Methamphetamine toxicity and its implications during HIV-1 infection

Abstract

Over the past two decades methamphetamine (MA) abuse has seen a dramatic increase. The abuse of MA is particularly high in groups that are at higher risk for HIV-1 infection, especially men who have sex with men (MSM). This review is focused on MA toxicity in the CNS as well as in the periphery. In the CNS, MA toxicity is comprised of numerous effects, including, but not limited to, oxidative stress produced by dysregulation of the dopaminergic system, hyperthermia, apoptosis, and neuroinflammation. Multiple lines of evidence demonstrate that these effects exacerbate the neurodegenerative damage caused by CNS infection of HIV perhaps because both MA and HIV target the frontostriatal regions of the brain. MA has also been demonstrated to increase viral load in the CNS of SIV-infected macaques. Using transgenic animal models, as well as cultured cells, the HIV proteins Tat and gp120 have been demonstrated to have neurotoxic properties that are aggravated by MA. In addition, MA has been shown to exhibit detrimental effects on the blood-brain barrier (BBB) that have the potential to increase the probability of CNS infection by HIV. Although the effects of MA in the periphery have not been as extensively studied as have the effects on the CNS, recent reports demonstrate the potential effects of MA on HIV infection in the periphery including increased expression of HIV co-receptors and increased expression of inflammatory cytokines.

Full text

REVIEW
Methamphetamine toxicity and its implications
during HIV-1 infection
Peter S. Silverstein &Ankit Shah &Raeesa Gupte &
Xun Liu &Robert W. Piepho &Santosh Kumar &
Anil Kumar
Received: 23 May 2011 / Accepted: 22 June 2011 / Published online: 23 July 2011
#Journal of NeuroVirology, Inc. 2011
Abstract Over the past two decades methamphetamine
(MA) abuse has seen a dramatic increase. The abuse of MA
is particularly high in groups that are at higher risk for HIV-1
infection, especially men who have sex with men (MSM).
This review is focused on MA toxicity in the CNS as well as
in the periphery. In the CNS, MA toxicity is comprised of
numerous effects, including, but not limited to, oxidative
stress produced by dysregulation of the dopaminergic system,
hyperthermia, apoptosis, and neuroinflammation. Multiple
lines of evidence demonstrate that these effects exacerbate the
neurodegenerative damage caused by CNS infection of HIV
perhaps because both MA and HIV target the frontostriatal
regions of the brain. MA has also been demonstrated to
increase viral load in the CNS of SIV-infected macaques.
Using transgenic animal models, as well as cultured cells, the
HIV proteins Tat and gp120 have been demonstrated to have
neurotoxic properties that are aggravated by MA. In addition,
MA has been shown to exhibit detrimental effects on the
blood–brain barrier (BBB) that have the potential to increase
the probability of CNS infection by HIV. Although the effects
of MA in the periphery have not been as extensively studied
as have the effects on the CNS, recent reports demonstrate the
potential effects of MA on HIV infection in the periphery
including increased expression of HIV co-receptors and
increased expression of inflammatory cytokines.
Keywords Methamphetamine .HIV-1 .Dopamine .CNS .
Immune system
Through the 1990s and well into the first decade of the
twenty-first century, methamphetamine (MA) abuse has
been responsible for an increase in admissions to publicly
funded drug treatment programs (Gonzales et al. 2010). In
2005, it was estimated that 10.4 million people of age
12 years and over had used MA at least once in their life,
and over half a million people reported current use of the
drug (Office of Applied Studies 2007). Furthermore,
hospital emergency department visits related to MA abuse
exhibited a dramatic increase between 1995 and 2002. The
problem of MA abuse is not limited to the USA, since
significant use is also reported in Eastern Europe and
Southeast Asia (Degenhardt et al. 2010). The abuse of MA
is particularly high among men who have sex with men
(MSM; Gonzales et al. 2009). In this group, MA use is
associated with an increase in high-risk sexual activities
such as decreased condom use and increased numbers of
sexual partners (Gonzales et al. 2010; Shoptaw and Reback
2007). Studies have indicated that the HIV incidence is
doubled or tripled in MSM who use amphetamines
compared with MSM who do not use drugs (Buchacz et
al. 2005). In addition, resistance to antiretroviral drugs has
been shown to be positively correlated with MA abuse in
MSM (Gorbach et al. 2008). Although research studies can
be confounded by factors such as the abuse of multiple
drugs (i.e., polydrug abuse) and differential levels of sexual
activity and exposure, the study by Gorbach et al.
accounted for some of these factors and still demonstrated
a significant correlation between MA abuse and the
acquisition of drug-resistant virus.
This review focuses on MA toxicity in both the CNS and
the periphery, especially in the context of HIV-1 infection.
The mechanisms responsible for the toxicity, as well as the
mechanisms involved in mediating interactions between the
effects of MA and HIV infection will be discussed.
P. S. Silverstein (*):A. Shah :R. Gupte :X. Liu :
R. W. Piepho :S. Kumar :A. Kumar
Division of Pharmacology and Toxicology, School of Pharmacy,
University of Missouri-Kansas City,
Kansas City, MO 64108, USA
e-mail: Silversteinp@umkc.edu
J. Neurovirol. (2011) 17:401–415
DOI 10.1007/s13365-011-0043-4

Furthermore, evidence that MA abuse affects the outcome
of HIV-1 infection will be reviewed.
The dopaminergic system and methamphetamine
MA is very similar in chemical structure to the neurotrans-
mitter dopamine, and this is thought to be the basis for
many of the effects of this drug (Riddle et al. 2006; Sulzer
et al. 2005). Early work that demonstrated the role of
dopamine in MA-mediated effects utilized various methods
of regulating dopamine synthesis, metabolism and disposi-
tion, followed by a determination of the effects of these
agents on MA-mediated neurotoxicity. In the neostriatum of
MA-treated rats, it was reported that the activity of tyrosine
hydroxylase (TH), the rate-limiting enzyme in dopamine
biosynthesis, was inhibited (Gibb and Kogan 1979). It was
also demonstrated that a-methyl-r-tyrosine, an inhibitor of
TH, abrogates the MA-induced decrease in TH activity in
the neostriatum. The protective effect of α-methyl-r-
tyrosine was abrogated by administration of L-DOPA,
which served to restore cytoplasmic dopamine levels. The
depressive effects of MA are even more pronounced on
tryptophan hydroxylase (TPH), the enzyme responsible for
serotonin synthesis (Hotchkiss and Gibb 1980; Schmidt et
al. 1985). Experiments utilizing the administration of a-
methyl-r-tyrosine and L-DOPA strongly suggested that the
effects of MA on TPH were mediated by the dopaminergic
system (Hotchkiss and Gibb 1980; Schmidt et al. 1985).
The effects of MA on the serotonergic system are blocked
by compounds that inhibit the effects of MA on the
dopaminergic system (e.g., α-methyl-r-tyrosine). However,
agents that specifically target the serotonergic system (e.g.,
5-HT uptake inhibitors) have no influence on MA-induced
effects on the dopaminergic system. This suggests the
overriding importance of dopamine in regulating both
systems in response to MA.
Components of the dopaminergic system
Dopamine receptors
Dopamine receptors comprise a family of G protein-
coupled receptors that are prominent in the CNS, as well
as in certain cell types and tissues in the periphery. In
addition to the CNS, dopamine receptors have also been
reported to be expressed in the cardiovascular and renal
systems, as well as in the retina and adrenal glands (Ozono
et al. 1997; Pivonello et al. 2004). In the cardiovascular
system, dopamine affects contractility (Ruffolo and Messick
1985) and vasodilation (Munch et al. 1991), it controls renal
filtration (Olsen 1998), whereas in the retina it is responsible
for circadian rhythm and retinal development (Witkovsky
2004). Dopamine receptors are also expressed on various
immune cells in the body. D
1
–D
5
receptor expression on
human lymphocytes has been demonstrated through the use
of radioligand binding (Amenta et al. 1999; Ricci and
Amenta 1994; Ricci et al. 1998; Ricci et al. 1997; Ricci et al.
1999).
The availability of antagonists for the dopamine recep-
tors D
1
and D
2
has facilitated the identification of these
proteins as key players in the effects of MA. Sonsalla et al.
(Sonsalla et al. 1986) demonstrated that both a D
1
antagonist, SCH23390, and a D
2
antagonist, sulpiride,
decreased the MA-induced effects on the striatal dopami-
nergic parameters. However, only the D
1
antagonist was
effective at reducing the effects of MA on the striatal
serotonergic parameters. The ability of the D
1
antagonist
SCH23390 to protect against MA-induced neurotoxicity
has also demonstrated (Angulo et al. 2004; Xu et al. 2005).
The report by Xu et al. also showed that raclopride, a D
2
antagonist, as well as SCH23390, ameliorated MA-induced
astrogliosis, depletion of the dopamine transporter (DAT),
and cell death. Jayanthi et al. (Jayanthi et al. 2005)
demonstrated the induction of the FasL-Fas death pathway
by MA treatment. Treatment with SCH23390 reduced the
level of TUNEL staining and blocked the MA-induced
cleavage of caspase 8. Taken together, these results strongly
suggest a role for both D
1
and D
2
receptors in the
modulation of MA-induced neurotoxicity.
Dopamine transporters
Dopamine transporters and their regulation will obviously
have profound effects upon the disposition of dopamine.
The effects of MA on dopamine transporters have been
examined by numerous investigators. Early work by
Wagner et al. (Wagner et al. 1980) showed that multiple
doses of MA were followed by striatal dopamine depletion
and loss of dopamine uptake. Other work that demonstrated
the importance of the DAT in mediating MA toxicity was
performed by Schmidt and Gibb (Schmidt and Gibb 1985).
These investigators demonstrated that amfonelic acid, an
inhibitor of DAT, prevented the MA-induced reduction of
TH activity in rats. Similarly, Marek et al. demonstrated that
dopamine uptake inhibitors, including amfonelic acid, were
able to ameliorate the neurotoxic effects of MA (Marek et
al. 1990). Additional confirmation of the role of DAT in
MA-induced toxic effects was provided using knock-out
mice that lacked DAT expression (Fumagalli et al. 1998). In
homozygous KO mice, the lack of DAT expression
abrogated the MA-induced depletion of striatal DA levels.
Animals heterozygous for DAT expression displayed levels
of striatal DA that were intermediate between the wild-type
and DAT knock-out animals. Similar differences between
wild-type and knock-out mice were observed in terms of
402 J. Neurovirol. (2011) 17:401–415

levels of MA-induced astrogliosis and oxygen radical
production. Taken together, these results confirm a central
role for DA and DAT in various MA-induced effects.
Vesicular monoamine transporter 2 (VMAT-2) is another
transporter that is important in terms of DA disposition
[reviewed in (Fleckenstein et al. 2009)]. In addition to
expression in neurons, VMAT-2 is expressed in β-cells of
the pancreas (Saisho et al. 2008) and mononuclear cells
(Anlauf et al. 2006; Tang et al. 2003). The function of this
transporter is to package monoamine transmitters such as
DA into synaptic vesicles in neurons. Mice that are
heterozygous for VMAT-2 expression were utilized to
demonstrate that altered vesicular transport of DA resulted
in increased neurotoxicity associated with altered distribu-
tion of DA and its metabolites (Fumagalli et al. 1999). MA-
treatment of mice was demonstrated to reduce binding of a
VMAT-2 ligand to its transporter (Hogan et al. 2000). The
role of VMAT-2 in DA transport and MA-associated
toxicity was confirmed by (Brown et al. 2002)who
demonstrated that the DA transport inhibitor methylpheni-
date (MPD) caused a redistribution of VMAT-2 from the
fraction associated with the plasmalemmal membrane to the
fraction associated with the cytoplasmic vesicles. Multiple
administrations of MA have been demonstrated to cause a
decrease in VMAT-2 immunoreactivity in the vesicular
subcellular fraction, while causing little change in the
plasmalemmal membrane or whole synaptosomal fractions
(Sandoval et al. 2003). Treatment with MPD after MA
treatment attenuated the MA-induced decrease in vesicular
DA uptake and vesicular DA content without altering the
total striatal dopamine content (Sandoval et al. 2003).
Further evidence for the importance of VMAT-2 in
modulating MA toxicity comes from a report that utilized
lobeline, an alkaloid that had been shown to inhibit MA-
induced behavioral characteristics (Eyerman and Yamamoto
2005). These investigators found that although lobeline did
not affect the MA-induced increase in extracellular striatal
DA, MA-induced hyperthermia and the loss of VMAT-2
immunoreactivity were ameliorated by the alkaloid. As
described above, MA, through its effects on DAT and
VMAT, has a major impact on the expression of transporters
modulating dopamine disposition. It is undoubtedly
through this mechanism that MA exerts at least a portion
of its effects on the CNS.
As can be seen from the brief review above, the
dopaminergic system plays a key role in mediating MA-
induced neurotoxicity. The effects of MA can be modulated
by alteration of DA levels, either through affecting DA
metabolism or it can be mediated through DAT or VMAT-2.
D
1
or D
2
receptors are also capable of affecting MA-
induced effects. Taken together, these results strongly argue
for a central role of the dopaminergic system in mediating
MA toxicity.
Methamphetamine-associated toxicity
The toxicity of MA has been studied in rodents, monkeys,
and humans at behavioral, cellular, and molecular levels.
Studies in rodent model systems
Rodent models have been used to study the effects of MA
at the cellular and molecular levels. In addition, these
models have been used to study MA-mediated hyperthermia
and oxidative stress.
a. Effects of Methamphetamine at the Cellular and
Molecular Levels. Siegel and colleagues have shown that
long-term MA exposure increases the expression of
muscarinic acetylcholine receptors in the hippocampus,
resulting in impaired novel location recognition in female
but not in male mice (Siegel et al. 2010). In contrast to
adult mice, exposure of adolescent mice to MA results in
impaired novel object recognition; the level of impairment
observed is equal in both male and female mice (Siegel et
al. 2011). In addition, MA exposure of adolescent mice
does not affect anxiety-like behavior, sensorimotor gating,
and contextual and cued fear conditioning. As seen in
adolescent mice and unlike that observed in adult mice,
juvenile mice do not show a gender difference in terms of
MA-induced neurotoxicity or increase in body temperature
(Dluzen et al. 2010).
Using in vitro cell cultures as well as a mouse model,
Narita and colleagues demonstrated that MA induces long-
lasting activation of astrocytes in the cingulate cortex and
nucleus accumbens through the protein kinase C pathway
(Narita et al. 2005). In MA-treated mice, the ratio of
activated microglia to non-activated microglia increases
from day 1 to day 7, as opposed to the control groups in
which the ratio is below 0.15. MA-induced glial activation
has been suggested to occur through inflammatory cytokines
based on the fact MA induces IL6 in the hippocampus and
striatum and it induces TNF-αin the hippocampus and frontal
cortex (Goncalves et al. 2008).
Genc and colleagues have shown that MA causes
cytotoxicity in rat oligodendrocyte cultures through the
induction of apoptotic cell death, which is evident from the
expression of pro-apoptotic proteins (Genc et al. 2003).
Exposure of cultured adult rat ventricular cardiomyocytes
(RVC) to acute MA treatment increases the size of RVC,
while chronic MA treatment decreases its size (Ruffolo and
Messick 1985). Furthermore, while acute MA exposure
increases microtubule (MT) assembly, chronic MA exposure
causes a reduction in MT assembly.
Overall, these studies have demonstrated that MA can have
a range of toxic effects on cells by induction of pathways that
include activation, cytokine induction, and apoptosis.
J. Neurovirol. (2011) 17:401–415 403

b. The Effects of Methamphetamine on Oxidative Stress.
Using a rat model, Acikgoz et al. demonstrated that acute
repeated administration, as well as chronic administration,
of MA causes an increase in SOD activity along with an
increase lipid peroxidation in the striatum (Acikgoz et al.
1998). Fluorescein derivatives, along with cell cultures
derived from VMAT-2 wild-type and mutant mice, were
used to demonstrate that MA exposure caused an increase in
ROS (Larsen et al. 2002). It was also demonstrated that the
loss of VMAT-2 expression was associated with higher levels
of ROS and increased levels of cysteinyl-DA, a metabolite
associated with oxidized DA. Using a rat model of MA-
induced neurotoxicity, it was demonstrated that MA admin-
istration at toxic levels resulted in an increase in protein-
cysteinyl DA as a result of an increase in the oxidative
metabolites of DA (LaVoie and Hastings 1999). Using mice
subjected to repeated doses of MA, Jayanthi et al.
demonstrated that levels of glutathione peroxidase, catalase,
and Cu/Zn-SOD were decreased in the striatum of these
animals (Jayanthi et al. 1998). Significantly, this correlated
with an increase in the products of lipid peroxidation. MA
has also been shown to have a similar effect on most, but not
all, peroxiredoxins in rat brain (Chen et al. 2007). In a model
similar to that of Jayanthi et al., repeated injections of MA
produced elevated levels of protein carbonyls and thiobarbi-
turic acid reactive substances, both of which are markers of
oxidative stress, in brain (Gluck et al. 2001). Proteomic
analysis has also been utilized to confirm the upregulation
of enzymatic markers of oxidative stress in MA-treated rats
(Iwazaki et al. 2006). In another study, MA-induced toxicity
was found to be associated with an increase in protein bound
quinone and increased expression of quinone reductase
(Miyazaki et al. 2006). Furthermore, pre-treatment of animals
with an inducer of quinone reductase, which is known to be
protective against quinine-induced toxicity, protected against
MA-induced toxicity.
c. The Effects of Methamphetamine on Hyperthermia and
Microglial Activation. Several studies on MA-induced
hyperthermia in a rat model have been reported by Kiyatkin
and colleagues. MA induces both brain and body hyper-
thermia but brain hyperthermia is much stronger and more
rapid than body hyperthermia (Brown et al. 2003). Unlike
body hyperthermia, brain hyperthermia is dramatically
enhanced at warm ambient temperatures, often resulting in
lethality in mice (Brown and Kiyatkin 2005). In general,
MA-induced brain hyperthermia causes damage to brain
cells, including neurons, glia, epithelial, and endothelial
cells (Kiyatkin 2005; Kiyatkin 2010; Kiyatkin et al. 2007).
MA-induced brain hyperthermia also causes acute glial
activation and edema. Furthermore, chronic MA-induced
brain and body hyperthermia, as well as acute MA
intoxication-induced brain hyperthermia have been corre-
lated with increased permeability of the BBB (Kiyatkin et
al. 2007; Sharma and Kiyatkin 2009). An earlier study
demonstrated that MA-induced hyperthermia induces heat
shock protein (HSP) (Kuperman et al. 1997), which is
consistent with the general phenomenon that hyperthermia
can induce the expression of heat shock proteins (HSPs). A
recent study confirms that acute MA intoxication in rats
causes induction of wide-spread HSP expression in neural
and glial cells, as well as in the cortex, hippocampus,
thalamus, and hypothalamus (Kiyatkin and Sharma 2011).
The induction of HSPs in these cells correlates with brain
hyperthermia, permeability of BBB, acute glial activation,
and brain edema. Although the induction of HSP is an
adaptive mechanism to counteract hyperthermia, it does not
counteract the damaging effects of oxidative stress, hyper-
thermia, and edema in rats.
In addition to hyperthermia, MA has been shown to
induce microglial activation (Kuhn et al. 2008; Thomas et
al. 2004a; Thomas et al. 2004b). Microglial activation was
determined by staining brain sections with isolectin B
4
, and
activation was found to be independent of hyperthermia.
Agents that changed dopamine disposition, such as L-DOPA
and reserpine, enhanced the effects of MA on microglial
activation but had no effects on microglial activation by
themselves. It is of particular interest that reserpine caused
hypothermia in mice, while L-DOPA caused hyperthermia.
However, attenuation of MA-induced microglial activation
by minocycline that resulted in reduction of IL-1a and IL-6
levels did not afford neuroprotection (Sriram et al. 2006).
Thus, although microglial activation is not dependent upon
hyperthermia, microglial activation alone could not account
for the observed neurotoxicity.
Studies in monkey model systems
Since acute high MA dosing regimens can lead to
considerable toxicity and even death in experimental
animals, a non-lethal chronic MA administration procedure
for the rhesus macaque that utilizes an escalating dose
protocol has been developed by Madden and colleagues
(Madden et al. 2005). This regimen produces several
behavioral and physiological effects, including decreased
food intake and increased cortisol excretion, which are
similar to MA-induced effects in humans. In vervet
monkeys, MA exposure has been correlated with the
oxidative stress that occurs during aging (Melega et al.
2007). They showed that, after 1 month of MA treatment,
there is an increase in iron levels in the substantia nigra pars
reticulata and the globus pallidus, along with a concurrent
increase in ferritin-immunoreactivity and a decrease in
tyrosine hydroxylase-immunoreactivity in the substantia nigra.
While the increase in tyrosine hydroxylase-immunoreactivity
is observed after 1.5 years of simulated MA abuse, iron levels
404 J. Neurovirol. (2011) 17:401–415

of the adult MA-exposed animals (age 5–9 years) are
comparable with those of drug-naive, aged animals (19–
22 years). In a subsequent study, these investigators demon-
strated that multiple doses of MA administered to socially
housed vervet monkeys cause a progressive increase in
abnormal behavior and a decrease in social behavior (Melega
et al. 2008). In this study, the vervet monkeys exhibited an
increase in anxiety on ‘no injection’days and a decrease in
aggression was observed throughout the study. Finally, since
some behavioral and pharmacological patterns of chronic MA
abuse and schizophrenia are similar, a primate animal model
of schizophrenia has been established using chronic phency-
clidine (PCP) monkeys. An acute MA injection to the
chronically treated PCP monkeys exacerbated the behavioral
effects of PCP, suggesting that these monkeys can be used as
a primate model of schizophrenia (Mao et al. 2008).
Clinical studies
Clinical studies have been used to study the effects of MA
at behavioral, cellular, and molecular levels. In addition,
clinical investigations have also focused on MA-mediated
oxidative stress.
a. The Effects of Methamphetamine at the Cellular and
Molecular Levels. Chung and colleagues have shown that
the chronic use of MA in humans decreases the cerebral
blood flow in subcortical and dorsal cortical brain regions
(Chung et al. 2010). However, its binge use is associated
with severe neurotoxicity to the monoaminergic neurotrans-
mitter system as a result of long-term changes in both
global and regional blood flows. This produces a pattern of
hypoperfusion, which resembles the pattern of atypical
Parkinson’s disease. Thus, binge use of MA has been
employed as an experimental model of Parkinson’s disease
in animals (Garcia de Yebenes et al. 2000; Romero et al.
2006).
To understand MA-induced neuronal changes in humans,
several imaging techniques have been utilized as described
below. Iyo and colleagues used single photon emission
computed tomography, magnetic resonance spectroscopy,
and positron emission tomography to investigate MA-
mediated psychosis (Iyo et al. 2004). In MA users, these
studies have shown (1) a high incidence of multiple patchy
deficits in cerebral blood flow, (2) a significantly reduced
ratio of creatine plus phosphocreatine/choline-containing
compounds in the brain, and (3) a decrease in the density of
dopamine transporter in the nucleus accumbens and
caudate/putamen. These effects correlate with the duration
of MA use and the severity of residual psychotic symptoms.
High-resolution genetic resonance imaging (Gorbach et al.)
and surface-based computational image analyses in MA
abusers have revealed severe gray-matter deficits in the
cingulate, limbic, and paralimbic cortices, as well as a
decrease in hippocampal volumes and white-matter hyper-
trophy (Thompson et al. 2004). In addition, MA abuse
causes a selective cerebral deterioration resulting in
impaired memory and damage to the medial temporal lobe
and cingulate-limbic cortex. Furthermore, findings from
functional magnetic resonance imaging (fMRI) suggest a
relationship between decision-making dysfunction and
neural activation in different prefrontal areas (Paulus et al.
2002). MA abusers show a decrease in the activation of
dorsolateral prefrontal cortex and fail to activate the
ventromedial cortex during the two-choice prediction task
compared with the two-choice response task.
A recent finding from a study that focused on prenatal
exposure to MA using neuroimaging suggests that MA
exposure in utero is toxic to dopamine-rich basal ganglia
regions (Roussotte et al. 2010). High levels of MA
exposure during pregnancy have been associated with
increased lethargy and physiological stress; first trimester
produces more stress, while third trimester results in
lethargy, poorer quality of movement, and hypotonicity
(LaGasse et al. 2011; Smith et al. 2008).
b. The Effects of Methamphetamine on Oxidative Stress.
MA-induced oxidative stress has also been studied using
human cell cultures. Cubells and colleagues have demon-
strated MA-induced neurite damage and ROS production in
neuronal cultures using differential interference contrast and
fluorescence techniques, respectively (Cubells et al. 1994).
MA exposure has also been shown to increase the
permeability of brain microvascular endothelial cell
(BMVEC) monolayers by decreasing the expression of tight
junction (TJ) proteins and increasing ROS formation
(Ramirez et al. 2009). It has also been shown that MA
modulates TJ expression, leading to decreased transendothe-
lial resistance and enhanced transendothelial migration of
immunocompetent cells across the BBB (Mahajan et al.
2008). Furthermore, N27 dopaminergic neuronal cells have
been used to demonstrate the role of cathepsin-D in MA-
induced autophagy and apoptosis as a result of increased
oxidative stress (Kanthasamy et al. 2006).
c. The Effects of Methamphetamine on Behavior. Al-
though acute use of MA is known to elevate energy and
alertness, its chronic use is associated with increases in
psychosis, anxiety, and depression(Glasner-Edwards et al.
2010; Gonzales et al. 2009; Gonzales et al. 2010; Rawson
et al. 2002;Zwebenetal.2004). Furthermore, MA
intoxication is associated with violent, agitated, and suicidal
behaviors (Newton et al. 2004). The severity of MA-mediated
effects is related to the quantity and frequency of MA
administration. The route of administration as well as
individual genetic differences has an effect upon behavioral
J. Neurovirol. (2011) 17:401–415 405

outcomes. The symptoms of MA-induced psychosis are
similar to the symptoms of schizophrenia, such as paranoid
ideation, delusions, and auditory and visual hallucinations
(Zweben et al. 2004). Although in most users, psychosis
occurs temporarily and is typically abolished within a week
of abstinence, it may persist for several months in a small
fraction of users.
Taken together (overview presented in upper half of
Fig. 1and Table 1), the studies described above demon-
strate that MA exposure has a wide range of toxic effects in
both the CNS and the periphery. These toxic effects include
brain and body hyperthermia, induction of apoptotic path-
ways, increased levels of markers of oxidative stress, as
well as behavioral effects (Krasnova and Cadet 2009). Even
in the absence of additional agents, the toxic effects of MA
are rather significant. In the context of viral infection, they
will show themselves to be even more deleterious.
Methamphetamine and HIV
Effects of methamphetamine on the CNS
Globally, at least 33.3 million people are estimated to be
living with HIV as of 2009. At least 20–30% of the patients
infected with HIV-1 will eventually be diagnosed with HIV-
associated dementia (HAD; McArthur et al. 1993; Nath et
al. 2000; Navia et al. 1986a; Navia et al. 1986b). The
neurotoxic effects of HIV-1 are primarily attributed to its
ability to readily penetrate into the central nervous system
(CNS) early during the course of infection. Deficiency in
the functionality of dopaminergic neurons has been ob-
served to be associated with early stage HIV-1 infection
(Berger et al. 1994). Although the introduction of highly
active antiretroviral therapy (HAART) has significantly
reduced the incidence of HAD (Clifford 2008), milder
neurotoxicity, including minor cognitive motor disorders
and HIV-associated neurodegenerative disorders (HAND)
have increased in incidence (Antinori et al. 2007). Many
anti-retroviral drugs fail to penetrate the blood brain barrier
(BBB), thus making it difficult to treat HAND patients
(Thomas 2004). HIV-associated neurotoxicity is primarily
thought to be mediated by the neurotoxins released from
infected cells, mostly resident microglia, after migration of
the infected cells through the BBB (Gendelman and
Meltzer 1989; Meltzer and Gendelman 1992; Meltzer et
al. 1990). The frontostriatal regions of the brain are highly
vulnerable to this so-called “Trojan Horse”mechanism by
which HIV-1 penetrates the CNS (Itoh et al. 2000; Reyes et
al. 1991). MA also targets these frontostriatal regions by
increasing DA and glutamate transmission, which further
leads to neuronal damage and cell death (Davidson et al.
2001; Langford et al. 2003; Stephans and Yamamoto 1994;
Wilson et al. 1996). Multiple models for MA-mediated
neurotoxicity have been proposed (Cadet and Krasnova
2007; Reiner et al. 2009). However, MA-mediated neuronal
damage is chiefly attributed to depletion of dopamine and
5-HT (Cadet et al. 1994; Wagner et al. 1980), dopamine
transporters (DAT) (Xu et al. 2005), and vesicular mono-
amine oxidase (Mao et al.) in the corpus striatum (Frey et
al. 1997).
The effects of methamphetamine and viral proteins on CNS
toxicity
In an early study, it was demonstrated that treatment with
MA and Tat increased neuronal cell death when human fetal
neurons were exposed to these agents in culture (Magnuson
et al. 1995). Based upon their earlier studies, along with
other relevant data, Nath et al. proposed that dopaminergic
MA
Non-HIV
HIV
Impaired novel location recognition
Activated microglia and apoptotic cell death
Oxidative stress, temperature, and BBB permeability
Abnormal behavior, anxiety, and oxidative stress
Social behavior
Rodent
Monkey
Human Psychosis, anxiety, and depression
Lethargy and physiological stress during pregnancy
Oxidative stress and BBB permeability
Immune
system
Effects
CNS
Effects
Viral replication
HIV-1 co-receptor expression
Altered cytokine secretion
Impaired antigen presentation
Oxidative stress
Dopamine levels
Neuronal apoptosis
Behavioral sensitization
Oxidative stress
Altered cytokine expression
BBB permeability
Fig. 1 Schematic of an over-
view of the effects of MA and
MA in the context of HIV
infection. The upper portion of
the figure focuses on the effects
of MA in rodent and monkey
model systems, as well as those
results derived from clinical
studies on humans. The bottom
portion of the figure focuses on
the effects of MA in the context
of HIV infection
406 J. Neurovirol. (2011) 17:401–415

Table 1 Overview of the effects of MA and MA +HIV/Tat or gp120 in different model systems
Treatment Tissue/cell type Effect Reference
MA Rat neostiatum Tyrosine hydroxylase ↓Gibb and Kogan 1979
Rat neostiatum Tryptophan hydroxylase ↓Hotchkiss and Gibb 1980
Rat caudate DAT ↓;DA↓Wagner et al. 1980
Rat body, rat brain Hyperthermia↑Brown et al. 2003
Brown and Kiyatkin 2005
Sharma and Kiyatkin 2009
Rat striatum Altered VMAT-2 localization Brown et al. 2002
Sandoval et al. 2003
VMAT-2↓Eyerman and Yamamoto 2005
Oxidative stress markers ↑LaVoie and Hastings 1999
Oxidative metabolites ↑
Quinone levels ↑
Oxidative stress markers ↑Iwazaki et al. 2006
Rat neurons Neurite degeneration↑Cubells et al. 1994
Rat neural and glial cells HSP expression ↑Kiyatkin and Sharma 2011
Mouse neurons Apoptosis ↑Jayanthi et al. 2005
Mouse hippocampus Muscarinic acetylcholine receptor ↑Siegel et al. 2010
Mouse hippocampus Impaired novel location recognition Siegel et al. 2011
Mouse hippocampus IL-6 ↑; TNF-α↑Goncalves et al. 2008
Mouse striatum/hippocampus DA levels ↓; 5-HT levels ↓Fumagalli et al. 1998
Mouse striatum Altered VMAT-2 ligand binding Hogan et al. 2000
Mouse striatum Microglial activation ↑Thomas et al. 2004a
Kuhn et al. 2008
Mouse neuron Lipid peroxidation ↑Jayanthi et al. 1998
Mouse HSP expression ↑Kuperman et al. 1997
Vervet monkey Oxidative stress ↑Melega et al. 2007
Food intake ↓Melega et al. 2008
Social behavior ↓
Anxiety ↑
Rhesus macaques Food intake ↓Madden et al. 2005
Cortisol excretion ↑
Human brain Cerebral blood flow ↓Chung et al. 2010
DAT ↓Iyo et al. 2004
Neural activation ↓Paulus et al. 2002
Hippocampal volume↓Thompson et al. 2004
Human dendritic cells TNF-α↑, IL-1β↑, CCR5 ↑, IL-8 ↑Mahajan et al. 2006
p38 MAPK phosphorylation ↑
PI3K phosphorylation ↓
CXCR4 ↑, CCR5 ↑Nair et al. 2006
p38 MAPK phosphorylation ↑
MIP-1α↓, MIP-1β↓, RANTES ↓Nair and Saiyed 2010
Human MDM CCR5 ↑, IFN-α↓Liang et al. 2008
Mixed neuron/astrocyte cultures MMPs ↑Conant et al. 2004
Human brain Endothelial cells Tight junction proteins ↓Ramirez et al. 2009
Human Psychosis ↑, anxiety ↑, depression ↑Rawson et al. 2002
Zweben et al. 2004
Depression ↑Glasner-Edwards et al. 2010
Psychosis ↑Gonzales et al. 2009
Anxiety ↑, depression ↑Gonzales et al. 2010
MA+HIV HIV-1 transgenic rats Behavioral sensitization ↑Liu et al. 2009
J. Neurovirol. (2011) 17:401–415 407

activation-mediated depletion in dopamine levels impaired
the function of the DA transporter and that the resultant
alterations in DA reuptake (Nath et al. 2000)were
responsible for the toxic effects of MA and HIV-1 on
dopaminergic neurons. Later, various MRS studies (Chang
et al. 2005;Schweinsburgetal.2005)showedthatMA
abuse by HIV-positive individuals aggravated damage in the
brain in terms of N-acetyl aspartate reduction.
Multiple studies have been undertaken that focus on the
molecular mechanisms involved in the cross-talk between
the viral proteins and MA. Studies by Maragos et al.
revealed altered dopamine levels due to the combined
effects of MA and HIV-1 Tat (Maragos et al. 2002). Using
Sprague–Dawley rats treated with threshold doses of Tat
and MA, they demonstrated greater depletion in the striatal
DA levels of rats treated with both Tat and MA when
compared with the depletion of DA levels upon treatment
with either MA or HIV Tat. Using neuronal cultures, they
also showed that MA and Tat treatment resulted in higher
levels of cell death and mitochondrial dysfunction as
compared with either agent alone. They also showed that
Tat and MA together can cause further decreases in the
overflow of dopamine as compared with either treatment
alone in the striatal regions of the rats. This suggests that
both the DA levels and the dynamics of DA release in the
striatum are affected by the interaction of MA with HIV-1
proteins. These alterations of the DA levels and activation
could be responsible for basal ganglia dysfunction in MA-
abusing HIV-infected patients (Cass et al. 2003). Turchan et
al. demonstrated synergistic toxicity of gp120/Tat with MA
that resulted in neuronal cell death and alteration of
mitochondrial membrane potential (Turchan et al. 2001).
These findings suggested the possibility that oxidative
stress may play a role in the synergy between MA and HIV.
Increased oxidative stress is found to be associated with
HIV-associated neuroinflammation. Banerjee et al. showed
that intrastriatal MA injection in mice resulted in synergistic
interactions between MA and HIV that were mediated
through oxidative stress (Banerjee et al. 2010). Mice treated
with MA following gp120 or Tat injections showed high
levels of oxidative stress markers such as malonyl dialde-
hyde (MDA) and protein carbonylation along with higher
lipid peroxidation in the brain. In addition, the presence of
both agents resulted in levels of antioxidant enzymes like
GSH and GPx that were significantly decreased when
compared with either treatment alone. The involvement of
oxidative stress was demonstrated through the use of the
antioxidant N-acetyl cysteine amide, which prevented the
disruption of mitochondrial potential that was caused by
MA+Tat or MA+gp120. Flora et al. highlighted the role of
redox-sensitive pathways in the combined effects of MA
and HIV-1 Tat (Flora et al. 2003; Flora et al. 2002).
Interestingly, the intrahippocampal injection of Tat and MA
in mice showed increased activity of transcription factors
associated with oxidative stress particularly in the cortical,
striatal, and hippocampal regions of the brain. The
transcription factors NF–κB, AP-I, and CREB showed
increased DNA binding activity in the hippocampal and
cortical regions of mice treated with Tat and MA as
compared with either substance alone. The increase in the
Table 1 (continued)
Treatment Tissue/cell type Effect Reference
Human immature dendritic cells Adhesion protein (galectin-1, filamin 1 )↑Reynolds et al. 2007
Human PBMC Peroxiredoxin6 ↑, HSP70p5 ↑,vimentin↑Reynolds et al. 2009
Human MDM Viral replication ↑Liang et al. 2008
T cells Viral replication ↑Toussi et al. 2009
Dendritic cells Viral replication ↑Reynolds et al. 2007
MA+SIV Macaque Viral load in brain ↑Marcondes et al. 2010
SOD ↑, GST ↑Pendyala et al. 2011
MA+gp120 Mouse brain Oxidative stress markers ↑Banerjee et al. 2010
Protein carbonylation ↑
Transgenic mice Behavioral changes ↑Roberts et al. 2010
Human BMEC Z0-1 ↓, claudin 3/5 ↓, JAM-2 ↓Mahajan et al. 2008
Human fetal brain cells Cell death ↑Turchan et al. 2001
Alteration of mitochondrial membrane
MA+Tat Rat striatum MCP-1 ↑,IL-1α↑, IL-1β↑, TNF-α↑Theodore et al. 2006a,b
Rat brain Altered dopamine levels Maragos et al. 2002
Mouse striatum TNF-α↑, lipid peroxidation ↑, AP-1 ↑Flora et al. 2002
Oxidative stress ↑Flora et al. 2003
Mixed neuron/astrocyte cultures MMP ↑Conant et al. 2004
408 J. Neurovirol. (2011) 17:401–415

DNA binding activity of the transcription factors further led
to increased expression of IL-1β, TNF-α, and ICAM-1,
particularly in mouse striatum. In a later report, Langford et al.
extended these findings and showed that the combination of
HIV-1 Tat and MA can induce oxidative stress and alter
mitochondrial membrane calcium potentials, which can
further result in neuronal cell death (Langford et al. 2004).
High levels of various inflammatory cytokines are
associated with the toxicities observed in neuroinflamma-
tion. In particular, increased expression of TNF-αis
positively correlated with HAD (Glass et al. 1993). Flora
et al. showed increased expression of TNF-αin the brains
of mice treated with intrahippocampal Tat injections
following IP MA administration. In addition to TNF-α
induction in various regions of brain like frontal cortex,
corpus striatum, hippocampus, and cerebellum, elevated
levels of IL-1βand ICAM-1 were observed in the same
regions. The increase in these genes was found to be
associated with increased oxidative stress signaling. Be-
cause TNF-αand IL-1βalso act as pro-inflammatory
cytokines, the toxicities produced by MA and Tat together
could prove to be a “double-edged sword”of inflammation
and oxidative stress (Flora et al. 2003). Theodore et al.
(Theodore et al. 2006a) confirmed the previous findings by
using TNF-αR1 and TNF-αR2 double knockout mice. In
the DKO mice, Tat+ MA failed to deplete the DA levels as
compared with the depletion observed in Tat+ MA-treated
WT animals. The induction of TNF-αwas also found to
result in increased hippocampal neuron loss. Increased
levels of the pro-inflammatory cytokines MCP-1, TIMP-1,
and IL-1αwere found in a cytokine array prepared from rat
striatum treated with MA and Tat as compared with either
treatment alone. Furthermore, MCP-1 KO mice did not
show the depletion of DA observed in the combined
treatments as compared with the treatments by a single
agent (Theodore et al. 2006a,2006b). Together all these
findings provide strong evidence for the role of cytokines in
mediating the interactions observed between MA and HIV
infection in terms of increasing neurodegeneration.
Blood–brain barrier integrity is essential for maintenance
of brain homeostasis. Tight junction proteins are a critical
component responsible for maintaining the high level of
impermeability of the BBB. Mahajan et al. showed that
HIV-1 gp120 and MA synergistically disrupt the BBB and
deplete various tight junction proteins such as ZO-1, JAM-2,
and Claudin-3/5 (Mahajan et al. 2008). Furthermore, studies
by Banerjee et al. showed that mice treated with MA and
viral proteins like gp120 or Tat had decreased levels of TJ
proteins like ZO-1 and occludin. Treatment with antioxidants
also demonstrated restoration of levels of TJ proteins. This
observation confirmed the role of oxidative stress in the loss
of BBB integrity Banerjee (Banerjee et al. 2010). Studies by
Conant et al. also demonstrated synergy between MA and
Tat in the induction of MMP levels in the striatum (Conant et
al. 2004).
Behavioral effects of methamphetamine in transgenic
rodents
Various transgenic rodent models have been developed that
simulate conditions of HIV/AIDS. Using HIV transgenic
rats, it was shown that MA increases behavioral sensitiza-
tion in these animals (Liu et al. 2009). HIV-1 transgenic rats
treated with MA showed increased behavioral sensitization
in terms of rearing and head movements when compared
with control transgenics that were not treated with MA. It
was also shown that D1R expression was higher in the
transgenic rats treated with MA. This cohort also showed
lower brain to body weight ratios, suggestive of brain
atrophy. Another study utilized a transgenic mouse model
expressing gp120 to demonstrate that MA-induced stereotypic
behavior and locomotion are significantly increased in HIV
transgenic mice (Roberts et al. 2010). This report, in
conjunction with the prior study, indicated possible behavioral
alterations that underscore the complexity associated with the
aggravating effects of MA abuse on HIV-associated CNS
toxicity. Taken together, these findings provide strong
evidence of increased CNS impairment in HIV-infected
individuals consuming illicit drugs.
The effects of methamphetamine on viral replication
One of the major contributing factors to HIV disease
progression due to MA is the increase in viral load due to
MA exposure. MA causes a dysregulation of dopamine
disposition, which has been shown to enhance viral
replication and also activate latent virus in T lymphocytes
(Rohr et al. 1999). This suggests the possibility that MA
may be able to increase HIV replication in the CNS.
Recently, the effect of MA administration on brain viral
load using macaques was determined. Rhesus macaques,
when infected with simian immunodeficiency virus (SIV),
can serve as a model of HIV infection in humans. Although
MA administration in monkeys produced no change in the
plasma viral load, the brain viral load was significantly
higher (Marcondes et al. 2010). The increased activation of
microglia and astrocytes in the brain demonstrates the toxic
potential of MA in HIV-1 infected individuals. Activation
of NK cells in the periphery and the expression of co-
receptor CCR5 on brain macrophages were also observed to
increase. MA was also shown to increase CD14+/CD16+
macrophages in brains of HIV-1-infected animals, and these
macrophages are known targets for SIV/HIV infection in
the brain. The MA-mediated increase in macrophage
activation and brain viral load suggests that MA may
exacerbate the CNS effects of HIV infection.
J. Neurovirol. (2011) 17:401–415 409

There is evidence to suggest that MA use may result in
increased viral load in the periphery. Treatment of human
monocyte-derived macrophages with MA was able to
potentiate HIV reverse transcriptase activity in a dose
dependent manner, and the effects of MA could be
abrogated by blocking D1 receptors expressed on macro-
phages (Liang et al. 2008). Increased HIV replication was
also observed in immature dendritic cells treated with MA
prior to HIV-1 infection (Reynolds et al. 2007). Another
study examined both the in vitro and in vivo effects of MA
on HIV replication. In vitro, HIV replication was significantly
increased in monocytes and CD4
+
T cells treated with MA.
Viremia was also increased in vivo in mice transgenic for the
HIV provirus and human cyclin T1 as determined by p24
antigen production in splenocytes as well as viral RNA copy
numbers in serum. These effects were mediated by translo-
cation of NFКB p65 subunit into the nucleus and subsequent
transcription from the HIV-1 LTR (Toussi et al. 2009).
Because of the potential for infected monocytes to cross the
BBB, an increased viral load in the periphery may result in
higher viral loads in the CNS.
The effects of methamphetamine and HIV on the immune
system
HIV initially infects cells of the immune system and
subsequently invades and compromises various other
systems of the body. It is known to modulate various
immune functions such as activation of T cells and NK cells
as well as to disrupt cytokine balance. Because of its action
as a psychostimulant, the effects of MA in the context of
HIV infection have been primarily studied in the CNS.
However, dopamine receptors and transporters, which are
reported to mediate the effects of MA, are also expressed in
the periphery on various immune cells. It is therefore
relevant, and important, to study the effects of MA in the
immune system of HIV-infected individuals.
As mentioned previously, MA has been shown to
increase HIV replication in various immune cells such as
dendritic cells, monocytes, and CD4
+
T-cells (Reynolds et
al. 2007; Toussi et al. 2009). Several studies have also
documented the ability of MA to modulate other immune
functions. MA has been demonstrated to upregulate the
expression of the HIV co-receptor CCR5 on macrophages
while simultaneously suppressing the expression of the
anti-viral cytokine IFN-α(Liang et al. 2008). Microarray
studies on dendritic cells differentiated from normal human
PBMC and treated with MA showed altered gene expression
patterns. The expression levels of the pro-inflammatory
cytokines TNF-α,IL-1β, and IL-8 were upregulated, as was
the expression of CCR5. Phosphorylation of the signal
transduction molecule p38-MAPK was increased while
PI3K phosphorylation was decreased (Mahajan et al. 2006).
This study was followed up by performing proteomic
analysis using PBMC isolated from HIV-1 patients and
exposed to MA for 24 h. MA decreased expression of
HSP70p5 and peroxiredoxin 6 while increasing the expres-
sion of vimentin in these cells. HSP70 prevents vpr-induced
cell cycle arrest, whereas peroxiredoxins are antioxidants
that inhibit HIV-1 infection. Vimentin, on the other hand,
facilitates spread of HIV to adjacent cells (Reynolds et al.
2009). Proteomic analysis of MA-treated immature dendritic
cells infected with HIV-1 showed increased expression of
proteins that promote HIV adhesion, entry, and replication
such as galectin-1, PDI, filamin 1, and talin 1 (Reynolds et
al. 2007). MA may therefore act as a co-factor that promotes
HIV pathogenesis by increasing the susceptibility of cells to
viral invasion, activation of HIV transcriptional mechanisms,
and T cell depletion through apoptosis.
Dendritic cells (DC) are among the first lines of defense
against invading pathogens and consequently are among the
initial targets of HIV infection. MA treatment reduces the
expression of the mature DC marker CD83 that plays a role
in antigen presentation and T cell activation. It also
decreased secretion of the chemokines MIP-1α, MIP-1β,
and RANTES which can bind to the CCR5 co-receptor and
prevent entry of virus into cells (Nair and Saiyed 2010).
MA and gp120 synergistically upregulate DC ICAM-3 by
binding the non-integrin DC-SIGN. DC-SIGN is known to
promote HIV infection in the absence of CD4 or the HIV
co-receptors. In addition, MA also caused a dose-dependent
increase in the HIV-1 co-receptors CXCR4 and CCR5.
These effects were mediated by interaction of MA with D1
dopamine receptor and the phosphorylation of p38 MAPK
(Nair et al. 2006). Talloczy et. al investigated the effects of
pharmacologically relevant concentrations of MA on
antigen processing, presentation, and phagocytosis in
murine dendritic cells and macrophages (Talloczy et al.
2008). It was observed that MA induced alkalization in
acidic organelles and thereby impaired dendritic cell function
involving lysosomal degradation of foreign proteins. MA also
inhibited macrophage phagocytic function while promoting
fungal replication in macrophages. Therefore, the ability of
MA to disrupt the pH gradient in these cells was responsible
for loss of their respective functions.
A number of studies have also been carried out on non-
human primates, which serve as excellent model systems to
study HIV. Chronically SIV-infected rhesus macaques showed
changes in virus–host interaction due to MA exposure.
Though plasma viral loads were not elevated, significant
changes were observed in immune cells. NK cell activation
was prominent in brain, blood, and lymphoid organs as
determined by degranulation and cytokine expression on the
cell surface (Marcondes et al. 2010). Oxidative stress is also
believed to play a pivotal role in chronic SIV and MA co-
morbidity. Proteomic plasma analyses of chronically infected
410 J. Neurovirol. (2011) 17:401–415

macaques that were administered MA revealed significantly
elevated levels of the enzymes superoxide dismutase as well
as glutathione-S-transferase (Pendyala et al. 2011). This
suggests the utilization of these compensatory mechanisms
to combat oxidative stress.
Thus, MA has been implicated in exacerbating HIV-
induced effects in the CNS and periphery through number
of mechanisms promoting HIV replication and infectivity,
altering expression of important immune components,
impairing antigen presentation and elevating oxidative
stress (summarized in Table 1, Fig. 1).
Summary and future directions
A review of the literature shows that the chemical similarity
between MA and dopamine is thought to be the basis for
the toxic effects of this drug. Early work demonstrated that
treatment of rodents with MA results in altered expression
of many of the enzymes involved in dopamine biosynthesis.
Further work demonstrated that dopamine receptors and
dopamine transporters are key players in mediating the
effects of MA. The ability of MA to affect the function of
DAT and VMAT-2 causes an aberrant distribution of
dopamine and its metabolites. The altered distribution of
dopamine not only affects signaling, but it can also produce
oxidative stress. MA-abuse in humans has been demon-
strated to cause altered cerebral blood flow and severe gray
matter deficits in several regions of the brain. The use of
rodent models has also facilitated identification of brain
hyperthermia as one of the deleterious effects on the CNS
associated with MA abuse.
The frontostriatal regions of the brain that are most
susceptible to the deleterious effects of MA are also one of
the initial targets of HIV-1 infection. The HIV-1 viral proteins
Tat and gp120 interact with MA synergistically to increase
neuronal cell death, oxidative stress, and inflammatory
cytokine production by cells of the CNS. MA has been shown
to decrease tight junction proteins in the BBB such as ZO-1
and claudin-3/5. This may facilitateHIV-1 penetration into the
CNS. Using a macaque model of HIV-1 infection, one group
demonstrated that MA treatment of infected animals resulted
in an increase in the viral load in CNS.
More recently, MA has been shown to have the
potential to affect HIV infection in the periphery.
Treatment of human MDMs infected with HIV showed
increased levels of viral replication. HIV infection may
be exacerbated by the increased levels of inflammatory
cytokines and chemokines or increased levels of the
CCR5 co-receptor seen in MA-treated macrophages and
dendritic cells. Such increases may potentiate viral
replication in the periphery and thus increase the
potential for CNS infection.
Although the biological effects of MA abuse have been
extensively studied during the past two decades, much
remains to be explored regarding the effects of MA abuse
on HIV-1 infection. Although there have been some reports
regarding the effect of HIV and its associated proteins on
DAT, the effect of viral infection on the expression and
function of VMAT-2 is unknown. Because recent work has
demonstrated that both of these transporters affect dopa-
mine disposition, and both are also affected by MA, this
represents a major gap in our understanding of HIV-MA
interactions in the CNS. Another unanswered question
regards the potential role of dopamine receptors in affecting
HIV replication in microglial cells. These receptors have
already been demonstrated to increase HIV replication in
human MDMs treated with MA. Although the data is
limited, it has already been demonstrated that MA treatment
of macaques increases the CNS viral load. This raises the
question as to whether the primary mechanism is an
increase in the permeability of the BBB or an increase in
HIV replication in microglial cells. The effects of MA are
obviously not limited to the CNS, and the findings that
have shown an MA-induced increase in HIV-1 replication
in human MDMs, and increased co-receptor expression on
dendritic cells certainly suggest that further investigation of
the effects of MA on HIV pathogenesis in the periphery are
warranted. The next several years should yield some
interesting results regarding MA–HIV interactions.
Acknowledgments The preparation of this review was supported by
funding from National Institute on Drug Abuse (DA025528 and
DA025011).
Conflicts of interest The authors declare no conflicts of interest.
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