REVIEW

CURRENT
OPINION Immune activation and immune aging
in HIV infection
Victor Appay a,b and Anthony D. Kelleher c,d

Purpose of review
The development of serious non-AIDS-related pathologies typically associated with aging, and the
premature immune aging that characterizes HIV-1-infected patients, even with suppressive antiretroviral
therapy, have raised increasing concerns in recent years. Deciphering the causes of these phenomena is
key for our understanding of HIV pathogenesis and for the clinical care of patients living with the virus.
Recent findings
An important basis for the immune parallels between HIV infection and aging lies in the exhaustion of the
lymphopoietic capacity of infected individuals, which eventually affects all compartments of the immune
system. The alleged cause for these immune alterations, and the onset of age-related comorbidities, is the
systemic chronic immune activation that is established in patients. However, there is a multiplicity of
contributors to this immune activation.
Summary
Our understanding of the precise link between immune activation and aging in HIV infection is complicated
by the influence of coinfections and life style factors. Developing rational interventions to reduce the hyper-
inflammatory status of HIV-1-infected patients requires a clearer delineation of the factors contributing to the
increased levels of systemic immune activation.
Keywords
age, comorbidities, HIV-1, inflammation, lymphopoiesis

INTRODUCTION Elevated inflammation, because of multiple poten-

The development of highly effective, well tolerated
antiretroviral therapy (ART) has changed a deadly
viral infection into a chronic, manageable disease.
As a result, the life expectancy of HIV-infected
patients, who have access to treatment, has
increased tremendously, and is currently predicted
as 70 years [1]. This impacts profoundly on HIV care.
Long-term HIV infection, even when antiviral treat-
ment is successful, is associated with an accelerated
and accentuated onset of serious non-AIDS-related
pathologies (SNAEs), which are typically associated
with aging (e.g. neurocognitive, cardiovascular, liv-
er and kidney diseases, metabolic syndrome, osteo-
porosis, and non-HIV associated cancers) [2]. The
combination of greater survival, complicated by
increased rates of diseases associated with aging
rather than immune deficiency, poses a potential
challenge to the healthcare systems of both in the
developed and developing world [3]. In the elderly,
the onset of these pathologies is thought to be a
consequence, at least in part, of the hyper-inflam-
matory status that usually occurs with old age.
tial causes, is also considered a major issue in HIV
pathogenesis [4]. Moreover, HIV-mediated chronic
immune activation is the alleged cause for a prema-
ture immune aging process, which likely contributes
to disease progression, the onset of AIDS and SNAEs
[5]. We provide here an overview of the recent
findings regarding the association of chronic
immune activation with premature immune aging,
and the lessons these findings have yielded in terms
of clinical care for HIV-infected patients. In particu-
lar, we will concentrate on the residual immune
a
Sorbonne Universités, UPMC Univ Paris 06, DHU FAST, CR7, Centre
d’Immunologie et des Maladies Infectieuses (CIMI-Paris), bINSERM,
U1135, CIMI-Paris, Paris, France, cThe Kirby Institute of Infectious
Diseases in Society, UNSW Australia and dSt Vincent’s Centre for
Applied Medical Research, Darlinghurst, Sydney, NSW, Australia
Correspondence to Victor Appay, INSERM, U1135, Centre d’Immuno-
logie et des Maladies Infectieuses (CIMI-Paris), 75013 Paris, France.
Tel: +33 140778183; fax +33 140779734; e-mail: victor.appay@upmc.fr
Curr Opin HIV AIDS 2016, 11:242–249
DOI:10.1097/COH.0000000000000240

www.co-hivandaids.com Volume 11  Number 2  March 2016

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 HIV infection and premature immune aging Appay and Kelleher
KEY POINTS
 The accumulation of CD28/CD57þ CD8þ T cells is
not necessarily a good marker of immunosenescence
and decline of immune competence.
 Exhaustion of primary immune resources including
naı̈ve T cells and CD34þ hematopoietic progenitors is
key in linking HIV pathogenesis and aging.
 Understanding the link between immune activation and
aging in HIV infection is complicated by the influence
of coinfections and life style factors.
 Multiple intervention strategies are being explored to
reduce immune activation in HIV-1-infected patients.
activation that persists in the presence of effective
ART as treatment guidelines suggest all HIV-infected
people should be offered ART.
EVIDENCE OF IMMUNE ACTIVATION
IN HIV INFECTION
From the earliest days of the infection, HIV-infected
patients have elevated cellular and soluble markers
of immune activation and inflammation, which
persist during chronic infection. Effective suppres-
sion of viral replication with ART does not com-
pletely normalize these changes. The first evidence
of immune activation has been the increased
expression of the activation marker CD38 on T cells
(in particular memory CD8þ T cells), which is an
independent predictor of disease progression
[6–11]. Signs of activation have also been reported
in natural killer (NK)- and B-cell populations
(reviewed in [12] and [13]), and monocytoid cellular
compartments. Compared with HIV-negative
adults, HIV-1-infected individuals have higher
proportions of inflammatory monocytes (i.e.
CD14þCD16þ), which show increased expression
of activation markers (CD11bþCD62L) [14]. More-
over, a state of hyperactivation of neutrophils has
also been recently reported, and was associated with
deregulation of the apoptosis/necrosis equilibrium
of these innate cells, and positively correlated with
the percentage of circulating cells producing inter-
&&
leukin 17 (IL-17) [15 ]. Furthermore, despite
their lower frequency, pDCs from HIV-1-infected
patients display persistent type I interferon (IFN)
production in response to stimulation with HIV-1 in
vitro [16]. This likely contributes to the higher
plasma levels of IFNa and interferon type I signa-
tures found during acute and chronic stages of HIV
infection, which have been associated with disease
progression [17,18].
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Various immune cells are therefore chronically
activated in the setting of HIV-1 infection. Overall,
this results in the release of multiple proinflamma-
tory soluble mediators [e.g. IFN-a, IL-1b, IL-6, IL-8,
tumor necrosis factor (TNF), TGFb, sCD14, sCD163,
MIP-1a, MIP-1b, RANTES, and IP-10] within both
plasma and tissues. These are only partially cor-
rected by ART. Several soluble markers such as
IFN-gamma-inducible protein (IP)-10 (CXCL10),
neopterin, sCD14, and sCD163, which reflect some-
what different aspects of monocyte activation, are
increased in HIV-1-infected patients. Levels of some
of these molecules in unsuppressed and suppressed
HIV-infected patients were found to be equivalent
to those found in healthy controls 12 and 4 years
older respectively, and to increase with age at a faster
rate in viremic patients than in ART suppressed or
&
control groups [19 ]. Although most studies have
been conducted in men, biomarkers of monocyte
activation are also increased in HIV-infected women
compared with healthy controls and increase with
age [20,21]. Of note, plasma levels of IP-10 measured
during primary infection were shown to be a strong
predictor of rapid disease progression in HIV-
infected patients [22]. The release of inflammatory
cytokines, and reactive oxygen species (ROS), by
these cells propagates systemic immune activation,
impacting directly on HIV pathogenesis and the
development of comorbidities. Interestingly, the
hyperactivated state of neutrophils in HIV-infected
individuals was greater in patients presenting with
diseases related to an inflammatory process (e.g.
osteoporosis, type II diabetes, cardiovascular dis-
&&
orders) [15 ]. Many of the above mediators have
been proposed as biomarkers to track the natural
history of HIV infection and effects of therapeutic
interventions. In addition, novel biomarkers for this
process and for predicting SNAEs have been sought
among circulating microRNAs. Although there is
evidence of variation in the levels of these molecules
in HIV-1 infection [23], no clear association between
these and poor clinical outcome could be demon-
strated in a large case–control study [24]. Eventu-
ally, heightened inflammation drives further viral
replication, establishing a vicious circle, of further
immune stimulation that results in premature
immune aging.
IMMUNE PARALLELS BETWEEN AGING
AND HIV-1 INFECTION
Accumulation of CD28S/CD57RCD8R T cells:
a good ‘immunosenescence’ marker?
A number of immune parallels have been drawn
between aging and HIV-1 infection. Immunological
www.co-hivandaids.com 243
 Immune activation
aging in HIV-1-infected patients was first high-
lighted through the accumulation of T cells (in
particular CD8þ T cells) lacking expression of the
coreceptor CD28 [25]. This is also a primary hall-
mark of the aging immune system [26]. Replication
of persistent viruses and chronic cellular activation
are major factors in this process, driving prolifer-
ation and T-cell differentiation of antigen experi-
enced cells, that eventually loose expression of
CD28, and have increasing expression of CD57
(a more precise marker of T-cell replicative history
and therefore replicative senescence) [27–30]. These
T-cell subsets are characterized by a reduced capacity
to produce IL-2 and to proliferate, and shortened
telomere lengths, so that highly differentiated cells
(CD28/CD57þ) have been considered as end-stage
senescent cells [27,28]. The accumulation of such
T cells is therefore commonly studied as a marker of
‘immunosenescence’ in HIV-infected patients, and
has been explored as a correlate of clinical outcome,
with some counterintuitive observations. For
instance, a recent study shows that increased fre-
quencies of CD28 – /CD57þCD8þ T cells are associ-
ated with the presence of Kaposi’s sarcoma among
successfully treated patients [31]. However, abnor-
mally low proportions of these cells were also shown
to predict increased mortality during treated HIV
&
infection [32 ].
These discrepancies may result from confound-
ing factors that drive the accumulation of CD28 – /
CD57þCD8þ T cells. For instance, HIV infection may
not necessarily result in high proportions of CD28 – /
CD57þCD8þ T cells [33], in contrast to CMV infec-
tion, which promotes expansion of terminally
differentiated T cells [34–36], even in virally sup-
&
pressed patients [37 ]. CMV infection, which is
extremely common in HIV-1-infected individuals,
plays a pivotal role in the acquisition of this ‘immu-
nosenescence’ phenotype, and may represent an
important confounding factor. Interestingly, on
average CMV seropositive patients experience more
rapid HIV disease progression than CMV seroneg-
ative patients [38], and CMV coinfection was associ-
ated with the risk of severe non-AIDS-related death,
especially related to cardiovascular and cerebro-
&&
vascular events [39 ]. Moreover, CMV seropositiv-
ity and strong CMV-specific responses impacted on
CD4þ T-cell counts and recovery with antiretroviral
therapy in HIV-1-infected individuals [40]. Overall,
these findings support an independent role of CMV
coinfection in the clinical outcome of HIV-infected
patients. Moreover, the accumulation of CD28 – /
CD57þCD8þ T cells may not be the best surrogate
for immune decline related to HIV disease pro-
gression (for instance, ART naı̈ve HIV controllers
present high levels of these cells [40]), and almost
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certainly represents only the tip of the iceberg of the
premature development of immune aging in HIV
infection.
Exhaustion of primary immune resources
in HIV infection and aging
Declining CD4þ and CD8þ naı̈ve T-cell levels may be
a more relevant feature to highlight the immuno-
logical similarities between aging and HIV disease
progression [40]. The progressive decrease in naı̈ve
T-cell counts in HIV-infected adults, which has long
been observed [41], likely results from the antigen-
driven consumption of these cells in the absence of
adequate T-cell renewal capacity associated with
the reduced thymic output [42]. Impaired thymo-
poiesis is indeed an important trait of HIV-infected
patients, as a result of either infection of the thymus
and thymocytes by the virus [43,44], or thymic
involution [45]. The frequency of naı̈ve T cells
may thus represent the best marker of immunologi-
cal age. Despite a younger age (i.e. mean of 40 years),
most HIV-1-infected individuals with a CD4þ T-cell
count below 200 cells/ml have naı̈ve CD4þ and CD8þ
T-cell blood frequencies comparable to elderly unin-
fected patients (i.e. mean of 85 years) [40]. In
addition, naı̈ve CD8þ T cells from HIV-infected
patients are functionally impaired with a lower
capacity to be activated upon T-cell receptor stimu-
lation [46], reminiscent of old age [47]. It will be
important to determine the impact of these quan-
titative and qualitative alterations of the naı̈ve T-cell
compartment on the capacity to mount effective
immune responses, including to vaccines. It has
long been recognized that both older age and HIV
infection are both associated with poorer responses
to vaccines. Recent works confirmed this obser-
vation in HIV-1-infected women following influ-
enza vaccination, even when CD4þ T-cell counts
are in the normal range (>600 CD4þ T cells/ml) and
viral load suppressed. In older HIV-infected patients,
this deficit appears to be related to reduced levels of
circulating follicular T helper cells and resting mem-
ory B cells. This lack of responsiveness correlated
with plasma levels of TNF and IL-6, which were
higher in nonresponders, and responses could be
improved by TNF blockade in vitro [48,49].
The origin of the immune parallels between HIV
infection and aging may also be caused by events
upstream of the naı̈ve lymphocyte compartment.
CD34þ hematopoietic progenitor cells (HPCs),
which represent the source of all blood cells, derived
from the bone marrow of HIV-viremic patients were
reported to be functionally different from those
found in healthy individuals [50]. The detailed
assessment of HPCs extracted directly from blood,
Volume 11  Number 2  March 2016
 HIV infection and premature immune aging Appay and Kelleher
allowing studies of a large number of donors,
revealed that HPCs from patients progressing
toward AIDS presented both quantitative and qual-
itative defects, that mirror those observed with old
age [51]. These defects are suggestive of an impaired
T-cell progenitor function in chronic HIV infection,
in line with results from fetal thymic organ culture
experiments performed on CD34þ HPCs from HIV-
infected progressors [52,53]. Defects of HPCs may
result from increased inflammation, possibly
directly affecting CD34þ cells and causing fibrosis
of primary lymphoid tissues (e.g. the bone marrow),
eventually damaging their architecture and hema-
topoietic capacity [54,55]. Taken together, this
points to impaired hematopoiesis in HIV infection,
which likely affects not only the production of new
CD4þ T cells and their reconstitution with ART, but
also, the production and properties of total lympho-
cytes, including CD8þ, NK, and B cells, and possibly
others leukocyte subsets with a myeloid lineage (e.g.
monocytes and pDCs).
Overall, many of the alterations discussed above
are reminiscent of the decline of the immune com-
partments and functions that can be observed with
advanced age, independently of HIV infection.
Interestingly, several of these hematopoietic defects
were also observed in untreated HIV controllers who
were immunological progressors (i.e. with decreas-
ing CD4þ T-cell counts below 350 cells/ml despite
natural control of viral replication) [51]. These find-
ings provide insights as to the processes underlying
HIV disease progression despite effective suppres-
sion of viral replication, suggesting that exhausted
lymphopoiesis, as a potential consequence of low-
grade chronic immune activation, may be the cause
of disease progression in HIV controller progressors,
and HIV-infected individuals who are virologically
suppressed but fail to reconstitute their pool of
CD4þ T cells [51].
CAVEATS WITH THE DISSECTION OF
THE RELATIVE CONTRIBUTIONS OF HIV
INFECTION, COINFECTIONS, AND LIFE
STYLE FACTORS TO IMMUNE ACTIVATION
AND AGING
Increasing data support apparent correlates of
immune activation and the onset of age related
manifestations in HIV-1-infected patients. However,
many of these results need to be interpreted with
care, as a range of coinfections (e.g. CMV as dis-
cussed earlier) and socioeconomic or life style fac-
tors (e.g. smoking, adiposity) can be associated with
increased levels of immune activation. The preva-
lence of these factors is often higher in HIV-infected
populations than in the noninfected populations
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and can act as unrecognized confounders. In
addition, the influence of ART regimen and time
on treatment further complicates data interpret-
ation, as antiretroviral drugs can drive mitochon-
drial damage, renal dysfunction, and lipodystrophy
(including fat redistribution and metabolic
changes). Often studies of biomarkers associated
with poor outcomes, including the aging phenom-
enon, involve relatively small numbers of patients
studied in cross-section, without an ideal control or
comparator group, making it difficult to control for
confounding variables. Therefore, the exact nature
of the immune activation and the aging process and
how much of it is directly attributable to HIV-infec-
tion remains somewhat elusive.
These issues have been accounted for in a few
large studies. Interestingly, although these studies
show that there is a more rapid degree of aging and
an increased levels of immune activation in HIV-1-
infected patients compared with age-matched con-
trols, in the HIV-1-infected population, the higher
levels of activation biomarkers often do not corre-
late with increased risk of age-related comorbidities.
A cross-sectional comparison of more than 500 HIV-
1-infected patients (CD4 count >500 cells/ml, 95%
on ART for greater than 10.5 years, and median viral
load of 50 copies/mL) with 500 age-matched con-
trols showed that the HIV-infected group had a
higher number of age associated noncommunicable
comorbidities (AANCC). Furthermore, the number
of AANCCs in each 5-year stratum in the HIV-
infected patients resembled those of the controls
who were 5 years older. After adjusting for age, sex
and race, metabolic abnormalities, smoking, alco-
hol use, and hepatitis C coinfection, the carriage of
HIV and time spent with less than 200 CD4þ T cells/
ml remained independently associated with a higher
number of AANCC. Although levels of high-sensi-
tivity (hs) C-reactive protein (CRP), CD14, and
CD163, but not D-dimer, were higher in the HIV-
infected group, only hsCRP and sCD14 were shown
to be independent correlates of risk, once life style
factors and intercurrent infections had been
adjusted for, and then these only just reached sig-
nificance. Furthermore, cumulative use of high-dose
ritonavir, but not of abacavir, stavudine, or didano-
sine, was identified as an independent risk factor for
&&
AANCC [56 ]. In a second large European study of
350 predominantly male HIV-1-infected patients on
effective ART with normal range CD4þ T-cell counts
and suppressed viral load and 59 controls, immune
activation markers such as hsCRP, IL-6, d-dimer,
cystatin-C, and b-microglobulin, but not sCD14,
were significantly higher in the HIV-1-infected
group. However, these associated with personal fac-
tors such as age, adiposity, smoking and HCV
www.co-hivandaids.com 245
 Immune activation
infection rather than with either HIV infection per se
or measures of the severity or chronicity of HIV
&&
infection [57 ]. Similarly in a much smaller study
looking at an extended panel of biomarkers, which
included osteopontin, sVCAM, sICAM, and CD57
expression on T cells and those considered in the
two studies summarized above, many of these acti-
vation markers were higher in treated HIV-infected
patients, but there was no association between these
markers and the degree of physical impairment
&
[58 ]. These three recent studies show the import-
ance of having appropriate control groups, which
allow for the rigorous accounting of confounding
non-HIV factors in studies attempting to relate the
effect of HIV mediated immune activation to
increased morbidity and aging. These data suggest
that intercurrent infections, various life style con-
founders and certain older treatment modalities,
rather than inflammation and immune activation
resulting from HIV infection per se, may be the main
contributors to the excess morbidity in the HIV-1-
infected population.
INTERVENTIONS TO LIMIT BOTH IMMUNE
ACTIVATION AND IMMUNE AGING
IN HIV INFECTION
As a large component of immune activation is
driven by life style factors, then standard health
advice for behavior modification, for example
reduction in smoking, or control of intercurrent
predisposing factors such as adiposity, diabetes,
and hypertension is a rational mode of intervention.
In addition, a number of biomedical intervention
strategies have been considered to directly reduce
immune activation or its underlying causes. As the
pathogenesis and impact of immune activation in
HIV-1 infection is unclear, these trials have been
empiric and somewhat opportunistic. These inter-
ventions fall into the several categories: intensifica-
tion of ART to reduce residual virus and improve
immune reconstitution; anti-inflammatory mol-
ecules; prevention of bacterial translocation by
impacting of the integrity of gut mucosa or on
the microbiota; treatment of intercurrent infections
such as herpesviruses; and reduction of metabolic
abnormalities such as hypercholesterolemia.
Effective ART regimens are associated with
marked reductions in immune activation [59,60].
However, ART intensification studies showed little
or no additional effect on residual immune acti-
& &
vation [61 ,62,63 ,64]. Although, earlier treatment,
such as at primary infection (at Fiebig stage III/IV
stages or later), reduces the reservoir size and allows
better immune reconstitution, it does not seem to
& &
affect residual activation levels [61 ,63 ]. Of note,
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one recent study indicates though that very early
initiation of therapy during acute infection (at Fie-
big stage I/II) resulted in decreasing activation
markers (percentages of CD38þ/HLA-DRþCD8þ
T cells in both the mucosa and periphery), to levels
&&
observed in uninfected individuals [65 ]. The tim-
ing of treatment initiation during primary infection
may therefore be crucial to reduce immune acti-
vation levels. START, a large randomized, clinical
end point study of early ART initiation, showed
improved outcomes both in terms of AIDS and
serious non-AIDS events [66]. The long-term effects
of early ART intervention require confirmation or at
least further observation, but the result of this trial
suggests it will lessen morbidities and thereby
reduce their impact on aging. How these results
relate to alterations in the extent of immune acti-
vation will be extremely interesting to follow.
Interventions with agents that act directly to
reduce immune activation, hydroxychloroquine
(despite initially encouraging results [67]), mesal-
amine, or pentoxifylline had little impact when
given to those on effective ART [68–70]; and
hydroxychloroquine may even be deleterious in
those not on ART [71]. Of note, supplementation
of vitamin D, a naturally synthesized hormone with
important immunomodulatory functions, has been
suggested to help reducing residual immune acti-
vation in vitamin D-deficient HIV-1-infected
patients on ART in two recent pilot studies
[72,73]. The use of cytokines such as IL-21 or IL-7
to improve immune function have shown encour-
aging results as judged by improvements in surro-
gate markers [74,75]. However, given the disconnect
between effects on robust surrogate markers (CD4þ
T-cell count) and outcome with IL-2 therapy, the
effect of this type of intervention, on unproven
surrogates, needs to be interpreted cautiously in
terms of possible clinical outcomes, especially as
IL-7 appears to induce other apparently adverse
outcomes such as increasing the viral reservoir [76].
Several interventions have attempted to modu-
late gut flora or to reduce the effects of microbial
translocation in order to reduce the immune acti-
vation induced by lipopolysaccharide or other trans-
located bacterial products. These include the use of
hyperimmune bovine colostrum alone or in con-
junction with ART intensification [77], and the use
of rifaximin, in patients with poor immune recon-
stitution [78]. The former had no effect, and the
latter did not reduce immune activation. The use of
sulphamethoxazole/trimethoprim in addition to
ART may have effects on certain markers of gut
translocation in late-stage patients [79]. An alterna-
tive approach is to alter the gut microbiota through
the use of probiotics. The consumption of probiotics
Volume 11  Number 2  March 2016
 HIV infection and premature immune aging Appay and Kelleher
in ART patients reduced a range of markers of
immune activation over a 48-week period [80]. In
contrast, a small but randomized placebo-controlled
study showed a small effect of probiotics on CD4þ
T-cell percentage, but not on biomarkers of immune
activation [81].
The results of treating herpesvirus infections are
mixed. Treatment with acyclovir or valacyclovir was
shown to decrease immune activation markers in
HIV-1-infected patients under ART [82], although a
randomized trial in treated patients failed to show
any effect on immune activation [83]. Another
observational study showed a minimal effect on
monocyte activation [84].
Low-dose aspirin rapidly induces desired effects
on platelet aggregation when administered to
patients on ART [85], whether this converts into
reductions in morbidity requires further investi-
gation.
Statins have been explored because they both
reduce cholesterol and have anti-inflammatory
properties. Several trials have been undertaken.
Randomized comparison of rosuvastatin in addition
to ART showed maintenance of lean body mass,
reductions in lipoprotein-associated phospholipase
A2, cystatin C, monocyte, and T-cell activation
markers, without an adverse effect on bone mineral
density, suggesting a possible long-term benefit in
& &
preventing frailty [86 ,87–89]. However, there was a
concomitant increase in insulin resistance [90]. Sim-
ilarly, Atorvastatin has been shown to reduce cel-
lular measures of immune activation in those with
& 2. Pathai S, Bajillan H, Landay AL, High KP. Is HIV a model of accelerated or
poor immune reconstitution [91 ]. However, no
effect on CD4þ T-cell count, viral load, or cellular
markers of immune activation was seen in a group
commencing lovastatin at the same time as starting
ART [92]. Therefore, there may not be a class effect.
Moreover, both the risks and benefits of these inter-
ventions need to be carefully considered. A similar
strategy underlies the use of dipeptidase-4 (CD26)
inhibitors, such as sitagliptin, which may improve
glucose tolerance and have anti-inflammatory prop-
erties [93]. A small randomized trial in patients on
ART with reduced glucose tolerance showed prom-
ising results, with reduced levels of CRP and IP-10
[94].
CONCLUSION
HIV-1-infected patients present a number of
immune alterations and serious non-AIDS-related
diseases, which are typically associated with aging.
Identifying the best biomarkers and understanding
the causes of these phenomena and their relation-
ship to immune activation will provide clues to
interventions that will reduce the burden of
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chronic diseases for both individuals and commun-
ities. Several empirical studies are now aimed
at developing potential intervention strategies
to reduce immune activation in HIV-1-infected
patients. Although encouraging, many of these
studies have been small and have surrogate
marker endpoints rather than clinical endpoints;
well designed randomized studies of interventions
and natural HIV infection history studies both
with well matched control groups are therefore
needed.
Acknowledgements
None.
Financial support and sponsorship
V.A. and A.D.K. have received financial support from
INSERM, FRM, ANR, ANRS and Sidaction, and the
NHMRC Australia.
Conflicts of interest
There are no conflicts of interest.
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