‘

Mitochondrion 4 (2004) 119–129

www.elsevier.com/locate/mito

Review

HIV-associated dementia, mitochondrial dysfunction,

and oxidative stress
Victor Valcour*, Bruce Shiramizu
NeuroAIDS Specialized Neuroscience Research Program, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
Received 11 March 2004; received in revised form 4 May 2004; accepted 6 May 2004

Abstract

Over the past several decades, researchers have made large advances in unraveling the pathogenesis of HIV-related
neurological disease leading to substantial benefits for affected individuals. Concomitant advances in HIV-treatment have
changed the landscape of HIV care, resulting in alterations in HIV neuroepidemiolgy and potentially the neuropathogenesis of
cognitive disorders. Specifically, widespread ARV medications use has heightened our awareness of mitochondrial toxicity,
oxidative stress, and metabolic abnormalities and stimulated more research into the related cognitive consequences. Specific
sources of oxidative stress among HIV-1-infected individuals to be discussed in this article include the direct effects of HIV-1,
chronic immune activation in response to HIV-1 and other pathogens, and co-morbid factors. Continued research in this area
could provide novel therapeutic targets.
q 2004 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

Keywords: AIDS; Mitochondria; Oxidative stress

Beyond diseases with a clear mitochondrial basis mitochondrial dysfunction has been hypothesized for a
such as mitochondrial encephalopathy with lactic wide range of common neurodegenerative disorders
acidosis and stroke-like episodes (MELAS) and (Castellani et al., 2002; Dawson and Dawson, 2002;
myoclonus epilepsy with ragged red fibers (MERRF), Orrell and Schapira, 2002). A commonly referenced

Abbreviations: AACTG, adult AIDS clinical trials group; AD, Alzheimer’s disease; AIF, apoptosis-inducing factor; ARV, antiretroviral
medications; BBB, blood brain barrier; CNS, central nervous system; CSF, cerebrospinal fluid; FDRA, Friedreich’s Ataxia; GRID, gay related
immune deficiency; GSH, glutathione; HAD, HIV-associated dementia; HNE, 4-hydroxynonenal; MAO-B, monoamine oxidase B; MCMD,
minor cognitive motor disorder; MELAS, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes; MERRF, myoclonus
epilepsy with ragged red fibers; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetra hydropyridine; NAC, N-Acetyl cysteine; NF-K beta, nuclear
transcription factor beta; NO, nitric oxide; NOS, nitric oxide synthase; NRTI, nucleoside reverse transcriptase inhibitors; PD, parkinson’s
disease; PET, positron emission tomography; ROS, reactive oxidative species; SOD, superoxide dismutase; TK, thymidine kinase.
* Corresponding author. Address: Office of Neurology and Aging Research, Sinclair 202, Leahi Hospital, 3675 Kilauea Avenue, Honolulu,
Hawaii 96816, USA. Tel.: C1-808-411-1582; fax: C1-808-735-8274.
E-mail address: vvalcour@hawaii.edu (V. Valcour).

1567-7249/$ - see front matter q 2004 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
doi:10.1016/j.mito.2004.05.009
120 V. Valcour, B. Shiramizu / Mitochondrion 4 (2004) 119–129
mechanistic pathway involves accumulation of oxi-
dative stress, a process also associated with aging
(Nicholls, 2002). In some cases (e.g. Alzheimer’s
disease (AD)), speculation concerning alternative
mechanistic pathways is common; however, consensus
among reported mechanisms is generally poor (Cas-
tellani et al., 2002). The variety of these propositions
may be more reflective of the heterogeneity commonly
associated with mitochondrial disorders themselves
(Cohen and Gold, 2001). Tissue specificity, hetero-
plasmy of genetic material, threshold levels of genetic
abnormality or mitochondrial dysfunction required to
trigger disease, and incomplete penetrance of genetic
defects all contribute to a variable degree of pheno-
typic expression and implicit difficulty in diagnosing
and researching clinical mitochondrial disorders
(Cohen and Gold, 2001; Wallace, 1999; Schon and
Manfredi, 2003).
Interest in mitochondrial dysfunction relative to
HIV-1 infection has increased in recent years
paralleling a heightened awareness of antiretroviral
(ARV)-induced cellular toxicity (Lewis et al., 2001).
ARV medications and particularly dideoxynucleotide
reverse transcriptase inhibitors (NRTI) are toxic to
mitochondria partially through inhibition of mito-
chondrial DNA polymerase gamma (Lewis et al.,
2003). While our understanding of such toxicity is a
relatively recent phenomenon, HIV-associated risk
for mitochondrial damage, chiefly through oxidative
mechanisms, is not new and is inherently associated
with acute and chronic viral infections (Peterhans,
1997; Schwarz, 1996; Akaike et al., 1990). Additional
specific aspects of HIV-1 itself and those of chronic
immune activation contribute further to reactive
oxidative species (ROS) and disruption of energy
homeostasis (Mollace et al., 2001; Toborek et al.,
2003; Aksenov et al., 2003; Kruman et al., 1998).
Among HIV-1-infected individuals, accompanying
oxidative risk factors, which include a high rate of
tobacco smoking, disproportionate representation of
illicit drug use, and, more recently, an aging
seropositive population may further contribute to
increased oxidative stress among this vulnerable
population (Burns et al., 1996; Valcour et al., 2004).
This paper reviews existing data relating to the
potential mitochondrial mechanisms associated with
HIV and cognition. Mitochondrial dysfunction
and oxidative stress may play important adjunct
roles in HIV neuropathogenesis.
1. The changing epidemiology of HAD and
neuronal susceptibility to mitochondrial
dysfunction
Mortality from HIV-1 infection has declined
remarkably within developed countries over the past
10 years; yet little benefit has been realized concern-
ing the associated cognitive complications (McArthur
et al., 2003). Much attention has been placed on direct
HIV-1-related mechanisms and viral dynamics; how-
ever, existing evidence suggests that the direct actions
of HIV-1 itself, by and large, are insufficient to fully
explain the cognitive deficits associated with infection
(Mollace et al., 2001; Gartner, 2000; Albright et al.,
2003). Support for this concept includes knowledge
that the amount of HIV DNA in the brain does not
differ among demented compared to non-demented
patients at post-mortem examination (Johnson et al.,
1996). Moreover, while HIV-1 is present in the brain
early in infection, the onset of cognitive symptoms is
variable and typically more strongly associated with
advanced stages of immune suppression (McArthur
et al., 2003; Gartner, 2000).
The neuroepidemiology of HIV-1-cognitive dis-
orders is changing in the face of widespread ARV use.
Neurocognitive disease is often clinically less fulmi-
nate. The rate of mild impairment (minor cognitive
motor disorder (MCMD)) may be rising in proportion
to that of HIV-associated dementia (HAD) (McArthur
et al., 2003). Consequently, a continued and vigilant
investigation into potential contributing factors
associated with HIV-1 neurodegeneration is needed
and may yield important therapeutic targets to be
further interrogated.
A mitochondrial hypothesis is particularly intri-
guing. Multiple schemes including direct toxicity to
mitochondria resulting in acute energy depletion,
mutations and consequent DNA sequencing errors
leading to depletion of important mitochondrial
proteins, and cumulative oxidative stress contributing
to cell membrane defects and signaling errors have
been speculated and have received variable levels of
testing (Mollace et al., 2001; Turchan et al., 2003;
Haughey et al., 2004; Baier-Bitterlich et al., 1997;
 V. Valcour, B. Shiramizu / Mitochondrion 4 (2004) 119–129
Hulgan et al., 2003; Olinski et al., 2002). For example,
the disruption of oxidative phosphorylation and the
presence of ROS may induce mitochondrial-mediated
apoptosis through steric alteration of the mitochon-
drial permeability transport pore resulting in loss of
neuronal cell populations (Schon and Manfredi,
2003). Post-translational modifications of proteins
associated with ROS have been implicated in
decreased blood brain barrier (BBB) defenses with
HIV-1 infection (Mollace et al., 2001).
Neurons, like muscle cells and especially cardiac
muscle cells, are particularly vulnerable to the
effects of mitochondrial damage due to their high
dependence on energy (Schon and Manfredi, 2003;
Thyagarajan and Byrne, 2002; Facchinetti et al.,
1998). Consequently, many well-recognized mito-
chondrial diseases have both myocardial and central
nervous system consequences (Thyagarajan and
Byrne, 2002). Additionally, there are numerous
substrates prone to oxidation and consequent
dysfunction in the brain including catecholamines,
structural lipid components such as myelin, and
signaling molecules (Tong et al., 2002). Decreased
anti-oxidant defenses have also been described
within the brain, potentially increasing susceptibility
to ROS (Rego and Oliveira, 2003). Since NRTI-
induced mitochondrial toxicity is related to a higher
concentration of mitochondrial thymidine kinase
(TK) as opposed to cytoplasmic TK, and since this
concentration is typically higher in cells with less
mitotic turnover, one could speculate that mitochon-
dria in neurons may be particularly prone to their ill
effects (Lewis et al., 2003). An increased concen-
tration of iron in selective cells within the brain,
particularly dopaminergic cells within the substantia
nigra pars reticulata, may increase the risk further
by enhancing the development of more toxic
free radicals locally through the Fenton reaction
(Facchinetti et al., 1998). Such highly reactive states
associated with the presence of transition metals
have been identified in the neurofibrillary tangles in
Alzheimer’s disease and in Lewy bodies in Parkin-
son’s disease (Smith et al., 1997; Castellani et al.,
2000). Cumulatively, these circumstances argue that
the central nervous system (CNS) may be particu-
larly prone to the deleterious effects of mitochondria
dysfunction and ROS.
121
2. Models of neurodegeneration and mitochondrial
disorders
Mitochondrial disorders often include important
neurodegenerative components with central
nervous system findings (Schon and Manfredi, 2003;
Thyagarajan and Byrne, 2002). In some cases, such as
Friedreich’s Ataxia (FDRA), point mutations in
mitochondrial DNA have been identified. Since the
resultant defect is one of mitochondrial dysfunction
with disruption to the electron transport chain and
since many symptoms are similar to disease states
in treated HIV-1-infected patients (Shikuma and
Shiramizu, 2001), FRDA may provide some
insight into various potential mechanisms relating to
HIV-associated mitochondrial dysfunction.
FRDA is manifest by progressive limb ataxia,
axonal sensory neuropathy, and pyramidal signs
(Cooper and Bradley, 2002). Non-neurological seque-
lae include skeletal abnormalities, cardiomyopathy,
and an increased incidence of diabetes mellitus. It is
associated with an autosomal recessive inheritance
pattern involving a GAA trinucleotide expansion on
chromosome 9 leading to a marked reduction in
frataxin and consequent insufficiency of oxidative
phosphorylation (Cooper and Bradley, 2002). The
resultant cellular state is one of marked decrease in
reserve for oxidative stress possibly associated with
abnormalities in mitochondrial iron homeostasis and
the consequent development of free radicals via the
Fenton reaction (Cooper and Bradley, 2002; Rotig
et al., 1997; Puccio et al., 2001). Superoxide
dismutase (SOD) deficiency in cultured FRDA cells
and both decreased myocardial hypertrophy and
attenuation of oxidative markers with antioxidant
treatment (Idebenone) support an important role
of oxidative stress in the pathogenesis of FRDA
(Rustin, 2003).
Alzheimer’s disease is the most common form of
dementia in humans exhibiting an exponential rise in
incidence associated with aging (Cummings et al.,
1998). While specific genetic determinants to early
onset familial disease have been identified (e.g.
amyloid precursor protein and the amyloid beta
processing proteins presenilin-1 and presenilin-2),
the etiology for the vast majority of cases remains
illusive (Lannfelt and Nordstedt, 2000). Existing data
support a possible secondary role for the effects of
122 V. Valcour, B. Shiramizu / Mitochondrion 4 (2004) 119–129
mitochondrial dysfunction and oxidative stress. This
hypothesis underlies the study of antioxidant medi-
cations including selegiline, Vitamin E, and poten-
tially Ginkgo biloba, and somewhat relates to the
investigation of anti-inflammatory agents as disease
modulators (Aisen, 2002; Andersen et al., 1995; Sano
et al., 1997; Le Bars et al., 1997).
Unlike FRDA, no underlying unifying mitochon-
drial deletions or mutations have been consistently
associated with AD; nevertheless, abnormalities
associated with mitochondrial function are character-
istic findings in well-established disease (Castellani
et al., 2002; Swerdlow and Kish, 2002). Brain
bioenergetic studies reveal a decrease in brain
metabolism in biopsy specimens (Sims et al., 1987)
and with positron emission tomography (PET)
(Friedland et al., 1983; Foster et al., 1983) with PET
changes often preceding detectable cognitive abnorm-
alities (Haxby et al., 1987). Abnormalities in the
Krebs cycle have been implicated; yet irregularities in
cytochrome C oxidase (Complex IV) are the most
commonly cited oxidative phosphorylation abnorm-
alities in AD (Castellani et al., 2002). While these
findings point to a mitochondrial contribution, it is not
known if defects in mitochondrial DNA, per se, play a
significant role as anomalies in the respiratory chain
proteins, including proteins encoded by nuclear DNA
and a heightened role of exogenous oxidative stress
could be involved (Castellani et al., 2002). A decrease
in mitochondria associated with increased mitochon-
drial degradation and oxidative stress has been
identified among neurons in AD biopsy specimens
(Castellani et al., 2002).
The associations among Parkinson’s Dementia
(PD), mitochondrial dysfunction, and oxidative stress
may be most strongly supported by existing research.
Owing to an animal model for PD utilizing 1-methyl-4-
phenyl-1,2,3,6-tetra hydropyridine (MPTP), a mito-
chondrial hypothesis has been advanced (Dawson and
Dawson, 2002; Schon and Manfredi, 2003).
A mitochondrial outer membrane protein, monoamine
oxidase B (MAO-B), converts MPTP to N-methyl-4-
phenyl pyridine (MPP), which is a direct inhibitor
of NADH ubiquinone oxidoreductase (Complex I).
Decreased immunoreactivity for complex
I subunits has been further identified in the neurons
of PD patients (Schon and Manfredi, 2003;
Dawson and Dawson, 2003). Increased total iron
(implying enhanced risk for ROS) increased lipid
peroxidation, and decreased glutathione levels within
the substantia nigra of PD patients add further evidence
that an oxidative mechanism may underlie this disease
(Facchinetti et al., 1998; Dexter et al., 1992). While
effects on dopamine homeostasis are the primary
mechanism supporting the use of selegiline in the
treatment of PD, the co-incident anti-oxidant qualities
may further enhance its benefit prompting a recent
clinical trial for HIV-related cognitive deficits
(Maruyama and Naoi, 1999).
3. HIV-associated cognitive disorders-potential
mechanisms of mitochondrial dysfunction
3.1. Oxidative stress
Mitochondria efficiently maintain a proton gradient
across their membranes (Nicholls, 2002). Under
normal physiological conditions, only a small
inherent leak exists (Castellani et al., 2002; Dawson
and Dawson, 2002; Orrell and Schapira, 2002), which
is augmented by sources of oxidative stress and
counter-balanced by endogenous antioxidants
(Facchinetti et al., 1998). This delicate balance of
oxidant and anti-oxidant substrates is critical to
cellular survival; imbalance, as seen in HIV-infected
patients and particularly among patients effectively
treated with ARV, results in oxidative stress (Fig. 1)
(Hulgan et al., 2003; Pace and Leaf, 1995).
The existence of endogenous ROS is inherent with
host responses to pathogens via neutrophils, activated
macrophages, and through the process of phagocy-
tosis (Jarstrand and Akerlund, 1994; Xiong et al.,
2000). Secreted cytokines may further induce oxi-
dative stress through induction of key enzymes such
as inducible nitric oxide synthatase (NOS) resulting in
additional ROS (nitric oxide (NO)) (Mollace et al.,
2001; Baier-Bitterlich et al., 1997). Nitric oxide is
released by neurons in response to excitotoxic stimuli
and with exposure to the HIV-1 glycoprotein GP120,
possibly through indirect mechanisms (Mollace et al.,
1993). TNF alpha and interleukin-1-beta, both
implicated in HIV neuropathogenesis, have been
shown to induce NOS in astrocytes as well (Hori
et al., 1999). Increased cerebral spinal fluid (CSF)
oxidative stress markers (e.g.: 4-hydroxynonenal
 V. Valcour, B. Shiramizu / Mitochondrion 4 (2004) 119–129
Fig. 1. Some sources of oxidant stress and consequences among HIV-1-infected adults.
(HNE)) have been identified in patients with HAD in
research conducted by Turchan et.al. (Turchan et al.,
2003). Advancing an hypothesis implicating a mito-
chondrial basis to the oxidative stress, this group
further identified progressively decreased mitochon-
drial potential activity with advancing stages of HAD.
The mechanisms by which ROS induce their
detrimental effects are varied and, in some cases,
may be more applicable to cells within the brain.
Hydroxylation of various cellular moieties contributes
to cellular disruption. Lipid peroxidation, resulting in
disruption of membrane fluidity and increased
permeability, is seen with HIV infection (Facchinetti
et al., 1998; Revillard et al., 1992). An interplay
between changes in membrane permeability and the
induction of endothelial NOS associated with HIV
infection is proposed to diminish BBB defenses
(Mollace et al., 2001). Peroxynitrite, a consequence
of increased nitric oxide free radical formation within
cells, has been co-localized to perivascular regions
of HAD brains (Mollace et al., 2001) and associated
with loss of tight junctions (Boven et al., 2000).
Peroxyinitration of structural proteins can have
123
further consequences for neurofilaments and neuronal
structure (Beckman and Koppenol, 1996). ROS can
have a direct effect on complexes involved in
oxidative phosphorylation, such as inhibition of
complex I resulting in decreased energy production
(Nicholls, 2002). Oxidation of thiol-containing amino
acids is thought to play a role in the potential
disruption of receptor mediated cellular signaling
(Facchinetti et al., 1998).
Free radicals can damage DNA through a number
of mechanisms including direct alteration of base
pairs resulting in miscoding; some changes can be
pre-mutogenic (Olinski et al., 2002). Miscoding can
result in a decrease in critical proteins within neurons.
DNA analyses in HIV-infected lymphocytes demon-
strated heightened hydroxylation of guanine and
uridine residues when compared to lymphocytes
from controls (Jaruga et al., 1999). Suppl.ementation
with vitamins A, C, and E resulted in decreased
oxidative damage (Jaruga et al., 2002).
Anti-oxidant defenses are impaired in HIV infec-
tion; however, the underlying mechanisms are not
clearly defined. Mitochondrial glutathione (GSH) is
124 V. Valcour, B. Shiramizu / Mitochondrion 4 (2004) 119–129
an important endogenous electron donor (anti-oxi-
dant) which is critical for efficient detoxification of
hydrogen peroxide via enzymes found only in
mitochondria (Cadenas and Davies, 2000). In vitro
studies suggest marked sensitivity to decreased levels
of GSH resulting in oxidative stress (Jurma et al.,
1997). Before widespread use of ARV, several studies
indicated decreased GSH in several compartments
including CSF among HIV-1-infected individuals
(Buhl et al., 1989; Staal et al., 1992; Castagna et al.,
1995). Further GSH depletion has been associated
with detoxification of ARV medications (Mollace
et al., 2001). GSH plasma levels correlate to HIV
disease progression and survival (Herzenberg et al.,
1997). Decreased activity of both catalase and SOD
have also been described (Pace and Leaf, 1995).
The latter may be due to direct actions of the HIV
trans-activator protein, tat (Flores et al., 1993).
The hypothesized consequences of these dimin-
ished antioxidant reserves are untested in vivo among
HIV-1-infected patients. A small study of limited
duration aimed at treating HIV-related neuropathy
through supplementation with micronutrients, includ-
ing potent anti-oxidants, resulted in an unexpected
beneficial change in absolute CD4 T-lymphocyte
counts, but no change in neuropathy symptoms
(Kaiser et al., 2004). In vivo and in vitro pilot data
support use of selegiline in HAD (Turchan et al.,
2003; Sacktor et al., 2000). Consequently, a random-
ized placebo controlled intervention with transdermal
selegiline, an inhibitor of MAO-B, is underway
through the Adult AIDS Clinical Trials Group
(ACTG 5090, National Institutes of Health). Treat-
ment of HIV-1 infection with the antioxidant
N-Acetyl cysteine (NAC) has been proposed to
decrease ROS and deactivate nuclear transcription
factor beta (NF-K beta) (Kelly, 1998; De Rosa et al.,
2000; Staal, 2000).
3.2. Attenuated energy stores and activation
of apoptosis
Energy depletion associated with mitochondrial
DNA abnormalities has been postulated to underlie
some aspects of metabolic complication in ARV-
treated patients (Lewis et al., 2003). Elevated lactate
levels, possibly representing altered energy homeo-
stasis, have been described with unclear clinical
consequences (Ogedegbe et al., 2003). Apoptosis
may be a more critical issue associated with
attenuated energy, oxidative stress and excitotoxicity.
In vitro models indicate a critical mitochondrial role
in signaling apoptosis through the actions of
the mitochondrial permeability transport pore
(Nicholls, 2002). The opening of this membrane
pore results in loss of the electrochemical gradient and
release of a number of inner membrane constituents
including cytochrome c, apoptosis-inducing factor
(AIF), and caspases with the ultimate result of
signaling apoptosis (Nicholls, 2002; Wallace, 1999;
Rego and Oliveira, 2003). Excitotoxicity, such as that
caused by glutamate stimulation of NMDA receptors
or oxidative stress can lead to apoptosis through this
mitochondrial mechanism (Rego and Oliveira, 2003;
Pace and Leaf, 1995). Enhanced apoptotic cell death
is associated with exposure to TNF and hydrogen
peroxide and somewhat attenuated with addition
of anti-oxidants in experiments conducted with
HIV-1-infected cells (Malorni et al., 1993).
3.3. Mitochondrial DNA deletions
Mitochondrial DNA deletions represent a theoreti-
cal mechanism of ARV toxicity in HIV patients.
NRTI triphosphates inhibit mtDNA pol-gamma
resulting in such deletions (Lewis, 2003). Mitochon-
drial DNA deletions underlie some encephalomyelo-
pathies, such as Kearns Sayre Disease (Graeber and
Muller, 1998) and elevated quantities have been
reported in some neurodegenerative disorders
(Mawrin et al., 2004; Corral-Debrinski et al., 1994)
providing a precedent for HIV-associated neurologi-
cal diseases. Currently, there are limited data on the
frequency of such deletions associated with ARV
treatment. While mtDNA deletions have been shown
in one case report (Bartley et al., 2001) and in sperm
samples of patients on ARV (White et al., 2001) they
have not been convincing reported in association with
disease states among ARV users, including data from
our center relating to lipodystrophy (Walker and
Venhoff, 2001; Shikuma et al., 2001). Nevertheless,
with prolonged exposure to ARV, cumulative oxi-
dative stress, and aging of the HIV population,
threshold levels of mtDNA deletions could be met
resulting in clinically important consequences.
 V. Valcour, B. Shiramizu / Mitochondrion 4 (2004) 119–129
4. Contributing factors
Over half of HIV-1-infected patients are past or
present smokers in comparison to 25–38% of the
general public (Wei et al., 2001; Mamary et al., 2002;
Smola et al., 2001). Smoking is associated with
oxidative damage, representing a modifiable risk
factor among HIV-1-infected individuals (Wei et al.,
2001; Morrow et al., 1995; Reilly et al., 1996). In a
study of 3221 HIV-1-infected men and women
enrolled in the Terry Beirn Community Programs
for Clinical Research on AIDS, current smokers were
more likely than never smokers to develop AIDS
dementia complex after adjustment for CD4 count,
prior disease progression and use of ARV therapy
(Burns et al., 1996). These limited data require
confirmation with attention to nicotinic effects on
attention and working memory (Rezvani and Levin,
2001). While this epidemiological data by no means
implies oxidative mechanisms, it is reasonable to
speculate that an additive oxidative stress associated
with multiple sources among individuals could occur
and that smoking status should be a considered
covariate in research efforts concerning these poten-
tial mechanisms.
Illicit drug use is a well-recognized risk factor for
HIV-1-infection. Cocaine and methamphetamine, two
commonly abused drugs, have important effects on
the homeostatic balance of oxidative species poten-
tially resulting in added risk for individuals with illicit
drug use and HIV (Devi and Chan, 1996; Shor-Posner
et al., 2002; Nath et al., 2002; Tang and Smit, 2000;
Lee et al., 2002). An increase in oxidative stress
has been described with heavy alcohol use as well
(Nath et al., 2002).
As a consequence to effective ARV treatment, it is
increasingly common to encounter HIV-1-seroposi-
tive patients in their sixth and higher decade of life
(Valcour et al., 2004) Aging has been associated with
increased cognitive dysfunction in a number of
studies (Valcour et al., 2002; Goodkin et al., 2001;
Chiesi et al., 1996). Mitochondrial abnormalities and
oxidative stress are thought to contribute to the
progressive senescence associated with aging among
HIV-seronegative individuals and could further
enhance neuronal damage among HIV-1-infected
patients (Wallace, 1999; Tong et al., 2002). As
hypothesized, the accumulation of ROS damage
125
associated with life-long environmental exposures
and ongoing physiological endogenous production
eventually results in a threshold level of damage,
which, in turn, attenuates energy production and
disrupts cell structure (Tong et al., 2002). Decreased
mitochondrial function and increased mitochondrial
DNA rearrangements are seen with advancing age
(Wallace, 1999). Age-related accumulation of oxi-
dation-related mitochondrial damage may be
enhanced in regions of high dopamine production in
the brain, including the caudate, putamen and
substantia nigra (Soong et al., 1992) The clinical
presentation of HIV neurocognitive disease suggests
that subcortical structures may be particularly vulner-
able (Capaldini, 1998).
Co-existing medical conditions could further
contribute to oxidative stress. Treatment of HIV
infection is associated with the development of
metabolic complications, many of which are
associated with increased cardiovascular and cerebro-
vascular risk (Valcour et al., 2004). Recent data
support a role of oxidative stress in the pathogenesis
of atherosclerotic disease (Lee et al., 2001). Early data
support a heightened cardiovascular risk with HIV
infection and treatment; however, evidence for
cerebrovascular complications is mixed (Bozzette
et al., 2003; Cole et al., 2004; Friis-Moller et al.,
2003). While speculative at this time, atherosclerotic
cerebrovascular disease could modify the risk for
HIV-related cognitive abnormalities (Valcour and
HIV-associated, 2002). HIV-related immunodefi-
ciency results in opportunistic infection. While
attenuated due to underlying immunodeficiency,
these infections trigger further immune activation
and ROS. Non-opportunistic infections are
potential contributors as well. Hepatitis C, which
occurs in 15–30% of HIV-infected individuals,
represents another trigger of the immune system
resulting in consequent oxidative stress (Sulkowski
and Thomas, 2003).
5. Concluding remarks
In the early 1980s a cluster of Kaposi’s Sarcoma and
pneumocystic carinii pneumonia among gay men in
Los Angeles marked the beginning of what would later
be called Gay Related Immune Deficiency (GRID)
126 V. Valcour, B. Shiramizu / Mitochondrion 4 (2004) 119–129
and subsequently be recognized as the greatest
pandemic of our time (MMWR Morb Mortal Wkly
Rep. 31 (23) 1982). The first decade of research yielded
tremendous advances in the treatment of opportunistic
diseases, which subsequently improved life for
afflicted individuals. The second decade of research
provided potent treatments to combat the virus,
transforming the landscape of AIDS from a subacute
illness with near certain death to a chronic disease with
hope for long-term survival for many individuals.
As we enter the third decade of research and
continue to search for a cure, we must also focus our
efforts on combating the detrimental side effects to our
treatment armamentarium and the long-term conse-
quences of chronic infection. Some effort must be
focused on mitochondrial mechanisms as a growing
volume of evidence supports a potential contribution to
the pathogenesis of associated disorders. Consequent
discoveries may direct treatment options for this
vulnerable, chronically ill, and aging population.
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