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Ageing Research Reviews 10 (2011) 163–172
Contents lists available at ScienceDirect
Ageing Research Reviews
journal homepage: www.elsevier.com/locate/arr
Review
Aging and HIV infection
Vivian Iida Avelino-Silvaa,b,∗, Yeh-Li Hoa,b, Thiago Junqueira Avelino-Silvac, Sigrid De Sousa Santosa,b
aInfectious and Parasitic Diseases Division, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo – Avenida
Dr. Eneas de Carvalho Aguiar 255, 4◦Andar do Instituto Central, Sala 4028 – 05403-000–Sao Paulo, SP, Brazil
bInfectious and Parasitic Diseases Department, Faculdade de Medicina da Universidade de Sao Paulo – Avenida
Dr. Eneas de Carvalho Aguiar 470, 2◦Andar do Instituto de Medicina Tropical I – 05403-000–Sao Paulo, SP, Brazil
cGeriatrics Division, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo – Avenida
Dr. Eneas de Carvalho Aguiar 255, 8◦Andar do Predio dos Ambulatorios, Bloco 8 – 05403-000–Sao Paulo, SP, Brazil
article info
Article history:
Received 8 June 2010
Received in revised form 12 October 2010
Accepted 15 October 2010
Keywords:
Aging
Immunosenescence
HIV
abstract
Introduction: Population aging has become a global phenomenon, and HIV infection among older indi-
viduals is also increasing. Because age can affect the progression of HIV infection, we aimed to evaluate
the present knowledge on HIV infection in older patients.
Methods: Literature review of the last 20 years.
Results: Older HIV-infected patients have lower CD4+T cell counts, higher viral load and are more fre-
quently symptomatic at diagnosis. The infection progresses more rapidly, with higher morbidity and
lethality rates. However, older patients are more compliant to antiretroviral treatment; they experience
a better virologic response, and treatment represents a positive clinical impact. Aging affects the complex
interaction between HIV infection and the immune system. Both conditions contribute to the dysfunc-
tion of immune cells, including a decrease in the phagocytes’ microbicidal capability, natural killer cells’
cytolytic function, expression of toll-like receptors and production of interleukin-12. Chronic immune
activation responsible for the depletion of CD4+and CD8+T cells in HIV infection appears to worsen with
senescence. Older patients also exhibit a less robust humoral response, with the production of less avid
and specific antibodies.
Conclusion: Both HIV and aging contribute to immune dysfunction, morbidity and mortality. However,
highly active antiretroviral therapy (HAART) is beneficial for older patients, and treatment of older
patients should not be discouraged.
© 2010 Elsevier B.V. All rights reserved.
1. Introduction
Population aging has been observed in countries around the
world, including developing countries. On an individual level, aging
is associated with complex modifications of the immune system
that result in increased susceptibility to infectious, autoimmune,
and neoplastic diseases (Pawelec, 1999) in addition to a decreased
response to active immunization (Haynes, 2005).
In parallel, human immunodeficiency virus (HIV) infection has
been spreading among older individuals through the decades. In
Brazil there has been an absolute and relative increase in AIDS cases
in this population (Brasil, 1980), mainly due to heterosexual trans-
mission, and the aged population is greatly vulnerable to this mode
of transmission (Stall and Catania, 1994).
∗Corresponding author at: Rua Frei Caneca, 557, Cerqueira Cesar, São Paulo, zip
code 01307-001, SP, Brazil. Tel.: +55 11 3120 5290.
E-mail address: viviansilva87@gmail.com (V.I. Avelino-Silva).
The course of HIV infection can differ between older and younger
people. Thus, it is fundamental to study the specific characteristics
of HIV infection in older patients.
2. Methods
We performed a review of the literature from the last 20 years
using the electronic databases MEDLINE, LILACS, EMBASE, and
SCIELO. The search terms “aged,” “elderly,” “aging,” and “HIV”
were combined with the term “immunology” using the “AND”
Boolean operator. The search terms “aged,” “elderly,” and “aging”
were combined with the term “HIV” using the “AND” Boolean
operator. We excluded case reports and articles related to the
diagnosis or treatment of opportunistic infections or comorbidi-
ties. In addition, articles and other data sources were found from
bibliographic references and from informal channels of com-
munication, such as personal correspondences and unpublished
events.
1568-1637/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.arr.2010.10.004
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164 V.I. Avelino-Silva et al. / Ageing Research Reviews 10 (2011) 163–172
3. Results
3.1. Definitions
While aging is a continuous and dynamic process, World Health
Organization and most clinical and geriatric references define the
chronological age of 60 years as a cutoff of “elderly” or older popu-
lation (World Health Organization, 2010). However, the Centers for
Disease Control and Prevention defines older HIV people as those
ages 50 and over, originally because 50 years was considered the
upper age range for HIV infection (Linsk, 2000). Accordingly, most
articles referred in the text follow the 50 years cutoff for HIV older
patients and 60 years cutoff for general geriatric population.
3.2. Clinical aspects
Aside from any of the effects of HIV infection, aging is also asso-
ciated with an increased susceptibility to infectious complications
such as pulmonary and urinary tract infections (Gavazzi and Krause,
2002), which occur at increased frequency and clinical severity, and
are more often associated with comorbidities (Kovaiou et al., 2007).
Age-related degenerative processes and comorbidities affect pri-
mary defense barriers such as dermal integrity, coughing reflexes,
and mucociliary clearance (Castle, 2000).
The clinical presentation of infections also differs between older
and younger people. Older patients are usually less symptomatic
and may have atypical symptoms such as anorexia, confusion,
asthenia or fatigue. Fever may be very low or even nonexistent in
up to 50% of older patients with documented infections (Gavazzi
and Krause, 2002).
Older people are at higher risk for hospitalization and death
due to influenza infections. Although they offer protective benefits,
influenza vaccinations are less effective in the elderly compared
to younger adults (Prevention, 1999; Webster, 2000). Aging has
also been observed to be associated with a lower response to the
pneumococcal vaccine (Musher et al., 1986), a lower reactivity to
intradermal tests (Carvalho, 1970), and a greater susceptibility to
neoplastic diseases (Gavazzi and Krause, 2002).
Older HIV-infected patients present with lower CD4+T cell
counts (Phillips et al., 1991; Operskalski et al., 1995), higher viral
load and are more frequently symptomatic at diagnosis (O’Brien
et al., 1996; Ferro and Salit, 1992; Ena et al., 1998). The diagno-
sis of HIV infection is frequently late in patients over 50 years
old. The vulnerability of this group is often neglected by health
professionals who assume that older patients are neither sexually
active nor users of intravenous drugs. In addition, symptoms such
as weight loss, fatigue, and visual and cognitive impairments are
repeatedly assumed to be part of the normal aging process (Sanders
et al., 2008). Older patients themselves are less likely to suspect
HIV infection. Up to 81.3% of HIV-infected patients over the age of
60 never suspected they had an infection prior to testing (Castro,
2007; Babiker et al., 2001). Furthermore, the course of infection is
more rapidly progressive, with higher morbidity and lethality rates
probably as result of immunosenescence, comorbidities, and later
diagnosis (Ena et al., 1998; Soriano et al., 1998; Carre et al., 1994;
Skiest et al., 1996; Butt et al., 2001).
3.3. Morphofunctional changes of immune organs
Aging and HIV infection both contribute to peripheral blood
cytopenia of one or more lineages. The bone marrow hematopoietic
compartment becomes gradually smaller with age, and it is substi-
tuted by adipose tissue (Compston, 2002). This structural change
is probably associated with hormonal modifications, such as the
decline in human growth hormone production (Lamberts et al.,
1997; French et al., 2002). In addition, HIV infects bone marrow
accessory cells, causing defective stromal function and alteration of
the hematopoietic growth factor network (Isgro et al., 2005; Alexaki
and Wigdahl, 2008); older HIV patients frequently present with
dysplasia affecting the myeloid, erythroid and platelet precursor
cells (Tripathi et al., 2005).
Old mice have an increased number of bone marrow
macrophages with impaired ability to generate or release tumor
necrose factor ␣(TNF␣)(Wang et al., 1995). Among all the stromal
cells, the macrophage is the most important cell type that is produc-
tively infected by HIV-1, and macrophages express viral antigens
both in vivo and in vitro (Isgro et al., 2005).
Age diminishes interleukin-7 production by bone marrow cells
(Kang et al., 2004; Tsuboi et al., 2004). This cytokine is apparently
involved in thymocyte proliferation, differentiation, the matura-
tion of T and B lymphocytes and the restoration of peripheral T-cell
counts in HIV-infected patients (Beq et al., 2004).
The thymus is the primary organ for T-cell maturation, and
with age, the thymus undergoes an important volume reduction,
an increase in the proportion of epithelial tissue and perivascu-
lar component, and a decrease in new lymphocytes production
(Steinmann, 1986; Aw et al., 2007). Thymic atrophy is associated
with a shift from a stimulatory to a suppressive cytokine pattern
(Gruver et al., 2007) and can be reversed by growth hormone (GH)
replacement (French et al., 2002). In older HIV-infected individuals,
thymic involution results in a lower production of naïve cells and
can affect CD4+T cell reconstitution during antiretroviral therapy
(Douek et al., 1998; Casau, 2005); GH replacement can enlarge the
thymic volume and increase naïve CD4+T cell counts (Napolitano
et al., 2002).
As suggested by Effros et al. (2008), age-related changes in
gut-associated lymphoid tissue (GALT) are likely to occur, since
gastrointestinal immunity against some intestinal pathogens is
reduced in the elderly. GALT is also profoundly affected by HIV
infection. HIV replicates most intensely in GALT, with rapid and
massive depletion of lamina propria CD4+T cells during acute
infection. Immune reconstitution of the gastrointestinal tract after
HAART is poor and occurs at a much lower rate than in the periph-
eral blood (Brenchley and Douek, 2008).
3.4. Innate immunity
Macrophages and neutrophils appear to lose their microbici-
dal capability with age. Their weakened respiratory burst results in
decreased production of reactive nitrogen and oxygen intermedi-
ates (Plackett et al., 2004; Gomez et al., 2005) as well as impaired
phagocytic function (Butcher et al., 2001).
Similarly, HIV-1-infected patients have a significant decrease in
macrophage phagocytic and oxidative capability, apparently medi-
ated by the Nef protein and related to CD4+T cells depression (Torre
et al., 2002; Noursadeghi et al., 2006). HIV glycoproteins gp120 and
gp41 also have inhibitory activity on monocyte chemotaxis and
activation by chemokines (Noursadeghi et al., 2006). An expected
consequence of the interaction of older age and HIV infection would
be an additional degeneration in macrophagic function. In addition,
macrophages exert an important role in HIV mucosal infection as
they act as a cellular reservoir for viruses and enable HIV penetra-
tion and persistence in the central nervous system through a Trojan
horse mechanism (Crowe et al., 2003; Orenstein, 2001). It is con-
ceivable that aged mucosa facilitates HIV infection due in part to a
macrophagic dysfunction.
In older patients, bacterial products, cytokines and inflamma-
tory mediators such as lipopolysaccharide, interleukin 2 (IL-2),
granulocyte macrophage colony-stimulating factor (GM-CSF) and
granulocyte colony-stimulating factor (G-CSF) are less able to pre-
vent apoptosis of aged neutrophils following stimulation. In the
young, inflammatory mediators are able to prevent apoptosis. This
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V.I. Avelino-Silva et al. / Ageing Research Reviews 10 (2011) 163–172 165
response would guarantee a continued involvement of neutrophils
in controlling microbes’ proliferation, while other cells traffic to the
site of injury. Bacterial products, cytokines and inflammatory medi-
ators as lipopolysaccharide (LPS), interleukin-2, GM-CSF, and G-CSF
are less able to prevent apoptosis of aged neutrophils following
stimulation (Plackett et al., 2004).
Aging is associated with a decrease in toll-like receptors expres-
sion and function in monocytes and macrophages; in particular,
these cells have decreased expression of TLR1 and TLR4 and conse-
quently decreased production of TNF-␣and interleukin 6 (IL-6).
This defect in cytokine expression may be responsible for the
absence of the systemic signals of infection in older patients (Panda
et al., 2009; Renshaw et al., 2002). Experimental evidence has sug-
gested that HIV-1 infection also reduces monocyte expression of
TLR4 (Noursadeghi et al., 2006), thus increasing risk of delayed
diagnosis of infectious illnesses due to lack of specific symptoms.
The production of prostaglandin E2 (PGE2) is enhanced in aged
macrophages (Wu et al., 2001); PGE2 induces interleukin-10 (IL-
10) production, inhibits major histocompatibility complex class II
(MHC-II) expression by dendritic cells, and up-regulates T-helper
cell type 2 (TH2) cytokines (Plackett et al., 2004). Despite the associ-
ation between HIV, cytokine profile, and disease progression is still
controversial, researchers have observed an over-representation
of TH2 responses against viral capsid proteins in subjects with
chronic-progressive HIV-1 infection (Chevalier et al., 2009). Pos-
sible consequences of TH2 cytokines up-regulation include an
exacerbation in allergic reactions and an antagonistic effect on TH1
responses, reducing microbicidal activity of phagocytes and elimi-
nation intracellular microbes.
Dendritic cells (DC) play a critical role in HIV mucosal transmis-
sion and dissemination (Wu and KewalRamani, 2006), and recently
they have been implicated as HIV-1 long-term reservoirs (Coleman
and Wu, 2009). Simultaneously, however, DC are potent stimula-
tors of immune responses and have been used in prophylactic and
therapeutic approaches for HIV infection (Lu et al., 2004). Aging
is associated with a reduced capacity of these cells to phagocy-
tose antigens, produce interleukin-12, and migrate in response
to chemokines (Agrawal et al., 2007). Furthermore, older patients
experience a progressive decline of follicular myeloid DCs (Della
Bella et al., 2007). In older HIV patients, several paradoxical impli-
cations could derive from this decline in dendritic cells function
with age, including a less effective HIV transmission, dissemination
and long-term maintenance, as well as a decrease in the control of
HIV infection.
Natural killer (NK) cells are innate cytotoxic lymphocytes that
do not express T-cell antigen receptors. They play an important
role in the defense against malignancies and viral infections. NK
cells contribute to resistance of certain individuals to HIV infec-
tion, and to immune response in the chronic infection (Fauci et al.,
2005). Although the number of NK cells increases with age, they
are more likely to have a mature phenotype (CD56dim), a dimin-
ished lytic efficiency, and impaired production of cytokines (IFN-␥,
IL-2) and chemokines (MIP-1a, RANTES, and interleukin 8) (Panda
et al., 2009; Renshaw et al., 2002). HIV infection further affects
the NK cell compartment and induces a decreased proportion of
immature:mature subsets (CD56dim/CD56bright ), lower expression
of natural cytotoxicity receptors and reduced cytolytic potential
(Mantegani et al., 2009). Therefore, elderly individuals could be
more susceptible to HIV induced NK cell dysfunctions.
3.5. Cell-mediated adaptive immunity
In healthy individuals the T cell population shows exceptional
homeostatic control regarding numbers and proportions of the two
major functional subsets of T lymphocytes – CD8+T cells, whose
principal function is to kill virus-infected cells, and CD4+T cells,
which are critical for activating other immune cells (Vrisekoop
et al., 2009).
In HIV-infected individuals, the depletion and dysfunction of
CD4+T cells are responsible for the majority of AIDS complications.
CD4+T cell loss results from a complex interplay between the virus
and the immune system, and it seems to be a biphasic phenomenon,
with an initial massive depletion of CD4+T cells in mucosal tis-
sues during acute HIV infection (Veazey et al., 1998; Kewenig et al.,
1999), followed by a slow decline of the remaining CD4+T cells
during chronic infection. Direct viral cytopathicity alone cannot
explain the course of the disease, particularly during the chronic
phase of infection, since only 0.01–1% of CD4+T cells are infected
in both the peripheral blood and lymph nodes (Chun et al., 1997;
Haase, 1999; Haase et al., 1996; Anderson et al., 1998; Douek et al.,
2002). Another reasonable explanation for CD4+T cells depletion is
that HIV is likely to either directly or indirectly induce a chronic
immune activation that disrupts T cell homeostasis (Vrisekoop
et al., 2009; Douek et al., 2003). Indeed, the degree of chronic acti-
vation is a good predictor of disease progression (Simmonds et al.,
1991; Leng et al., 2001; Roussanov et al., 2000; Giorgi et al., 1999).
Two causal models for this immune activation have been pro-
posed. The first is a homeostatic T cell imbalance due to a chronic
activation of innate immunity through plasmacytoid dendritic
cells activation (Mandl et al., 2008; Meier et al., 2009) and to a
damage in the mucosal surfaces resulting in translocation of pro-
inflammatory microbial products from the intestinal lumen into the
circulation (Brenchley et al., 2006). Alternatively, the second model
purposes a chronic immune activation due to CD4+T cells deple-
tion, either a general decline in CD4+T cells number or a decline
in particular subsets of effector CD4+T cells or T regulatory lym-
phocytes (TREG) (Brenchley et al., 2008; Fazekas de St Groth and
Landay, 2008). Immune activation induced by HIV infection gen-
erates new available target cells for viral replication, resulting in
a positive feedback loop with further CD4+T cells destruction and
immune activation (Douek et al., 2003; Grossman et al., 2002).
Age also induces changes in the number, proportion and func-
tion of lymphocytes. Naïve lymphocytes of elderly mice have a
lower capacity of activation, cytokine production and differenti-
ation to Th1 and Th2 subpopulations (Aw et al., 2007; Haynes et al.,
2003; Haynes et al., 2005; Haynes and Maue, 2009). The aging
process is associated with a reduction in the naïve lymphocyte pop-
ulation, lower expression of CD27 and CD28 and a decrease in T-cell
receptor (TCR) diversity (Haynes and Maue, 2009; Pawelec et al.,
2009; Derhovanessian et al., 2009). Naïve lymphocyte survival is
influenced by cytokines such as interleukin 7 (IL-7). Accordingly,
the elderly have decreased serum IL-7 levels (Kang et al., 2004),
but among centenarians, who represent a living model of survival
accomplishment, plasma levels of IL-7 are relatively high (Nasi
et al., 2006), suggesting an influence on longevity.
Thymic involution with aging seems to result in the inability
to replace CD4+T cells depleted by HIV infection (Casau, 2005;
Douek et al., 1998, 2003). HIV infection is also associated with a
decrease in the replicative ability of T lymphocyte precursor cells
(Effros et al., 1996). The continuous recruitment and turnover of
naïve T cells, required to maintain the memory pool, eventually
becomes unsustainable (Hazenberg et al., 2000) leading to exhaus-
tion of some T-lymphocytes clones. Moreover, telomeric length in
CD4+and CD8+T cells has been shown to be significantly shorter
in HIV-infected patients (Bestilny et al., 2000).
The number of memory lymphocytes increase with age, but
these cells exhibit a decreased capacity for activation, signaling
and proliferation in aged mouse models (Miller et al., 1997; Nel
and Slaughter, 2002). Memory cells have a diminished ability to
respond to primary antigen when challenges occur at advanced
ages (Haynes et al., 2003; Haynes et al., 2005; Miller et al., 1997;
Kapasi et al., 2002). Several steps in TCR signal transduction are
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166 V.I. Avelino-Silva et al. / Ageing Research Reviews 10 (2011) 163–172
declined, possibly due to changes in lipid raft composition in the
surface membrane of senescent T cells (nel). CD4 T cells from young
(2- to 4-month-old) and aged (14- to 16-month-old) mice have
been tested regarding proliferation and effector cytokine produc-
tion, and sticking differences have been demonstrated both ex vivo
and in vivo, with decreased proliferation in response to antigen
stimulation, in IL-2 production by Th1 and IL-4 and IL-5 production
by Th2 memory cells, and in cognate helper function.
HIV infection decreases the CD8+T cells population by apoptosis
or direct cytotoxicity. In addition, HIV perturbs CD8+T cell cyto-
toxic function by impairing perforin production and expression of
Fas-ligand (FasL). The interaction between FasL and Fas molecules
induces the apoptosis of infected target cells (Saha et al., 2001;
Piazza et al., 2002).
Aging results in a progressive decrease in CD28 expression
on CD8+T cells. CD28 is a co-receptor essential to elicit strong
responses to antigenic challenge; CD28 signal transduction acti-
vates IL-2 gene transcription, enhances IL-2 receptor expression,
modulates T cell migration and homing, and, notably, enhances
telomerase activity (Effros, 2004). Consequently, CD28-negative T
lymphocytes produce lower levels of IL-2 and IL-2r, have shorter
telomeres and thus, lower activating, signaling and proliferative
potential (Effros and Pawelec, 1997; Plunkett et al., 2007).
Progressive loss of CD28 expression on CD8+T cells with aging
is apparently related to cytomegalovirus (CMV) infection (Pawelec
et al., 2009; Hadrup et al., 2006; Pawelec et al., 2004; Akbar and
Fletcher, 2005). As a permanent infection, CMV requires a persis-
tent immune control which would lead to a marked expansion of
CD8+CD28−CMV-specific cells (Pawelec et al., 2004). Accordingly,
CMV-seropositivity has been included in a cluster of age-related
changes in immune parameters, named “immune risk phenotype”
(IRP), which was found to predict mortality in a Swedish longitudi-
nal study (Wikby et al., 1994). Other immune parameters described
in the IRP are poor T-cell proliferative responses to mitogens, low
numbers of B cells and inverted CD4:CD8 ratio (Hadrup et al.,
2006; Wikby et al., 1998). The clonal expansion of CD8+CD28−
T lymphocytes additionally decreases the response to vaccines
(Saurwein-Teissl et al., 2002).
It is possible that HIV infection induces an immunologic effect
similar to that of CMV infection through a chronic immune activa-
tion (Moanna et al., 2005). A shift in the CD4:CD8 ratio occurs in
advanced HIV infection due to the fall in CD4+T cell counts and the
severe decrease in CD28 expression (Effros, 2000). Thus, it could be
expected that HIV-infected elderly may experience an accentuation
of the deleterious effects already characteristic of the aged immune
risk profile. When higher proportions of CD8+CD28−T lymphocytes
were detected at early stages of infection, disease progressed faster
(Cao et al., 2009a).
It is also reasonable to imagine that CMV infection and its
immunological consequences could negatively impact the immu-
nity to HIV by leading to a premature aging of T cells. However,
this association needs to be further investigated. Despite its poten-
tial harmful effects, the maintenance of an adequate immune
response against CMV is essential in preventing its reactivation
during advanced stages of AIDS.
Older patients have a higher concentration of cholesterol in
their cell membranes, which leads to a decrease in membrane flu-
idity and consequent impairment in lymphocyte capacity of lipid
raft internalization. This may weaken lymphocyte signaling and
further contribute to the inefficiency of acquired cellular immune
responses in the elderly (Larbi et al., 2006). Changes in cholesterol
metabolism are also very frequent in HIV-infected/AIDS patients,
especially those under HAART, and elevated cholesterol levels
in this population may be related to a lower cellular membrane
fluidity and lymphocyte signaling impairment (Dube, 2003). For
an aged HIV-infected individual, it is possible to hypothesize this
overlap membrane fluidity impairment could further decrease
lymphocyte signaling.
3.6. Humoral adaptive immunity
Older individuals experience both quantitative and qualitative
modifications in their humoral immune response (Weksler and
Szabo, 2000). Production of B lymphocytes in the bone marrow
is reduced in the elderly as a result of lower levels of precursor
cells and extrinsic factors, such as bone marrow stem cells and
IL-7 (Szabo et al., 1998). HIV infection seems to exert an opposite
effect as it promotes B-cell activation by increasing the produc-
tion of several cytokines and growth factors, such as interferon-␣,
tumor necrosis factor, interleukin-6, interleukin-10, CD40 ligand,
B-cell-activating factor, and IL-7 (Moir and Fauci, 2009).
Despite the decreased production of B lymphocytes by the bone
marrow, B cell number is strictly regulated and remains constant
with age. This is probably due to peripheral regeneration and
improved cell survival. Nevertheless, following drug-induced lym-
phopenia, aged mice regenerate a more restricted repertoire of B
lymphocyte than younger mice, probably due to a decreased bone
marrow production (Weksler and Szabo, 2000).
Peripheral B lymphocytes may be classified by their expression
of IgD and CD27 markers. The B cell subset that is IgD−and CD27−
is significantly increased among older patients. These cells do not
act as antigen presenting cells, nor do they express significant lev-
els of the CD40 molecule necessary to interact with T lymphocytes
(Caruso et al., 2009). HIV also drives the expansion of some human
B-cell subpopulations, such as immature transitional B cells, acti-
vated mature B cells, and exhausted B cells that are CD27−(Moir
and Fauci, 2009).
Older mice and humans both have elevated production of
polyreactive antibodies that are less avid and specific (Weksler and
Szabo, 2000; Ben-Yehuda et al., 1998). The elderly population, espe-
cially those who suffer from chronic diseases, has increased levels
of autoantibodies, a mortality risk factor in this group (Weksler
and Szabo, 2000; Hallgren et al., 1973). Additionally, HIV infec-
tion is characterized by B-cell hyperactivation and poorly inducible
antibody responses. B-cell hyperactivation is manifested by hyper-
gammaglobulinemia, polyclonal B-cell activation, increased cell
turnover, expression of activation markers, and differentiation of
B cells to plasmablasts, with increased production of autoantibod-
ies and an increase in the frequency of B-cell malignancies (Moir
and Fauci, 2009).
A large number of studies have recently demonstrated that a
variety of vaccines are less efficient in elderly persons, includ-
ing influenza vaccine, pneumococcal polysaccharide vaccine and
hepatitis A vaccine. These impaired responses are correlated to a
decrease in several innate and adaptive immune mechanisms with
age, such as a reduced phagocytosis, processing and presentation
of antigens, a decline in naive T cell counts and an accumulation
of highly differentiated effector T cells with impaired stimulatory
and replicative capacities (Weinberger et al., 2008). All these age-
related impairments could lead to a decreased uptake of antigen at
the site of injection, diminished activation and stimulation of adap-
tive immune cells and reduced responses to neoantigens (Weinberg
et al., 2008).
HIV infection is also associated with a reduced efficacy of vac-
cines and lower titers of vaccine-elicited antibodies. One of the
abnormalities probably linked to poor vaccine response in HIV
infection is a defect in class switching, particularly pronounced
in patients with CD4+T cell counts of less than 200 cells/mm3
(Doria-Rose and Connors, 2009). Regardless of the immunologic
reconstitution after HAART, patients with lower pretreatment CD4+
T cell count nadir have a weaker response to vaccination (Lange
et al., 2003).
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V.I. Avelino-Silva et al. / Ageing Research Reviews 10 (2011) 163–172 167
3.7. Immunosenescence and immune response imbalance
Autoreactive immature lymphocyte clones are usually produced
by the lymphoid organs, and one of the main immune tolerance
mechanisms resides in suppression by TREG. In particular, the TREG
subset characterized as CD4+CD25+Foxp3+cells has been shown to
exert immune modulation in experimental and observational mod-
els (Belkaid and Rouse, 2005; Dejaco et al., 2006; Rouse and Suvas,
2007). These cells seem to balance the immune response between
two poles, one overstimulated with the occurrence of autoimmune
diseases, and one suppressed pole with opportunistic recurrent
infections (Maloy et al., 2003; Sugimoto et al., 2003; Boyer et al.,
2004).
High TREG counts might contribute to immune response sup-
pression in the elderly, leading to a lower response to vaccines
and a higher susceptibility to infections and cancer (Miller et al.,
1997). Theoretically, an elevation in TREG lymphocyte counts
could also damage the CD4+T cell responses to HIV infection
in older patients (Miller et al., 1997). Moreover, a recent study
found TREG lymphocyte expansion in HIV-infected patients and
established its association with disease progression (Cao et al.,
2009b).
Immunosenescence implies much more than just a decline in
immune function and is actually an imbalance between suppres-
sion and exacerbation of a chronic inflammatory status (Licastro
et al., 2005). For instance, peripheral mononuclear cells from older
individuals stimulated in vitro produce more proinflammatory
cytokines than cells from younger people (Effros, 2004; Fagiolo
et al., 1993). This might also happen in vivo in older patients suffer-
ing from inflammatory injuries (Bruunsgaard et al., 2001).
Therefore, aging results in chronic immune activation associated
with several clinical conditions, such as bone reabsorption, frailty
and sarcopenia, metabolic syndrome, osteoarthritis, atheroscle-
rosis and cardiovascular diseases, Parkinson’s and Alzheimer’s
diseases, and cancer (Castle, 2000; Licastro et al., 2005). This state
of chronic immune activation is sometimes defined as “autotoxic-
ity” rather than autoimmunity in which there is a direct immune
aggression against “self” antigens (McGeer and McGeer, 2004).
Aside from immunosuppression with polyclonal B-cell acti-
vation, chronic immune activation is a characteristic feature
of progressive HIV disease; including increased T-cell turnover,
increased frequencies of activated T cells, and increased serum lev-
els of proinflammatory cytokines and chemokines (Douek et al.,
2003). This inflammatory state may be elicited by circulating
microbial products possibly derived from the gastrointestinal tract
(Brenchley et al., 2006), and it can be manifested by the exac-
erbation of inflammatory rheumatic and dermatologic conditions
(Cuellar and Espinoza, 2000; Dlova and Mosam, 2006).
Fig. 1 illustrates the main changes in the immune organs and
in innate, cell-mediated, and humoral immunity expected in older
HIV-infected patients.
3.8. Treatment response in HIV-infected older patients
Several authors have studied the immunologic and virologic
response to antiretroviral therapy in older HIV-infected patients
and found conflicting results (Table 1).
Some studies have established that older patients who undergo
HAART present a lower elevation in CD4+T cell counts and a
decreased production of naïve lymphocytes (Goetz et al., 2001;
Grabar et al., 2004; Manfredi and Chiodo, 2000; Manfredi et al.,
2003; Cohen Stuart et al., 2002; Lederman et al., 2000; Teixeira
et al., 2001; Kalayjian et al., 2005; Yamashita et al., 2001). A few
authors have described an inverse relationship between age and
immunologic HAART response (Viard et al., 2001; Florence et al.,
2003). In contrast, other studies have not observed such relation-
ships (Grimes et al., 2002; Knobel et al., 2001; Tumbarello et al.,
2004; Nogueras et al., 2006).
Although the immunologic response to HAART in older patients
is controversial, there is no doubt regarding a better virologic
response (Paredes et al., 2000; Wellons et al., 2002) and a signif-
icant reduction in the mortality among them (Perez and Moore,
2003). Better compliance and lower treatment abandonment might
explain these results (Hinkin et al., 2004). Additionally, advanced
age may be associated with lower viral load independent of
antiretroviral use (Goodkin et al., 2004).
The higher prevalence of comorbidities and polypharmacy in
HIV-infected older individuals can influence the occurrence of
adverse effects of antiretroviral drugs but do not seem to adversely
affect treatment (Shah et al., 2002; Adeyemi et al., 2003). HAART
discontinuation because of adverse effects occurs at earlier stages
of treatment in patients over 50 years of age. Treatment discontin-
uation as the result of neuropsychiatric and hematologic adverse
effects were more frequent among older patients than younger
patients (Cuzin et al., 2007).
4. Discussion
Aging is one of the current characteristics of the HIV epidemic.
It is not only a consequence of effective treatment and care of peo-
ple living with HIV/AIDS but also an effect of increasing sexual
transmission of HIV among older individuals (Myers, 2009).
Clinically, older patients with HIV infection are especially prone
to infectious and neoplastic complications and death (Ena et al.,
1998; Soriano et al., 1998; Carre et al., 1994; Skiest et al., 1996;
Butt et al., 2001), and several symptoms of HIV infection can be
confounded by the natural processes of aging (Sanders et al., 2008).
However, this population has better treatment compliance com-
pared to young people despite more frequent comorbidities and
polypharmacy (Hinkin et al., 2004; Shah et al., 2002; Adeyemi
et al., 2003). Therefore, the interest in detecting HIV infection in the
elderly is essential for appropriate early diagnosis and treatment
and to prevent serious complications.
The senescence process affects the complex interaction between
HIV infection and the immune system. Sufficient knowledge of
these changes is essential to improve the care of this growing pop-
ulation.
Both HIV infection and aging contribute to changes and dysfunc-
tion in the bone marrow, thymus and GALT, particularly in terms of
the number and function of immune and stromal cells (Compston,
2002; Isgro et al., 2005; Alexaki and Wigdahl, 2008; Tripathi et al.,
2005; Steinmann, 1986; Aw et al., 2007; Gruver et al., 2007; Effros
et al., 2008; Brenchley and Douek, 2008). Some of these alterations
may be related to the decreased production of growth hormone
and interleukin-7 (Lamberts et al., 1997; French et al., 2002; Kang
et al., 2004; Tsuboi et al., 2004; Beq et al., 2004; Napolitano et al.,
2002). The knowledge about pathophysiology of HIV infection in
the elderly will be beneficial for the development and use of some
immune-based therapies (Deeks, 2009).
Innate immunity is equally affected by HIV infection and senes-
cence; there is a decline in the macrophages’ and neutrophils’
microbicidal capability, monocytes’ expression of toll-like recep-
tors, dendritic cell production of interleukin-12 and in natural killer
cell function, in addition to an increase in neutrophils’ susceptibil-
ity to apoptosis (Plackett et al., 2004; Gomez et al., 2005; Butcher
et al., 2001; Torre et al., 2002; Noursadeghi et al., 2006; Panda
et al., 2009; Renshaw et al., 2002; Agrawal et al., 2007; Della Bella
et al., 2007; Mantegani et al., 2009). Some experimental and clinical
studies have tried to enhance the innate immunological response
to both HIV infection and aging with several different substances.
Zinc supplementation showed beneficial effects in older individu-
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168 V.I. Avelino-Silva et al. / Ageing Research Reviews 10 (2011) 163–172
Table 1
Antiretroviral therapy response in older HIV-infected individuals.
Author, year Number of patients Design Follow-up (months) HAART response Observation
V. I.
Lederman et al., 2000 71 Prospective cohort 12 NE ↓Naïve CD4+T cell increase inversely related to age following dual
therapy
Manfredi and Chiodo, 2000 105 Retrospective cohort 12 = ↓Worse immunological and similar virological response over age 55
following first line HAART
Paredes et al., 2000 1469 Prospective cohort 9–20 ↑NE Older patients more likely to achieve virological success
Goetz et al., 2001 80 Retrospective cohort Mean 16.7 NE ↓Among virological responders, each decade of age decreased CD4+T
cell count response by 35 cells
Knobel et al., 2001 699 Prospective cohort 24 = = Trend towards better adherence, virological and immunological
response over 60
Teixeira et al., 2001 22 Retrospective case-control 12 NE ↓Poor CD4+T cell responders were older than good responders
Viard et al., 2001 1956 Prospective cohort 12–31 NE ↓Inverse relation between age and CD4+T cell increase
Yamashita et al., 2001 397 Prospective cohort 30–60 NE ↓Worse short-term (6 months) CD4+T cell increase with older age
Grimes et al., 2002 104 Retrospective cohort 24–102 = = No differences in AIDS-related mortality, CD4+T cell counts or viral
load
Cohen Stuart et al., 2002 45 Prospective cohort 12 NE ↓Naive T-cell recovery rate inversely related with age
Wellons et al., 2002 303 Retrospective cohort Mean 29 ↑= Better virological response and similar immunological response
Florence et al., 2003 225 Transversal Not applied NE ↓Unsatisfactory CD4+T cell response increases with age despite good
virological response
Manfredi et al., 2003 57 Retrospective cohort 12 = ↓Lower immunological response in patients aged 65 and older,
compared to those aged 55–65
Perez and Moore, 2003 797 Retrospective cohort 36.5 NE NE Older patients have a greater survival benefit with HAART
Goodkin et al., 2004 135 Transversal Not applied ↑NE Lower plasma viral load with older age independent of antiretroviral
use
Grabar et al., 2004 3015 Prospective cohort Mean 31.5 ↑↓Slower CD4+T cell response and higher risk of clinical progression
despite better virologic response over age 50
Tumbarello et al., 2004 243 Prospective cohort 6–78 = = No differences in virological or immunological responses
Kalayjian et al., 2005 80 Prospective cohort 12 = ↓Smaller increases in naive T cells and similar virological responses over
age 45
Nogueras et al., 2006 455 Prospective cohort 3–66 = ↓Similiar virological response, lower CD4+T-cell response and faster
progression to AIDS in older patients.
V., virological responde to HAART; I., immunological response to HAART; NE, not evaluated; ↑, higher response; ↓, lower response; =, similar response.
Author's personal copy
V.I. Avelino-Silva et al. / Ageing Research Reviews 10 (2011) 163–172 169
Fig. 1. Expected immune consequences of HIV infection in the elderly.
als, but there were contradictory results regarding its effects on HIV
infection (Prasad, 2009). Melatonin, a neurohormone secreted by
the pineal gland, has been shown to have a potentially therapeutic
value in older patients (Cardinali et al., 2008).
CD4+and CD8+T cells depletion and dysfunction caused by
chronic immune activation in HIV infection seems to worsen with
senescence (Vrisekoop et al., 2009; Douek et al., 2003; Haynes and
Maue, 2009; Licastro et al., 2005). Aging may theoretically decrease
the CD4+T cell response to HAART (Goetz et al., 2001; Grabar et al.,
2004; Manfredi and Chiodo, 2000; Manfredi et al., 2003; Cohen
Stuart et al., 2002; Lederman et al., 2000; Teixeira et al., 2001;
Kalayjian et al., 2005; Yamashita et al., 2001; Viard et al., 2001;
Florence et al., 2003). Therefore, it is necessary to emphasize the
importance of early diagnosis and treatment in older HIV-infected
patients.
Older individuals exhibit deficient humoral immune responses,
including a greater proportion of exhausted B cells and produc-
tion of less avid and specific antibodies (Weksler and Szabo, 2000;
Lange et al., 2003). Although HIV infection stimulates B-lymphocyte
growth and activation, there is a polyclonal activation with poorly
inducible antibody responses (Moir and Fauci, 2009). Consequently,
HIV infection and aging equally worsen humoral immunity, pre-
disposing an individual to infections and to a reduced efficacy of
vaccines.
5. Conclusion
In conclusion, HIV infection and aging undoubtedly contribute
equally to a complex immune dysfunction and to increased mor-
bidity and mortality in older HIV-infected individuals. Several
studies are currently trying to better understand the immune con-
sequences of the coexistence of these two clinical conditions and
how to manage them. However, evidence does favor the benefi-
cial use of HAART for older patients, which results in a virologic,
immunologic, and clinical response and a reduction of mortality.
One should, therefore, not use age as a discouraging factor in treat-
ing HIV-infected patients but as a stimulus to pursue early diagnosis
and thus, obtain the best possible treatment responses and clinical
outcomes.
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