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 Rev. Med. Virol. 2012; 22: 33–45.
Published online 23 September 2011 in Wiley Online Library
(wileyonlinelibrary.com)
Reviews in Medical Virology DOI: 10.1002/rmv.711
REVIEW
HIV-1 infection and neurocognitive impairment
in the current era
María del Palacio†, Susana Álvarez† and Mª Ángeles Muñoz-Fernández*
Laboratorio Inmunobiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain

S U M M A RY
Brain HIV-1-infection may result in a syndrome of profound cognitive, behavioral and motor impairment known as
AIDS dementia complex (ADC) in adults and HIV-related encephalopathy in children. Although the introduction of
highly active antiretroviral therapy (HAART) has prolonged and improved the lives of infected individuals, it is clear
that HAART does not provide complete protection against neurological damage in HIV/AIDS. HIV-1 associated de-
mentia is a complex phenomenon, which could be the result of several mechanisms caused by those players using dif-
ferent intracellular signaling pathways. Understanding the causes of neurodegeneration during HIV-1 infection and the
factors which certain individuals develop disease can provide researches on new therapeutic targets to positively affect
disease outcomes. Controlling CNS viral replication with HAART is an essential primary approach, but it should be
complemented with adjunctive CNS-directed therapeutics. Understanding the nature of HIV-1 infection within the
CNS as well as inflammatory responses will ultimately lead to the elimination of HIV-associated neurocognitive disor-
ders. Copyright © 2011 John Wiley & Sons, Ltd.
Received: 3 May 2011; Revised: 5 August 2011; Accepted: 9 August 2011

INTRODUCTION impairment (ANI), to minor neurocognitive disor-

Over 40 million people worldwide are infected by
HIV-1 (UNAIDS/WHO), and while HIV-1 is most
well known for its devastating effects on the im-
mune system and the resulting AIDS, it can also
cause several neurological disorders, collectively
known as HIV-associated neurocognitive disorders
(HAND). HAND encompass a hierarchy of pro-
gressively more severe patterns of CNS involve-
ment, ranging from asymptomatic neurocognitive
*Corresponding author: Dr Mª Ángeles Muñoz-Fernández, Laboratorio
Inmuno-Biología Molecular, Hospital General Universitario, Gregorio
Marañón, C/Doctor Esquerdo 46, 28007 Madrid, Spain.
E-mail: mmunoz.hgugm@salud.madrid.org
†
These authors contributed equally to this work.
Abbreviations used
ANI, asymptomatic neurocognitive impairment; ADC, AIDS demen-
tia complex; ART, antiretroviral therapy; BBB, blood brain barrier;
COX, cyclooxygenase; CT, computed tomography; HIVE, HIV-1 en-
cephalitis; HAD, HIV-associated dementia; HAART, highly active
antiretroviral therapy; HAND, HIV-associated neurocognitive disor-
ders; HDS, HIV dementia scale; LPS, lipopolysaccharide; LTR, long
terminal repeat; MCMD, minor cognitive motor disorder; MCP-1,
monocyte chemoattractant protein 1; MRI, magnetic resonance imag-
ing; MRS, magnetic resonance spectroscopy; NFL, neurofilament pro-
tein; NMDA, N-methyl-D-aspartate; NO, nitric oxide; PAF, platelet
activating factor; PET, positron emission tomography; PGE2, prosta-
glandin E2; QUIN, quinolinic acid; SIV, simian immunodeficiency vi-
rus; SPECT, single photon emission computed tomography; TJ, tight
junctions; TLR, toll-like receptors.
der (MND), to the more severe HIV-associated
dementia (HAD; also known AIDS dementia com-
plex, [ADC], or HIV encephalopathy) [1].
The advent of the highly active antiretroviral ther-
apy (HAART) has effectively reduced morbidity and
mortality in HIV-1 infection. In the vast majority of
antiretroviral-naïve HIV-1-infected patients intro-
duced to HAART, the plasma viral load decreases to
undetectable levels, and the cluster of differentiation
4 (CD4) count increases to normal values. Concur-
rently, the incidence of opportunistic complications
has decreased. HAART also dramatically decrease
the (CSF) viral load [2–4].
There are additional factors suggesting that
HAART may not provide sufficient protection to
prevent the CNS complications of HIV infection. Al-
though HAART may arrest neurocognitive impair-
ment in some populations with HAND [5], a subset
of patients is susceptible to develop a leukoencephalo-
pathy, secondary to immune reconstitution in an HIV-
infected CNS [6]. Chronic neuroinflammation is also
present even in HAART-treated patients [7]. These
findings suggest that HAART does not provide
complete protection from HIV-induced inflam-
matory responses in the CNS and subsequent neuro-
degeneration. Finally, as life expectancies among

Copyright © 2011 John Wiley & Sons, Ltd.

34
HIV/AIDS patients increase and as the population
ages, neurologic disorders associated with aging are
becoming more prevalent. Indeed, the risk of stroke
[8] and diabetes mellitus [9] is increasing among in
HIV/AIDS patients, because in part of the marked
metabolic abnormalities such as hyperglycemia and
hyperlipidemia associated with different combination
antiretroviral therapy regimens coupled with advanc-
ing age.
Effective control of CNS viral replication through
HAART is the essential primary approach, but that
it should be complemented with adjunctive CNS-
directed therapeutics. HIV-induced inflammation
and its consequences, expressed both systemically
and within the CNS, are attractive targets that
could be approached through multiple pharmaco-
logic agents.
CLINICAL FEATURES
Before the widespread use of HAART in the devel-
oped world, 20%–30% of individuals infected with
HIV-1 developed a range of cognitive and motor
symptoms, including impaired short-term memory,
reduced concentration, and leg weakness that are
collectively known as HAD. These symptoms often
occurred together with behavioral symptoms, such
as personality changes, apathy, and social with-
drawal, and HAD could, in its more severe forms,
lead to a nearly vegetative and mute state. The on-
set of HAD is correlated with high plasma viral
loads, which accounts for the strong effects of
HAART on reducing its incidence, although with
the longer lifespan of patients with HIV-1, there is
increasing prevalence of HAD [10,11]. Therefore,
with the use of HAART, a more subtle form of
CNS dysfunction, minor cognitive motor disorder
(MCMD), has either become more common or is
more obvious because it does not progress to
HAD [10,11]. In this syndrome, loss of memory
and decreases in computational and other higher
cortical functions are much less pronounced. It
has recently been estimated that ~10% of HIV-1
infected adults have HAD but that MCMD might
be several times more common, involving perhaps
as many as 30% of the HIV-1 infected population.
Furthermore, the clinical presence of MCMD has
been associated with pathological changes in the
CNS that are characteristic of HIV-1 invasion
(known as HIV-1 encephalitis; HIVE), and MCMD
is associated with a worse overall prognosis for
HIV-1 infected individuals [12]. The most notable
Copyright © 2011 John Wiley & Sons, Ltd.
M. D. Palacio et al.
change in the last research terminology revision
proposed by Antinori et al. is the addition of the
category of asymptomatic neurocognitive impair-
ment (ANI) based on the observation that some
individuals have demonstrable (and usually mild)
cognitive impairment demonstrated by formal neu-
ropsychological tests without any observed abnor-
mality in everyday functioning. ANI is defined by
performance, at least 1 SD below the mean of de-
mographically adjusted normative scores in at least
two cognitive areas [1].
There is evidence for a change in HAD in the era
of HAART, apart from the potentially increased im-
portance of confounding factors (hepatitis C, tes-
tosterona deficiency, effects of aging. . .)[13]. So,
there is an increased frequency of verbal memory
impairment along with a more classical distribu-
tion of impairment (fine motor incoordination),
the mesial temporal lobe abnormalities appear to
be more relevant in a completed prospective posi-
tron emission tomography (PET)–CSF study, and
standard CSF markers of ADC, such as beta-2
microglobulin and the viral load in the CSF, are
no longer sensitive to the presence or severity of
HAD [14].
Highly active antiretroviral therapy has, thus,
raised the CD4 cell count which is commonly seen
in patients with HAD and has introduced two po-
tentially new risk factors: nadir CD4 cell count
[15] and disease duration [14]. In the Cohen’s study
where they examine patterns of brain volume loss
in HIV-1 infected adults on HAART and demo-
graphic and clinical factors contributing to brain
volume loss, the results suggest that the duration
of a patient’s infection may influence certain brain
volumes, independent of other clinical factors, such
as cognitive status, viral load, and immunological
status. Similarly, nadir CD4 was a significant factor
in half the models examined, primary in the cortical
regions and the hippocampus, suggesting that a
story of advanced immune suppression may exert
a negative effect on brain structure. The association
between immune suppression and brain volume
has not yet been previously described in HIV-1 in-
fection and provides further rationale for initiating
antiretroviral treatment early in the course of infec-
tion [16].
HIV-1 infection is now a chronic condition and can
exhibit interactions with other neurodegenerative
disorders. Notably, increased b-amyloid is found in
the brain in HIV-1 infection, and patients with
Rev. Med. Virol. 2012; 22: 33–45.
DOI: 10.1002/rmv
NeuroAIDS in the current era
HAND show increased aggregation of b-amyloid
within neurons [17]. The complexities in disease
pathobiology for HAND are becoming even broader.
NEUROPATHOGENESIS
The CNS is susceptible to infection by retroviruses
of various species and by members of the lentivirus
family, in particular. The specific requirements for
entry to the brain and the many cell types in the
CNS increase the complexity of virus—cell interac-
tions in the brain. In theory, five main cell types
(astrocytes, oligodendrocytes, neurons, perivascu-
lar macrophages, and microglia) are susceptible to
retroviral infection, but of these five, the latter two
are the most commonly infected by HIV-1 [18].
Mechanisms of neuroinvasion of human
immunodeficiency virus-1
Human immunodeficiency virus-1 enters the brain
early in the course of infection, presumably via
infected macrophages and lymphocytes, and then
persists primarily in perivascular macrophages
and microglia [19,20]. Three pathways have been
proposed for viral entry into the brain: (i) carriage
of HIV-1 by infected leukocytes (“Trojan horse” hy-
pothesis); (ii) passage of cell-free virus into the
brain; and (iii) release of virus into the brain by
infected endothelial cells [18] (Figure 1). This can
occur within 1–2 weeks after the virus enters into
the systemic circulation [21]. In contrast to
Figure 1. HIV-1 neuroinvasion. (1) According to the "Trojan Horse hypothesis" entry of HIV-1 into the brain takes place by the migration
of infected monocytes, which differentiate into perivascular macrophage. (2) Entrance of HIV-1 by transcytosis of brain microvascular en-
dothelial cells. (3) The direct entrance of the virus. Once the virus is in the brain, it infects productively macrophages and microglia
Copyright © 2011 John Wiley & Sons, Ltd.
35
lymphocytes, an increased number of microglia
and macrophages correlates well with the severity
of pre-mortem HAND [19,22]. Infection of the
CNS by HIV-1 can be detected and monitored by
measurement of viral load in CSF. Several groups
have reported a positive correlation between CSF
viral load and the observed degree of cognitive
dysfunction in patients with HAND [23,24]. More-
over, CSF viral load appears to correlate with viral
load in brain measured by quantitative PCR
[24,25], and the highest concentrations of virus are
observed in those subcortical structures most fre-
quently affected in patients with severe HAND/
HAD [25].
In addition to initial neuroinvasion and infection
of perivascular macrophages and microglia, factors
associated with progressive HIV-1 infection in the
periphery, thus outside the brain, may be required
to eventually trigger the development of HAND
and dementia [26]. One such factor could be an el-
evated number of circulating monocytes expressing
two markers of activated monocytes, CD16 and
CD69. Another important player may be the blood
brain barrier (BBB), which separates the CNS from
the periphery and supposedly controls the traffic
of low-molecular-weight nutrients, peptides, pro-
teins, and cells in and out of the brain (see for
BBB review [27]). Thus, the condition of the BBB
may potentially determine continuing or repeated
neuroinvasion during the course of HIV disease.
Rev. Med. Virol. 2012; 22: 33–45.
DOI: 10.1002/rmv
36
Tumor necrosis factor-a is known to increase the
permeability of the BBB to HIV-infected cells [28],
induce expression of cell adhesion molecules, and
upregulate monocyte chemoattractant protein-1
(MCP-1) [29]. Following extravasation, infected
monocytes/perivascular macrophages begin to
actively produce and release HIV/SIV, as well
as a variety of proinflammatory mediators that
impacts the function of surrounding cells and
enhances further monocyte recruitment [30–32].
This occurs concurrently with dysregulation of
tight junctions (TJ). In vivo, several studies have
shown that the loss of transmembrane TJ proteins
and perijunctional proteins in microvessels is asso-
ciated with increased permeability of the BBB fol-
lowing HIV/SIV neuroinvasion [33]. Fiala et al.
have described changes in TJ protein zo-1 pattern-
ing in brains of patients with HIVE, with a com-
plete lack of zo-1 staining in cortical vessels of
one patient [28].
Human immunodeficiency virus-1 infection
compromises the structural integrity of the intesti-
nal tract and can cause leakage of bacteria into the
blood stream. Such microbial translocation results
in elevated plasma levels of bacterial lipopolysac-
charide (LPS), and in HIV-infected/AIDS patients,
is associated with increased monocyte activation
and dementia [34,35]. Additionally, it has recently
reported that HAND is associated with higher
systemic levels of plasma LPS. The hypothesis is
that HIV-1 infected patients with microbial traslo-
cation from the gut will have higher plasma LPS
and thus more systemic immune activation lead-
ing to increased risk of transit of HIV-infected
monocytes into end organs including the CNS.
Another study suggests that HIV-1 infection
increases the vulnerability of the BBB in response
to LPS and facilitates the transmigration of pe-
ripheral monocytes/macrophages [36]. These find-
ings support an important role for toll-like
receptors besides monocytes and macrophages in
HAD [36].
Cells target in brain infection
Cluster of differentiation 4 is a primary receptor
for HIV-1 infection and is commonly found on
peripheral blood mononuclear cells especially on
T-cells, monocytes, and macrophages. Microglia
and perivascular macrophages are the only two cell
types into the brain that express CD4 antigens.
Copyright © 2011 John Wiley & Sons, Ltd.
M. D. Palacio et al.
Other co-receptors for HIV-1 infection have also
been identified, which are known as chemokine
receptors.
Chemokine receptors belong in the large cate-
gory of G-protein-coupled seven transmembrane-
spanning domain receptors and mediate leukocyte
trafficking and contribute intimately to the organi-
zation of inflammatory responses of the immune
system [37–40]. Chemokines and their receptors
are in fact indispensable for maintenance, matura-
tion, and migration of hematopoietic and neural
stem cells [40]. However, the most prominent patho-
logical function of certain chemokine receptors
seems to be the mediation of HIV-1 infection [37–39].
Infection by HIV-1 of macrophages and lympho-
cytes in the periphery and microglia in the brain
can occur after binding of the viral envelope pro-
tein gp120 to one of several possible chemokine
receptors in conjunction with CD4. Depending on
the exact variant of gp120, different HIV-1 strains
may use CCR5, and CCR3, or CXCR4, or a combi-
nation of these chemokine receptors to enter target
cells [39]. It is assumed that HIV-1 in the brain uses
CCR5 as the principal coreceptor for infecting tar-
get cells [41], although R5, X4, and R5/X4 isolates
all have been found in the CNS of HIV-1-infected
individuals [42]. Several in vitro studies strongly
suggest that CXCR4 is prominently involved in
HIV-associated neuronal damage, whereas CCR5
may play a dual role by being able to either serve
a toxic or protective role [43–45]. It has been de-
scribed the presence of very different HIV-1 isolates
in the brain despite no great differences in clinical,
pathological, or immunological parameters, indi-
cating that there is not a particular phenotypic
property of the HIV-1 virus that might explain its
neurovirulence and/or neurotropism [46].
Neurons and astrocytes express CCR5 and
CXCR4 [47,48], however, it is unclear which recep-
tors are involved in HIV-1 entry in these cells. Al-
though most studies have found a lack of infection
of neurons, there are some reports of HIV-1 DNA
and protein expression in these cells [49], and we
have previously shown that neuroblastoma cells
are susceptible to HIV-1 infection [50,51]. The possi-
bility of neuronal infection certainly would be an
important factor in neuropathology, and infected
neurons, like astrocytes, may provide a reservoir of
virus with the capacity for reactivation. Oligoden-
drocytes are believed to be minimally involved in
HIV-1 dementia [18].
Rev. Med. Virol. 2012; 22: 33–45.
DOI: 10.1002/rmv
NeuroAIDS in the current era
Studies of cultured human astrocytes have
shown that HIV-1 infection is initially productive
yet noncytopathic and ultimately is converted to a
latent stage with little expression of viral protein.
The frequency of astrocyte infection at perivascular
regions in severe HIVE (16%–19%) is similar to the
frequency of lymphocyte infection in lymph nodes
of patients with AIDS (15%–30%)[52,53]. Because
approximately 70% of the cells in brain are astro-
cytes, they are a significant reservoir of latent
HIV-1 DNA, being a significant factor in HIV-1-me-
diated neuropathogenesis. Although astrocyte dys-
function is just one of several pathways leading to
neurodegeneration in AIDS, Churchill et al. demon-
strated that neurodegeneration resulting from as-
trocyte dysfunction may be a consequence of
astrocyte infection [54]. Under certain conditions,
latent HIV-1 infection of astrocytes can be reacti-
vated following stimulation with TNF-a and IL-1b
[55,56]. Production of viral structural proteins in
these seemingly latently infected cells could be
stimulated by the addition of those cytokines in
the persistent phase, but the stimulatory response
decreased with time after initial transfection. Stim-
ulation of fetal astrocytes with TNF-a led to an in-
crease of HIV-long terminal repeat (LTR) activity
and increased binding of NF-kB to consensus
kB binding sequence in the HIV-long terminal re-
peat [57]. However, cytokine-stimulation resulted
mainly in increase of the abundance of small early
mRNAs [56].
The inflammatory cascade
Although the low number of infected cells in the
brain cannot explain the extent of damage observed
in HIV-1 encephalopathy, it is widely accepted that
viral proteins shed by infected cells, as well as a vari-
ety of toxic products secreted by activated cells
(infected or uninfected), are the major factors in-
volved in the underlying neuropathology [58].
Excessive production of inflammatory biomole-
cules or mediators of inflammation produced by
different cell types of CNS may induce neurotoxic-
ity. Monocytes, lymphocytes, and activated macro-
phages after entering into CNS release various pro-
inflammatory, inflammatory cytokines, reactive ox-
ygen, and other biomolecules with high neurotoxic
potential. These mediators individually, additively,
or synergistically disrupt normal functioning of
cells of CNS by inducing neurotoxicity [59]. This
Copyright © 2011 John Wiley & Sons, Ltd.
37
may cause alterations in neurotransmitter action
and causes leukoencephalopathy resulting in neu-
ronal apoptosis [60]. TNF-a, platelet activating fac-
tor, prostaglandin E2 (PGE2), nitric oxide (NO), and
quinolinic acid (QUIN) also cause neurotoxicity.
NO is produced by microvascular endothelial cells,
macrophages, and neurons that may result in N-
methyl-D-aspartate type glutamate-associated neu-
rotoxicity. Elevated levels of NO synthase have
been reported in the brain of HAD patients,
whereas a 40-fold increase in expression of NO
synthase has been described in neurons of drug ad-
dict HIV-1 adults [61,62]. TNF-a is produced by
macrophages and microglia, and it mainly affects
oligodendrocytes, and it has been reported an ele-
vated level of TNF-a mRNA in HIV-1 adults with
neurological complications [63].
Enhanced levels of PGE2, the major product of
COX-2, have been detected in cerebrospinal fluid
in patients with HAD, and correlate with severity
of dementia [64]. Moreover, COX-2-positive macro-
phages infiltrating the brain of patients with HIV-1
encephalitis have been described [65], and viral
proteins as gp120 and Tat are able to induce COX-
2 and PGE2 synthesis in astrocytic and neuroblas-
toma cells [66,67].
It is, thus, apparent that the cellular responses to
infection, and the effects of these responses on dif-
ferent cell populations in the brain, are the links be-
tween HIV-1 infection, HIV-1 encephalopathy, and
HAD (Figure 2).
Neuropathology
The hallmarks of HIV-1 associated neuropathology
include the following: infiltration of macrophages;
the formation of microglial nodules and multinu-
cleated giant cells, suggestive of virus-induced fu-
sion of microglia and/or macrophages, in central
white matter and deep gray matter; widespread re-
active astrogliosis, indicative of astrocyte activation
and damage; the loss of specific neuron subpopula-
tions, particularly those involved in cognition (hip-
pocampus) and motor function (basal ganglia); the
loss of synaptic connections; and myelin pallor, or
the loss of myelin surrounding neuronal axons, in-
dicating damage to oligodendrocytes; and the pres-
ence of HIV-1 DNA in the CSF [58,68]. Table 1
shows potential complications associated with ex-
aggerated neuroinflammation following peripheral
immune challenge.
Rev. Med. Virol. 2012; 22: 33–45.
DOI: 10.1002/rmv
38 M. D. Palacio et al.

Figure 2. Mechanism of neuropathogenesis. The two main components of this mechanism are the direct effect of the HIV-1 infection,
including HIV-1 proteins, and the indirect consequence of infection comprising the secretion of cytokines and neurotoxins. The
infected macrophages and microglia participate actively in the neurodegeneration shedding viral proteins and releasing significant
amount of cytokines and neurotoxins into the CNS. The alteration of astrocytes function results in an increase in the level of neuro-
toxicity in the brain. Neurotoxins released from several sources lead to neuronal injury

Some of the risk factor for all forms of HAND in- sex [69]. In early cohorts, studies before HAART,
clude: a high viral set point early in HIV infection, higher CSF levels of viral load were associated with
age (risk increases with increasing age), low CD4 progression to HAD, but this relationship is not
counts [15,16], anemia [26], low body mass index, seen in HAART-treated individuals. In contrast to
systemic symptoms, injection drug use and the fre- a-chemokines, b-chemokines are only expressed at
quency of coinfection with hepatitis C and female relatively low levels in the brain under normal con-
ditions. However, several b-chemokines are found
at increased concentrations in the CNS following
Table 1. Complications associated with HIV infection: CCL2, MIP-1a, MIP-1b, and
enhanced neuroinflammation. RANTES/CCL5 [70]. Furthermore, microglia acti-
vated by interferons and astrocytes activated by
Potential complications IL-1b and TNF-a express CCL2, which could also
contribute to the positive correlation between
Behavioral and physiological
CCL2 levels and increased risk of HAND [71–73].
Prolonged sickness
b-chemokines may contribute to neuronal toxicity
Prolonged depressive-like behavior
via existing pathways that are overstimulated by
Altered febrile response
higher than normal concentrations of these factors.
Exaggerated weight loss
Circulating HIV DNA concentrations, which
Cognitive
might be related to persistence of infection in cells
Impaired hippocampal-dependent memory
of the monocyte/macrophage lineage, are higher
Delirium
in individuals with HAND [74,75]. The identifica-
Neuronal
tion of a subpopulation of long-term survivors sug-
Dendritic atrophy
gested the possibility that host genetic factors
Decreased neurogenesis
influence HIV-1 pathogenesis. Multiple studies
Impaired long term potentiation
have confirmed the protective impact of CCR5Δ32
Axonal damage
on HIV-1 disease and have identified additional

Copyright © 2011 John Wiley & Sons, Ltd. Rev. Med. Virol. 2012; 22: 33–45.
DOI: 10.1002/rmv
NeuroAIDS in the current era
polymorphisms that alter disease progression.
Apolipoprotein E is associated with severity of de-
mentia, specifically among older HIV-1 infected
individuals, making neurons more vulnerable to
oxidative stress.
DIAGNOSTIC STUDIES
Despite its basic characterization, more than two
decades ago, the nosology and diagnosis of HAND
are difficult both in clinical practice and clinical
trials. The diagnosis relies on recognition of the
clinical syndrome and exclusion of alternative diag-
noses, rather than on specific laboratory-based
findings. The suggested revision in research termi-
nology proposed by Antinori et al. adds quantita-
tive standardization to evaluation, but does not
add greater specificity to diagnosis [1].
Neuroimaging should be obtained in the process
of diagnostic evaluation in all patients with AIDS
and cognitive impairment. Certain findings on
computed tomography or magnetic resonance im-
aging (MRI) are consistent with or even suggestive
of HAD, including diffuse cerebral atrophy and
subcortical or periventricular white matter changes
that appear hypodense on computed tomography
or bright on T2 sequences on MRI. However, neu-
roimaging in this setting is most useful as a means
to exclude other common neurological conditions
in individuals with AIDS, because neither atrophy
nor white matter changes are sensitive or specific
for HAND [16,76]. Among other techniques, single
photon emission computed tomography, PET, and
magnetic resonance spectroscopy have been inves-
tigated as tools for both diagnosis and pathogenetic
studies of HAD [77].
Cerebrospinal fluid analysis is required in febrile or
encephalopathic patients to exclude opportunistic in-
fections, but is generally not necessary in the more
typical nonfebrile, slowly progressive forms of HAND,
although it gets obtained important information.
But patients now presenting with HAND fre-
quently have other comorbidities that both predis-
pose to HAD and confound diagnosis. Thus, HIV-
1-infected adults with a history of drug or alcohol
abuse, psychiatric disease, head trauma, or nutri-
tional deficiencies are more frequently excluded
from effective treatment and are more often poorly
adherent to medications. Because of concomitant
neurologic dysfunction related to their risk for
HIV-1 infection, it is often difficult to determine
the effects of HIV-1 on their cognitive and motor
Copyright © 2011 John Wiley & Sons, Ltd.
39
difficulties and whether these effects are active at
the encounter. It is anticipated that this dilemma
will become increasingly important as the HIV-1-
infected population ages and their vulnerability to
neurodegenerative disease, particularly Alzheimer
Disease, increases [78]. Additionally, newer, atypi-
cal CNS diseases have been described during the
treatment era that may need to be distinguished
from classic HAD, including CNS escape [79], im-
mune reconstitution syndrome [6,80], and HIV
leukoencephalopathy.
The second, related clinical shortcoming centers
on the problem of distinguishing ongoing disease
activity from static injury because of prior insults,
caused either by HIV-1 or by other conditions.
There is a clear need for objective, laboratory-based
criteria for this condition, both in the clinic and in
clinical trials, in order to predict risk, assess diagno-
sis, and aid ongoing management. These consid-
erations have rekindled interest in the use of CSF
(or blood) biomarkers and biological measures
obtained by magnetic resonance methodologies
[77]. Among the promising CSF indicators are mar-
kers of neural injury and local immune activation.
The axonal neurofilament light chain protein and
the neuronal protein tau are frequently elevated in
CSF in patients with HAD, may be detected before
the development of HAD, and normalize with
treatment, whereas CSF immunoactivation mar-
kers such as neopterin and MCP-1 (CCL2), and
CSF viral load can be used to measure the effects
of treatment on CNS intrathecal immunoactivation
and virus replication [81–83].
Various CSF markers of persistent intrathecal im-
mune activation or neuronal injury, such as neopterin,
B2 microglobulin, MCP-1, and neurofilament protein,
quinolinic acid (QUIN) also correlate with dementia
severity, but have not been fully validated [77].
Because of the obvious advantages of sampling
blood rather than CSF, it would be desirable to be
able to use blood markers for diagnosis and man-
agement. A number of studies have examined
blood concentrations of the same type of markers
as discussed for CSF, without suggesting clinical
utility. Cohen et al. demonstrate in a study that cy-
tokine concentrations (beyond MCP-1 and MIP-
1b), in particular, the interleukins (IL-1b, IL-6, IL-
8, IL-10, IL-16, IL-18..) were found to be strongly
predictive of neurocognitive performance across a
range of tests of attention, executive functioning,
and psychomotor speed [84].
Rev. Med. Virol. 2012; 22: 33–45.
DOI: 10.1002/rmv
40
Given the continued impact of HIV-1 associated
cognitive dysfunction across the world and the
evolving nature of neurological damage, it is even
more important to study the CSF in the context of
HIV-1 infection. We need the equivalent of the excel-
lent surrogate marker plasma viral load to apply to
the diagnosis, staging, and treatment of HAD [85].
The three conditions comprising HAND (ANI,
MND, and HAD) may be classified using a variety
of specific clinical and laboratory-based methods,
depending upon the resources available in the setting
where the patients are being evaluated. Nevertheless,
standardized procedures should be followed when-
ever possible, both to collect the needed information
and to interpret that information to make three types
of determination: (i) the presence and severity of neu-
rocognitive impairment; (ii) the presence and severity
of functional decline; and (iii) the degree to which
cognitive impairment or functional decline are likely
to have been influenced by comorbid conditions or
confounds (including HIV-related opportunistic
CNS conditions, or unrelated developmental, psychi-
atric, or neuromedical confounds).
A number of brief screening measures, including
the HIV dementia scale, mental alteration test, execu-
tive interview, and HIV dementia assessment have
been developed or adapted to screen for HAD. Over-
all, there remains a clinical need for reliable and brief
screening measures to detect and monitor HIV-re-
lated cognitive dysfunction as well as to quantify
any response to therapeutic interventions [86–88].
TREATMENT OF HUMAN
IMMUNODEFICIENCY VIRUS-ASSOCIATED
NEUROCOGNITIVE DISORDERS WITH
ANTIRETROVIRALS. ADJUNCTIVE AGENTS
A major obstacle in HIV-1 eradication is the ability
of the virus to remain latent in a subpopulation of
the cells it infects. Latently infected cells can escape
the viral immune response and persist for long per-
iods of time, despite the presence of successful
HAART. Given the appropriate stimulus, latently
infected cells can reactivate and start producing in-
fectious virions. The susceptibility of these cell
populations to HIV-1, their life span, their prolifer-
ative capacity, and their ability to periodically pro-
duce infectious virus subsequent to alterations in
cellular physiology and/or immunologic controls
are critical issues that determine the contribution
of these cells to viral persistence.
Copyright © 2011 John Wiley & Sons, Ltd.
M. D. Palacio et al.
There are several well-documented studies show-
ing that HAART has led to a very dramatic decline
in the incidence of HAD in adult population.
In general, CSF HIV-1 infection responds very
well to HAART [82,89], so that when plasma viral
load levels become undetectable, so do CSF levels.
However, the relative rates of viral decay in the
two compartments may differ in some patients,
with HIV-1 viral load concentrations falling more
slowly in the CSF than in plasma. Slower decay
has been noted in subjects with HAD and lower
CD4+ T-cell counts but without CSF pleocytosis
[90,91]. These observations can be interpreted as
being consistent with a simple model of compart-
mentalized CSF infection [92], with the lag in CSF
viral response due either to slow cell turnover and
consequent prolonged viral release by macro-
phages or to less potent drug concentrations within
the CSF as a result of reduced drug entry.
The CNS is a site that antiretroviral therapy
(ART) often has difficulty reaching. Owing to its
physical structure, the presence of efflux pumps
and its high expression of metabolizing enzymes,
the BBB is an effective barrier against many antire-
troviral drugs [93,94]. In addition, (ART) are com-
monly protein bound within the plasma, further
limiting their access to the CNS [93,95]. Drugs eas-
ily passing the BBB and affecting (macrophages in)
the CNS are so called neuroactive drugs (neuro-
HAART). As with most antimicrobials, brain pene-
tration is crucial to achieve the goal of maximal
suppression of HIV-1 replication, although it is un-
clear how well antiretroviral CSF concentrations
actually reflect parenchymal concentrations. Sev-
eral studies have shown an association between
the use of neuroactive drugs (defined in different
ways) and good neurocognitive performance. The
cerebral penetration effectiveness index (CPE)
ranking system has been proposed as a simple
method for estimating the combined CNS effective-
ness of antiretroviral regimens and has been shown
to correlate with CSF viral load in a cohort study
[96]. But despite this, increased levels of intrathecal
immune activation are found in a majority of sub-
jects successfully treated with antiretroviral ther-
apy, although it is unclear if immune activation
results from viral replication within the CNS or as
a response to other factors [97].
Human immunodeficiency virus-associated neu-
rocognitive disorders may only reverse slowly; for
example, in a study following individuals with
Rev. Med. Virol. 2012; 22: 33–45.
DOI: 10.1002/rmv
NeuroAIDS in the current era
HAND for up to 5 years after initiation of HAART
>50% of individuals had not shown reversal of def-
icits [98]. Therefore, HAART alleviates HAND [99]
but raise the question whether HAART is suffi-
cient to make HAND disappear [100]. Augment-
ing the power of an already effective regimen by
adding another potent drug, preferably one with
a different mode of action should reduce the level
of viral load insofar as it originates from ongoing
rounds of viral replication. Thus, treatment inten-
sification with maraviroc or lopinavir/ritonavir
(good CNS penetration) for 4 weeks and 4 weeks
with enfuvirtide (poor CNS penetration) has no ef-
fect on residual CSF viral load levels or intrathecal
immune activation over the course of the study
[101].
Given that aberrant immune activation is likely to
play a pivotal role in the CNS damage induced by
HIV-1, clinical trials have focused on adjunctive thera-
pies targeted at attenuating CNS inflammation [102],
neuroprotectants agents would be inhibitors of cell-
signaling pathways that are likely to be involved in
neurodegeneration, inhibitors of excitotoxicity, and
inhibitors of oxidative and nitrosative stress.
Adjuvant treatment strategies including neuro-
protection, immunomodulation, and symptom
control have been reviewed by Turchan and collea-
gues [103]. Overall, none has shown clear and sub-
stantial clinical effects. The monoamine oxidase-B
inhibitor selegiline, administered using the selegi-
line transdermal system, was one of the recently
tested antioxidative drugs for the treatment of
HIV-associated cognitive impairment psychiatric
medications, such as serotonin reuptake inhibitors
(citalopram, paroxetine), lithium and valproic acid
(both glucagon synthase kinase-3b inhibitors) have
been tested as adjunct treatments of HAND and
found to have limited beneficial effect [104]. Mino-
cycline, a tetracycline-type antibiotic, has emerged
as a potential inhibitor of microglial activation
and inhibits the reactive oxygen species production
and expression of proinflammatory cytokines by
reactive microglia, indicating that minocycline is
not only neuroprotective but also exhibits inhibi-
tory effect on microglial activation [105]. Future
trials might include using humanized, monoclonal
antibodies against IL-1, IL-6, or TNF-a. Another ap-
proach might target QUIN, a neurotoxin present in
large quantities in the CSF and brains of patients
with AIDS dementia that is produced by activated
macrophages and microglia.
Copyright © 2011 John Wiley & Sons, Ltd.
41
NANOMEDICINE AND CENTRAL NERVOUS
SYSTEM DRUG DELIVERY
Because HIV-1 can easily enter the CNS but antire-
troviral drugs cannot, the brain essentially becomes
a sanctuary for HIV-1 [106,107], acting not only as a
reservoir, making it difficult to completely eradi-
cate the virus, but also increasing the chance of a vi-
ral mutation leading to drug resistance [108].
Owing to the importance of getting antiretroviral
drugs into the brain, a number of nanotechnology-
based methods for crossing the BBB are being spe-
cifically developed for this class of compounds.
These methods include disruption of the BBB, de-
velopment of nanoparticles with increased BBB
permeability, uptake by brain microvascular endo-
thelial cells via adsorptive-mediated transcytosis
and cell-mediated delivery.
A broad range of nanomedicines is being devel-
oped to improve drug delivery for CNS disorders
[109,110]. BBB penetrance is dependent on nano-
particle size, shape, and protein and lipid coatings.
These all affect drug uptake, release and ingress
across the barrier. Recent reports support the no-
tion that nanotechnology can serve to improve the
delivery of antiretroviral drugs, called nanoART,
across the BBB and affect biodistribution and clini-
cal benefit for HIV-1 disease [111,112]. To test CNS-
penetrating ART, cell-based nanoparticle delivery
systems were developed in an effort to transport
ART across the BBB. Taking advantage of the Trojan
horse principle, these nanoparticles are taken up by
monocytes and sheltered within the monocytes as
they are carried across the BBB. The drug is then re-
leased to act within the CNS [113], and for this,
these cells make great candidates for cell-mediated
drug delivery to the CNS. Other laboratories have
conjugated nanoparticles with Tat, which has an af-
finity for nuclear transport mechanisms [114]. This
results in a nanoparticle that has high CNS penetra-
bility while still bypassing efflux transporters to
prolong exposure within the CNS.
CONCLUSIONS
Given the rising prevalence of HIV/AIDS in the in-
dustrialized and developing world, it is likely that
new HIV-associated neurologic syndromes will
emerge as time progresses. NeuroAIDS is expected
to be a major upcoming health issue among long-
term HIV seropositive survivors and AIDS
patients. Today in developed countries, HAART
has changed AIDS from a fatal disease to a more
Rev. Med. Virol. 2012; 22: 33–45.
DOI: 10.1002/rmv
42 M. D. Palacio et al.

manageable chronic infection. But even with ag-
gressive therapy, the virus cannot be completely
eradicated, and regions that remain relatively iso-
lated from the systemic circulation, such as the
CNS, might provide a “sanctuary” for latent or
slowly replicating virus.
Reduced severity of disease has paralleled low-
ered viral replication and reduced overt neuropa-
thology. What remains are neuroinflammatory
responses heralded by low levels of viral replication,
disordered glial crosstalk and monocyte transmigra-
tion into the CNS. With antiretroviral treatment that
specifically targets the CNS and adjunctive therapies
now becoming available, eliminating virus (and
virus-mediated activation) in the brain is a realistic
goal. Understanding the signals that lead to their
passage into the brain and in attenuating viral
growth and inflammatory responses within the
CNS will ultimately lead to the elimination of
HAND.
CONFLICT OF INTEREST
The authors have no competing interest.

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