclear. One explanation might be that thymic output is
higher in females than in males35
. Another one could be an anti-apoptotic effect of female sex
steroids on CD4+ T cells as observed for instance on neutrophils77
. Moreover, the level of
expression of CCR5 at the surface of CD4+ T cells, linked to CD4+ T cell recovery66
as
above-mentioned, is lower in women than in men78
.
Other genes
Genetic polymorphisms in the genes coding for the CXCR4-binding chemokine CXCL12 or
SDF-179
, for the chemokine receptor CX3CR179
, and in genes located in the major
histocompatibility complex75,80
have also been linked to treatment-induced CD4+ T cell
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Some antiretroviral agents such as AZT may be toxic for haematopoietic progenitor cells81
,
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 differenciation82
.
On the contrary, a better immunologic response has initially been reported with protease
inhibitor83
. Yet, other studies have shown that CD4+ T cell gain was independent of the
antiretroviral regimen28,84
. 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 as compared with efavirenz85
. The same result was reported at week 48 for the CCR5
antagonist maraviroc, that persisted at week 9686
.
CD4+ T cell nadir
Low nadir CD4+ T cell count36,54,87
and low pre-therapeutic CD4 count37,88
have been
identified as predictive factors of persistently reduced CD4+ T cell count. Obviously, if the
definition of immune response is exclusively based 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 pre-therapeutic CD4 count may cause
emergence of X4 strains89
, intense microbial translocation55
, development of co-infections
and immunosenescence, all factors hindering CD4+ T cell regeneration as discussed above.
HIV RNA plasma level
CD4+ T cell response has been reported to be low when the pre-therapeutic viremia is low28
.
The reasons for this correlation remain to be unveiled.
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marker of recent infection, is also not a routine assay47
. Other strategies need to be tested,
such as, for instance, the detection of HIV DNA in peripheral blood monocytes52
.
Immune activation
The marker of immune activation that is the best predictor of disease progression might be the
percentage of CD8+ T cells that overexpress CD3892
. 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 techniques41
. Alternatively, the
quantification of unspliced HIV RNA in PBMC might be used to track persistent synthesis of
viral particles93
. Active co-infection may be diagnosed by assays that are specific for the
various infectious agents participating in the residual immune activation. High level 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 density66
. Finally,
microbial translocation has been initially measured by quantifying lipopolysaccharides (LPS)
plasma level 94, but the quantification of bacterial ribosomal 16S RNA DNA (16S rDNA)
plasma level is more sensitive, more specific and more comprehensive74
.
Therapeutic possibilities
According to the etiology, various therapies may be considered (table 1).
Insufficient thymic activity
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HAART-treated subjects96
. The limitations might be that lymphopenic patients already
produce high amounts of IL-7, and a potential drawback is that by inducing CXCR4
expression, IL-7 might favour the emergence of X4 strains97
. IL-15 has also been considered
to boost immune recovery98
.
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 in order to boost thymic activity in animals99
.
Accordingly, in humans the administration of luteinizing hormone-releasing hormone
(LHRH) agonist has resulted in transient enhancement of thymic function100
, particularly
after hematopoietic stem cell transplantation101
. 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 the keratinocyte growth factor (KGF). In mice, KGF administration reverses age-
induced thymic and T cell dysfunction102
. 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 1103
. GH treatment has been shown to
improve thymic function in HIV-1-infected subjects104
. Yet, here again the risk of adverse
events, as carpal tunnel syndrome, hyperglycemia or cancer progression will have to be
carefully considered.
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payed to ensuring that the chosen therapeutic agents reach inhibiting concentrations in the
organs where this replication persits.
Immune activation
Two strategies may be adopted : on one hand, a symptomatic therapy aiming at reducing the
global level of polyclonal immune activation, and on the other hand, etiologic therapies
targetting 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, IL-10, anti-TNF agents, cyclosporin A,
FK506, and rapamycin105
. 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 trended to achieve
significance63
in non-immunologic responders. Thus, agents targeting CCR5 could have an
immunological 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 eventhough these virions do not cause de novo infection.
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chromatin, intravenous immunoglobulin injection and microRNA manipulation have been
proposed100-108
.
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 HAART68
. In the same way, 8
weeks of treatment with valganciclovir of CMV-seropositive HIV-infected patients with
CD4+ T cell counts
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Conclusion
Various mechanisms may be responsible in a given patient for an impaired immune recovery
under HAART in spite of a control of viral replication. In order to correctly address this issue
we need to design convenient tools to identify which ones of these mechanisms are at work in
each non immunologic responder. Based on this personnalized 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.
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Authorship
Conflicts of interest : PC has received honoraria for lectures or advisory boards from Bristol-
Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Pfizer 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, BMS, Boehringer Ingelheim, Gilead, GSK, Merck,
Pfizer, Roche, Schering-Plough, Tibotec.
P.C. wrote the manuscript; J.R. reviewed and edited it.
Correspondence: Pierre Corbeau, Laboratoire d'Immunologie, Hpital Saint Eloi, 80 avenue A.
Fliche, 34295, Montpellier cedex 5, tel : +33 467 33 71 35, fax: +33 467 33 71 29, e-mail address:
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Etiology Marker Treatment
Insufficient thymus activity
Naive T / memory T
Sj/TREC% CD31+ T cells
IL-7, IL-15
GH, KGFLHRH agonist
Immune
activation
Residual HIV
Production
Plasma viral load
Intracellular HIV RNA
Immunomodulator ?
CCR5 antagonist ?
Reservoir eradication
Bacterial
translocation
LPS plasma level16S rDNA plasma level
HAART intensificationProbiotics
Co-infection Specific diagnosis Specific treatment
CCR5
genetics
Genotyping CCR5 antagonist
Ongoing HIV replication
2-LTR
HIV sequence diversification
Intramonocytic HIV DNAPreintegrated HIV DNA
HAART intensification
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Legends to figures
Figure 1 : Average CD4+ 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.
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.
Figure 3 : Causes of impaired CD4+ T cell recovery under HAART.
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1-6 months 2 years 4 years
+20-30/month
+5-10/month
+2-5/month
+300-350
cells+200-250
cells
TimeCD4+
T
cell
count
Lymph
nodes Blood
Blood
Thymus
Cell division Lifespan increase
Figure 1
Thymus
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Thymus
W Y
W Y
W Y
W Y
HIVinfection
Figure 2
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Ongoing HIV
replication
Gender
Co-infection
Bim, Fas,
FasL, TRAIL
Bacterialtranslocation
Immune
activation
Bone marrow/thymus
output
HIV pathogenesis
Residual HIV
production
Genetics
CCR5
CCL3L1
IL-15, IL-15R
IL2
X4
TNFIL-6
Lymphopenia
Figure 3
Senescence
HAART