Immunology Letters 162 (2014) 329333

Contents lists available at ScienceDirect

Immunology Letters
journal homepage: www.elsevier.com/locate/immlet

Aging with HIV infection: A journey to the center of inammAIDS,

immunosenescence and neuroHIV
Milena Nasi a , Marcello Pinti b , Sara De Biasi a , Lara Gibellini a , Diana Ferraro c ,
Cristina Mussini a,d , Andrea Cossarizza a,
a

Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
c
Department of Biomedical, Metabolic and Neurosciences, University of Modena and Reggio Emilia, Modena, Italy
d
Infectious Diseases Clinics, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy
b

a r t i c l e

i n f o

Article history:
Available online 1 July 2014
Keywords:
Aging
HIV
AIDS
Inammation
Immune activation
Neurocognitive impairment

a b s t r a c t
In the last years, a signicant improvement in life expectancy of HIV+ patients has been observed in
Western countries. The parallel increase in the mean age of these patients causes a parallel increase
in the frequency of non-AIDS related complications (i.e., neurocognitive, cardiovascular, liver and kidney diseases, metabolic syndrome, osteoporosis, non-HIV associated cancers, among others), even when
antiviral treatment is successful. Immune activation and persistent inammation characterizes both HIV
infection and physiological aging, and both conditions share common detrimental pathways that lead
to early immunosenescence. Furthermore, HIV-associated neurocognitive disorders represent important
consequences of the infection. The persistent systemic immune activation, the continuous migration of
activated monocytes to the central nervous system and progressive patients aging contribute to develop
neuronal injuries, that are in turn linked to HIV-associated neurocognitive disorders, which can persist
despite successful antiretroviral treatment.
2014 Elsevier B.V. All rights reserved.

1. Introduction
In the last years, a signicant improvement in life expectancy
of HIV-positive patients has been observed in Western countries.
This improvement may be explained by several factors, including an increase of life expectancy in the general population, the
change in demographics and risk factors of the HIV+ population, a
decline in the transmission of drug-resistant virus strains, a good
immune response of patients taking highly active antiretroviral
therapy (HAART) [1] and an increased access to modern HAART
regimens. The increase in the mean age of HIV patients is causing
a parallel increase in the frequency of non-AIDS related complications (i.e., neurocognitive, cardiovascular, liver and kidney diseases,
metabolic syndrome, osteoporosis, and non-HIV associated cancers, among others), even when antiviral treatment is successful.
Most of these diseases are typically associated with aging, and are

Corresponding author at: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, via Campi, 287, 41125
Modena, Italy. Tel.: +39 059 205 5415; fax: +39 059 205 5426.
E-mail address: andrea.cossarizza@unimore.it (A. Cossarizza).
http://dx.doi.org/10.1016/j.imlet.2014.06.012
0165-2478/ 2014 Elsevier B.V. All rights reserved.

caused, at least in part, by the status of chronic inammation and

activation of the immune system typically present in elderly people.
Immune activation and inammation occur in both HIV infection and aging, and both conditions share common detrimental
pathways that lead to early immunosenescence [2]. The impact of
such chronic immune activation, the effects on the central nervous
system (CNS), and the onset of neurocognitive impairment in HIV+
elderly people, along with a theoretical road map of the development of neurocognitive impairment are summarized in Fig. 1.
2. An increasing population and emerging problems
UNAIDS and WHO estimate that out of the global total of 35.3
million (estimated range: 32.238.8 million) people living with HIV,
3.6 (3.23.9) million are people aged at least 50 years. The majority,
2.9 (2.63.1) million, live in low- or middle-income countries where
the percentage of HIV+ adults who are 50 years or older is now
>10%. In high-income countries, it has been estimated that about
1/3 of HIV+ adults are >50 years of age (see: http://www.unaids.
org/en/dataanalysis/knowyourepidemic/). Western countries have
shown a progressive change in the demography of the HIV+ population, caused by the striking increase in life expectancy and
improvement of the quality of life. As a consequence, nowadays

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M. Nasi et al. / Immunology Letters 162 (2014) 329333

Fig. 1. Road map that indicates the correlations of aging and relative severity of HIV
infection in the development of neurocognitive impairment.

the number of elderly HIV+ individuals is dramatically increasing.

As an example, in the USA, in 2005 about 15% of new HIV infection or AIDS cases reported to the Center for Disease Control and
Prevention regarded persons 50 years and older, while 2% of new
diagnoses were in patients over 65 years of age [3,4]. After one
decade, namely in 2015, it has been estimated that in USA more
than 50% of all HIV+ individuals will be >50 years [5].
This demographic trend is causing a relevant increase in
non-AIDS-related complications generally associated with aging.
Among these, HIV-associated neurocognitive disorders (HAND)
represent some of the most devastating consequences of the infection. Symptoms related to HAND include behavioral abnormalities,
motor dysfunction, and frank dementia [6], and clinical severity
ranges from asymptomatic neurocognitive impairment (ANI) and
mild neurocognitive disorder (MND) to its most severe form, HIVassociated dementia (HAD) [7]. The prevalence of HAND did not
change from the pre- to the HAART era, remaining at approximately
50%, being MND and ANI more common than HIV-associated
dementia. However, the prevalence of HAD has decreased (from
18% to <5%), whereas there is an increased prevalence of mild symptomatic impairment (from 12% to 17%) and of ANI (from 20% to
28%) [8]. There is a common agreement on the fact that in HIV+
patients aging, with its age-related comorbidities, increases the
risk of cognitive impairment. Thus, the convergence of aging and
HIV have CNS implications, raising the possibility of accelerated
neurodegenerative syndromes [9].
3. Immune activation and aging
3.1. Persistent immune activation: the tip of the iceberg
In the last decade, an increasing amount of data has profoundly
changed the view of HIV infection, which is now seen as a chronic
inammatory disease [10,11]. The rst step in the process that
leads to chronic inammation is the loss of CD4+ T cells resident in the gut, occurring during primary, acute infection. In this
phase, CD4+ T lymphocytes that express CCR5 molecule and reside
in the gut mucosa are rapidly depleted, in part through direct
killing by the virus, and in part due to bystander apoptosis [12].
The gut mucosa of HIV+ patients contains effector sites that are
severely depleted of CD4+ T cells, despite effective HAART. Activated mucosal T cells release cytokines, and exposure of HIV at the
mucosal surface leads to direct response of the mucosal epithelium [13]. This response is rapid, independent of viral infection,
and likely plays a key role in initiating the mucosal damage [14].

It has been shown that the depletion of mucosal CD4+ T cells

during acute infection is accompanied by the loss of several protective mechanisms of the gastrointestinal (GI) tract [15]. Indeed,
the virus, and/or the immune response to the virus, also alter the
physical barrier of epithelial cells [16], and change the functionality of macrophages, dendritic cells and innate lymphoid cells
[17]. These alterations ultimately lead to the translocation of the
microbial products into the lamina propria of the GI tract and into
systemic circulation [18,19]. Once into the circulation, bacterial
products elicit potent pro-inammatory responses by activating a
number of innate receptors, such as nucleotide-binding oligomerization domain receptors (NODs) and Toll-like receptors (TLRs),
which are expressed by the innate immune cells and many other
cell types. In innate immune cells such as monocytes, macrophages
and dendritic cells, binding of these receptors to microbial products
activates a signaling cascade, ultimately leading to the production
of the pro-inammatory cytokines [20].
Although these responses may be benecial, they may contribute to the establishment of chronic HIV infection. The persistent
inammatory status that characterizes HIV infection is the consequence of several factors, which directly or indirectly contribute
to maintain a chronic, low level of inammation even in patients
treated with successful HAART [21,22]. Since HIV infection is typically contracted by young or adult individuals, the aforementioned
status could persist for years or decades [23]. In the last few years,
the inammatory response in the systemic circulation has been
recognized as a key-driver of HIV pathogenesis, both in the periphery and in the CNS. In the CNS, there is considerable evidence that
this inammatory response drives the development of HAND or
worsens it, possibly independently of viral replication [24].
Given the causative role of gut mucosa dysfunctions in the
microbial translocation and in the immune activation, there has
been a growing interest in studies aimed to restore the integrity
of the mucosa and of resident immune mechanisms, in order to
reduce the disease progression [25]. Several therapeutic interventions are at present under investigation, with the aim to modulate
the composition of microbiota with probiotics [26], stimulate IL-17
production by intestinal T cells [27], enhance the IgA responses in
the gut [28], or improve the efcacy of vaccines by using mucosal
adjuvants [29].
3.2. Immune activation and aging: the immunosenescence
In elderly healthy subjects the immune activation and inammation play a crucial role in promoting a gradual age-related
decline of the functionality of the immune system, leading to the
so-called immunosenescence [30]. These two phenomena are
thought to occur because of the chronic stimulation of the immune
system, due to the presence of chronic or persistent infections that
are not eradicable, such as those induced by cytomegalovirus or
herpes viruses. Physiological aging is accompanied by a low-grade,
chronic and systemic up-regulation of the inammatory response
[31], and the underling inammatory changes are common to most
age-associated diseases [32]. This condition is mediated mainly
by the increased circulating levels of proinammatory cytokines,
many of which are produced by the hyperactivity of macrophages
[33], and increases the risk of frailty as well as the onset of agerelated chronic diseases.
In the case of HIV infection, the persistence of the virus causes
immune activation and continuous inammation. Indeed, not only
viral antigens exert a strong pressure on the immune system, but
they also change continuously because of the high rate of mutations that is characteristic of HIV. In turn, this causes continuous
modications of the epitopes that the immune system has to
recognize, and thus a relevant number of new cells have to be produced to recognize novel antigens. The fate of these cells, that are

M. Nasi et al. / Immunology Letters 162 (2014) 329333

actually directed toward antigens that are no longer present in

the organism since they have mutated, is anergy or apoptosis. This
phenomenon occurs during the entire course of the infection, and
mimics the accelerated replicative senescence of T cells that progressively accumulates during the normal course of human aging
[34].
Immunosenescence and HIV infection have several features in
common, among which the shrinkage of the T cell repertoire [35],
the accumulation of oligoclonal expansions of memory/effector
cells directed toward infectious agents, the involution of the thymus [36], the exhaustion of nave T cells and, nally, a chronic
inammatory status dened inammaging in one case, inammAIDS in the other [37].
4. HIV and the central nervous system
4.1. Neuroinammation: the innate immune system
The immune system is essential in maintaining tissue homeostasis and responding to infection and injury. In the CNS, the
innate immune system is mainly formed by microglia, along with
macrophages and astrocytes that trafc through this organ [38].
In the brain, microglia are the main resident immune cells, and
they constantly survey the microenvironment producing factors
that are able to inuence astrocytes and neurons. Under physiological conditions, microglia exhibit a deactivated phenotype that
is associated with the production of anti-inammatory and neurotrophic factors [39]. After pathogen invasion, microglia switch to
an activated phenotype and promote an inammatory response,
which is needed to engage the immune system and initiate tissue repair [40]. The interactions between resident innate immune
cells and inltrating immune cells (macrophages, T and B lymphocytes) in the CNS are highly involved in triggering inammation.
Neuroinammation is indeed a complex response to infections that
can ultimately lead to neurodegenerative phenomena [41]. However, depending on the circumstances, inammation in the CNS can
have either pathogenic or protective effects [42].
In most cases, neuroinammation is a self-limiting phenomenon that undergoes resolution after the eradication of the
infection, or the repair of the damaged tissue. The persistence of
a chronic inammatory stimulus may result from external factors
(such as a virus like HIV) or from the formation of endogenous factors (e.g., protein aggregates) that are recognized by the immune
system as strangers or danger signals. Such a recognition causes
an uncontrolled inammation, with the consequent production of
neurotoxic molecules that amplify the underlying disease state
[41].
4.2. The role of monocyte/macrophages system
During HIV infection, monocytes and macrophages act as viral
reservoirs throughout all stages of the disease, promote both
immune dysregulation and virus dissemination, and represent one
of the main obstacles to HIV eradication [43]. In particular, tissue
macrophages contribute to the establishment of viral reservoirs as a
consequence of their distribution, long half-life, relative insensitivity to the cytopathic effects of virus replication and, nally, to their
capacity of producing and storing mature HIV virions in intracellular compartments [44] [45]. In elderly HIV+ patients, who display a
prolonged chronic inammation, age-associated defects in innate
immunity are exacerbated by the infection, and viral clearance is
further compromised. This clearly increases the persistence of viral
antigens in the organism, and drives immunosenescence further,
which is in turn accelerated by the immunological impairment
caused by HIV [37].

331

Circulating monocytes and macrophages have the ability to

cross the intact bloodbrain barrier (BBB) and undergo differentiation within brain parenchyma, giving rise to long-lived brain
resident macrophages and microglia [46]. Inltrating macrophages
are able to acquire a ramied morphology in the CNS, indistinguishable from that of resident microglia, while microglial cells
could develop a phagocytic phenotype, indistinguishable from that
of inltrating macrophages. In case of infection by HIV, these cells
can bring the virus to the CNS.
Although neurons are not infected by HIV, they can be injured via
indirect mechanisms, i.e., neurotoxins resulting from the immune
response in the CNS. It has been suggested that, even during a successful HAART, a correlation exists among systemic inammation,
CNS inammation and HAND [47], demonstrated by the presence in
the cerebrospinal uid (CSF) of molecules released during immune
activation [48]. A signicant association has been reported between
systemic immune activation and HAND, and a causal relationship between increased systemic monocyte activation, increased
transendothelial migration of activated monocytes into the brain,
and neurocognitive decline secondary to neurodegeneration [47].
Neuroinammation is a common feature observed throughout the
progression of the disease from the latent, asymptomatic stage of
AIDS to HAD and it is characterized by gliosis, microglial nodules,
perivascular macrophage accumulation, and the presence of multinucleated giant cells. Immune activation is often out of proportion
to the amount of HIV virus present in the brain and peripheral
reservoirs continue to play an active role in brain injury despite
HAART [49,50]. Clearly, these phenomena have a more profound
deleterious effect when they occur in patients who have already
an age-related decline in immune functions, such as aged HIV+
patients.
Recent studies have highlighted that microglia and
macrophages in the CNS contain multimolecular complexes
termed inammasomes, that act as a sensors of infectious agents
or danger signals [42]. As innate immune sensing underlies the
activation of inammasome complexes, infections can contribute
to inammasome activation within the CNS [51] and to brain
injury. Inammasome activation is under current investigation
across a broad spectrum of neurological diseases, including infections [42]. For example, it has been shown that, in the mouse
model, the ablation of NLRP3 inammasome is able to protect
animals from the age-related increase in immune activation, from
alterations in CNS transcriptome and from astrogliosis [52]. Studies
are required in aged HIV+ patients, where the pathways triggered
by different inammasomes have never been investigated.
4.3. Aging and HIV in the central nervous system
In older individuals, there is a concern that HIV infection may
interact with the normal aging process, as cognitive impairment is
more than twice as common in older HIV+ people than in younger
people who have been ill for the same amount of time [53]. Several
studies have investigated the mechanisms that mediate cognitive
decline in older HIV+ adults. A rst possibility could be the presence of a greater risk of metabolic dysregulation and cardiovascular
or cerebrovascular comorbidities [54,55], especially in individuals
receiving regimens that include protease inhibitors [56]. Other possibilities include the occurrence of exacerbated inammatory glial
activation [57], poor adherence to medication [58], limited compensatory brain capacity, and the expression of apolipoprotein E4
(APOE4).
Aged HIV+ subjects show altered brain connectivity and
integrity, differences that are further exacerbated in carriers of the
ApoE4 genotype [59]. HAART-treated patients are at increased risk
for systemic and CNS diseases associated with aging: renal failure,
osteoporosis, cancer, cardiovascular disease, and cognitive decline,

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M. Nasi et al. / Immunology Letters 162 (2014) 329333

which can be associated with Alzheimers disease and Parkinsons

disease-like pathology [60,61]. This suggests that the aging brain
could be more vulnerable to neuronal injury associated with HIV
infection, although the presence of a number of comorbidities complicate the identication of a precise causal relationship between
age and HAND risk.
In seronegative subjects, neurodegenerative disorders are often
characterized by the accumulation in the brain of abnormal proteins such as ubiquitin, or amyloid-beta, -tau and -alpha synuclein
[62]. An abnormal accumulation of proteins in the brain can
also be present during HIV infection and indeed an excess of
hyper-phosphorylated tau, amyloid, and alphasynuclein has been
reported in relatively aged HIV subjects [63,64]. In HIV+ patients
who do not develop encephalitis, the age-related presence of intracellular amyloid- in pyramidal neurons along axonal tracts has
been described [65]. Studies on CSF revealed that levels of amyloid(142) in patients with HAND were similar to those seen
in Alzheimer disease [66], while cognitively normal HIV+ subjects
did not display increased amyloid levels [67]. Finally, other data
on CSF further indicate that the neuropathogenic pathways to CNS
injury in HIV+ individuals have distinct features compared to those
of Alzheimer disease [68].
Patients nave for HAART can display increased levels of amyloid precursor protein in damaged axons without evidence for
elevated p-Tau expression or neuritic plaque formation [69,70].
Latent HIV infection in the CNS might be associated with increased
levels of chromatin modiers and alterations of these epigenetic factors might activate proinammatory cascades associated
with neurodegeneration and neurocognitive impairment [71].
Although the increased lifespan of HIV+ patients obtained with
the use of successful HAART can be related to the accumulation
of neurodegeneration-related proteins, possible toxic effects of
HAART in the CNS have to be considered as a main factor that contributes to the development of HAND [62,72]. Indeed, it has been
shown that HIV+ patients who lived up to 15 years without treatment did not express excessive levels of hyperphosphorylated Tau
or beta-amyloid, nor were they associated with HAND [73].
5. Conclusions
Neurocognitive disorders associated to HIV infection remain
frequent despite the use of highly effective antiretroviral therapy, and the onset of asymptomatic cognitive impairment may
in fact be taken into account by clinicians. Among the factors
that can contribute to the impairment of CNS, a main role is
played by the persistent systemic immune activation, particularly
in older individuals with different comorbidities. The importance
of inammatory phenomena is self-evident, and future therapeutic
directions have to take into account the role of recently identied pathways such as those triggered by different inammasomes,
whose role in CNS diseases has achieved substantial recognition in
multiple animal models of neurological disorders.
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