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					                                                    Brain Research Reviews 50 (2005) 14 – 26
                                                                                                                                                                                    www.elsevier.com/locate/brainresrev

                                                                                            Review

              HIV-dementia, Tat-induced oxidative stress, and antioxidant
                             therapeutic considerations
                  Chava B. Pocernicha,b, Rukhsana Sultanaa,b, Hafiz Mohmmad-Abdula,b,
                                Avindra Nathc, D. Allan Butterfielda,b,d,*
                                       a
                                        Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
                                   b
                                     Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA
                                     c
                                      Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA
                                  d
                                    Sanders-Brown Center in Aging, University of Kentucky, Lexington, KY 40506, USA

                                                                           Accepted 4 April 2005
                                                                        Available online 10 May 2005



Abstract

    Oxidative stress is thought to play a role in the onset of dementia. HIV-dementia has recently been demonstrated to be associated with
oxidative stress as indexed by increased protein and lipid peroxidation in the brain and cerebrospinal fluid compared to HIV non-demented
patients. The HIV protein Tat induces neurotoxicity, and, more recently, Tat was found to induce oxidative stress directly and indirectly. The
role of Tat in HIV-dementia and possible therapeutic strategies involving endogenous and exogenous antioxidants are discussed.
D 2005 Elsevier B.V. All rights reserved.

Theme: Disorders of the nervous system
Topic: Infectious diseases

Keywords: HIV-dementia; Tat; Oxidative stress; Antioxidant




Contents

  1.   Introduction . . . . . . . . . . . .     .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   15
  2.   Oxidative stress . . . . . . . . . .     .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   15
  3.   Oxidative stress and HIV-dementia.       .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   15
  4.   HIV and antioxidants . . . . . . . .     .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   15
  5.   Tat . . . . . . . . . . . . . . . . .    .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   17
  6.   Tat-induced neurotoxicity . . . . .      .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   17
  7.   Indirect neurotoxicity of Tat . . . .    .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   18
  8.   Tat and apolipoprotein E . . . . . .     .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   19
  9.   Antioxidants and Tat . . . . . . . .     .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   20


   Abbreviations: HIV, human immunodeficiency virus; HIVD, human immunodeficiency virus-dementia; AD, Alzheimer’s disease; CSF, cerebrospinal fluid;
ROS, reactive oxygen species; HNE, 4-hydroxy-2-nonenal; GSH, glutathione; CNS, central nervous system; NAC, N-acetylcysteine; TRX, thioredoxin;
EGCG, epigallocatechin gallate; PKC, protein kinase C; PI, phosphatidylinositol; PLC, phospholipase C; DAG, diacylglycerol; IP3, inositol triphosphate; ER,
endoplasmic reticulum; LRP, low-density lipoprotein; TNF, tumor necrosis factor; IL, interleukin; INOS, inducible nitric oxide synthase; NO, nitric oxide;
QUIN, quinolinic acid; ApoE, apolipoprotein E; D609, tricyclodecan-9-yl-xanthogenate
 * Corresponding author. Department of Chemistry and Center of Membrane Sciences, 125 Chemistry – Physics Building, University of Kentucky, Lexington,
KY 40506, USA. Fax: +1 859 257 5876.
   E-mail address: dabcns@uky.edu (D.A. Butterfield).

0165-0173/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainresrev.2005.04.002
                                         C.B. Pocernich et al. / Brain Research Reviews 50 (2005) 14 – 26                                                                                                                          15


10. Protection of    astrocytes overexpressing Tat     .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   21
11. Conclusions.     . . . . . . . . . . . . . . . .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   21
Acknowledgments      . . . . . . . . . . . . . . . .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   21
References . . . .   . . . . . . . . . . . . . . . .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   22




1. Introduction                                                                                    3. Oxidative stress and HIV-dementia

   It is estimated that one-third of adults infected with                                             Oxidative stress in HIV-dementia patients has been
human immunodeficiency virus (HIV-1) develop dementia                                              demonstrated in the brain and CSF [33,159]. Staining of
[70]. HIV-1 dementia (HIVD) is now the leading cause of                                            HNE was found to be prominent in neurons, glial cells,
dementia in people younger than 60 years of age [105].                                             and perivascular cells in brain slices of patients with HIV
Oxidative stress is thought to play a role in the onset of                                         encephalitis and macaques with SIV encephalitis [159].
dementia associated with Alzheimer’s disease (AD)                                                  Protein oxidation was increased in the CSF of HIV-
[21,22,25,103]. Recently, we reported that oxidative stress                                        patients with mild and severe dementia compared to non-
has been demonstrated in the HIV brain and cerebrospinal                                           demented HIV-patients. Nitrated tyrosine residues, evi-
fluid (CSF) [159]. These observations have important                                               dence of peroxynitrite reaction with proteins, is increased
implications for therapeutic approaches for HIV-dementia.                                          in HIVD brains [14]. Activation of cytokine receptors and
                                                                                                   oxidative stress can induce the production of ceramide
                                                                                                   from membrane sphingomyelin, and recent findings
2. Oxidative stress                                                                                suggest that ceramide is an important mediator of a form
                                                                                                   of programmed cell death (apoptosis). Recently, it was
   Oxidative stress can be defined as the modification and                                         reported that levels of ceramide, sphingomyelin, and HNE
accumulation of biological molecules altered by various                                            are significantly increased in brain and CSF of HIVD
kinds of reactive oxygen species (ROS). Oxidative stress is                                        patients, and the HIV protein Tat can induce increases of
also defined as an imbalance between the antioxidant and                                           all three in cultured neurons [61]. Mass spectrometry
the pro-oxidant systems, with the shift towards the pro-                                           studies of HNE, sphingomyelin, and ceramide were
oxidant system. ROS are highly reactive, toxic oxygen                                              performed on autopsy tissue and CSF of HIV patients
moieties, such as hydroxyl radical, peroxyl radical, super-                                        prior to the use of highly active antiretroviral therapy
oxide anion, hydrogen peroxide, and peroxynitrite. The                                             (HAART). HNE in the CSF of HIV patients with inactive
half-life of ROS species varies from nanoseconds for the                                           HIVD (dementia status did not change in the last 6
hydroxyl radical to seconds for nitric oxide and peroxyl                                           months) slightly increased and greatly increased with
radicals. Because of the differences in half-lives, the ROS                                        active HIVD (a transition from a non-demented status to
reactivity differs from the aqueous environment in which                                           dementia within 6 months) compared to HIV patients with
they were formed (hydroxyl radical) to reacting deep within                                        no dementia (HIV-ND) [136]. Sphingomyelins were
the membrane (H2O2).                                                                               elevated in mild HIVD cases compared to HIV-ND in
   Collectively, ROS can lead to oxidation of proteins and                                         the CSF and medial frontal gyrus, while moderate HIVD
DNA, peroxidation of lipids, and ultimately cell death [24].                                       cases were elevated only in the CSF. Ceramide levels
Protein carbonyl groups are used as a marker of protein                                            were elevated in CSF and medial frontal gyrus in both
oxidation [23]. These protein carbonyl moieties result from                                        mild HIVD and moderate HIVD. Sphingomyelin and
a direct oxidation of many amino acids such as lysine,                                             ceramide can vary in length from 16 to 24 carbons.
arginine, histidine, proline and threonine, h-scission of the                                      Different length sphingomyelins and ceramides were
peptide backbone, or from binding of the lipid peroxidation                                        significant in different brain regions of HIVD patients
product 4-hydroxynonenal (HNE) to proteins [23,150].                                               (for review, see [136]).
Alterations in proteins can lead to aggregation, changes in
secondary and tertiary structure, susceptibility to proteol-
ysis, fragmentation, and loss of function. Lipid peroxidation                                      4. HIV and antioxidants
produces large amounts of aldehydes, such as HNE,
malondialdehyde, and acrolein, and leads to isoprostane                                               To counteract these damaging radicals, antioxidant
formation [27]. HNE and acrolein contribute to membrane                                            systems have evolved, including enzymes like glutathione
damage and cell death induced by a variety of oxidative                                            peroxidase, glutathione reductase, glutathione transferase,
insults [48], and through alterations of protein structure                                         superoxide dismutase, S-methyl transferase, and catalase.
[153] are capable of inhibiting DNA, RNA, and protein                                              Protection against free radicals can also come from small,
synthesis, glycolysis, and degradation of enzymes.                                                 non-protein, cellular antioxidants, such as glutathione,
16                                          C.B. Pocernich et al. / Brain Research Reviews 50 (2005) 14 – 26


vitamin C, vitamin E, carotenoids, flavanoids, thioredoxin,                    compounds that increase concentrations of brain glu-
and uric acid [23].                                                            tathione such as gamma-glutamylcysteine ethylester
    Antioxidant levels in HIV-infected patients are altered, a                 [41,42,126,127], might allow further advances in under-
situation that can lead to increased oxidative stress. The                     standing the processes underling HIV-dementia and
tripeptide glutathione (g-glutamate – cysteine – glycine,                      provide additional strategies in the treatment of HIV and
GSH), present in millimolar concentrations in the brain,                       HIV-dementia.
functions as an antioxidant and maintains sulfhydryl groups                        Thioredoxin (TRX) is a redox active thiol similar to
of proteins in the reduced form [126]. Glutathione protects                    glutathione. TRX reduces protein disulfides with the aid of
neurons against reactive oxygen species directly and                           TRX reductase and is a crucial antioxidant in the extrac-
indirectly, and binds lipid peroxidation products such as                      ellular space where glutathione levels are limited [114].
HNE, thereby providing neuroprotection [41,127,126].                           Plasma levels of TRX are significantly elevated in HIV-
Glutathione levels are decreased in HIV patients (Table 1).                    infected individuals compared to healthy controls [113] and
Serum glutathione levels and glutathione peroxidase activity                   inversely correlates with decrease in intracellular GSH
were significantly lower in HIV than in controls, while the                    levels in T cells (Table 1). The data suggest that oxidative
lipid peroxidation product malondialdehyde, DNA frag-                          stress in HIV infection leads to decreases of intracellular
mentation in lymphocytes, and total hydroperoxides were                        GSH levels and increases of plasma TRX levels.
increased [56]. The concentrations of GSH and other                                The major component of green tea, epigallocatechin
sulfhydryl compounds are decreased in the blood, liver,                        gallate (EGCG), has been shown to have antiviral, anti-
and central nervous system (CNS) of HIV-infected patients                      tumorigenic, anti-inflammatory, antioxidant, antibacterial,
[31,36], and low GSH is associated with poor survival in                       and antiproliferative effects [26,116]. Several mechanisms
HIV-infected patients, while administration of GSH to HIV-                     for the antiviral effects of EGCG on HIV-1 have been
infected patients decreases mortality [64].                                    proposed. EGCG inhibits the HIV protein gp120 from
    N-Acetyl-l-cysteine (NAC) acts as an indirect precursor                    binding to the host cell surface by binding the CD4 receptor
of glutathione by raising intracellular levels of cysteine, a                  on the cell surface [78]. Entry of the HIV virion is achieved
precursor of glutathione [126,127]. NAC also has antiox-                       by gp120 binding to the CD4 and chemokine receptors on
idant properties of its own due to the sulfhydryl group. We                    the host cell surface [85]. EGCG also inhibits HIV-1
demonstrated that NAC injected i.p. into rodents increases                     replication by blocking the activity of HIV-1 reverse
glutathione levels in the brain and protects brain against the                 transcriptase [49,115]. Lastly, EGCG induces virion destruc-
damaging effects of hydroxyl radicals and the lipid                            tion by deformation of phospholipids by binding to the
peroxidation product acrolein [126,127]. In vitro, NAC                         surface of the viral envelope [168]. Polyphenols also have
inhibits viral replication in human monocyte-derived macro-                    antioxidant capabilities [26]. HIV-positive patients who
phages and lymphocytes [66,74,109]. The administration of                      drank fruit and vegetable juices had increased lymphocyte
NAC to HIV-infected patients has been shown to decrease                        proliferation, which could restore disturbances in T-cell
mortality [64]. Recently, various NAC analogs including N-                     homeostasis [165]. Moreover, polyphenols such as curcu-
(N-acetyl-l-cysteinyl)-S-acetylcysteamine have been shown                      min and ferulic acid can induce stress response protective
to increase glutathione and display anti-HIV activity making                   genes, such as heat shock protein-32 (heme oxygenase-1)
them possible therapeutic candidates for HIV infection                         [29,30,140].
[41,42,122,126,127].                                                               Many other antioxidants have been tried for AIDS
    Whey proteins have been shown to increase glutathione                      therapy including selenium, vitamin C, vitamin E, lipoic
levels in humans, most likely by supplying the amino acid                      acid, and h-carotene. Selenium levels in blood of HIV-
cysteine necessary for the synthesis of glutathione. HIV                       infected subjects are decreased [123]. Selenium supple-
patients receiving a daily dose of whey proteins had a                         mentation increases glutathione peroxidase activity [138]
significant elevation of plasma glutathione levels after 2                     and inhibits TNF-a-induced HIV replication [67].
weeks [107,108]. The exogenous supplement action of                            Recently, lower plasma selenium levels were significantly
                                                                               associated with an increased risk of mortality in pregnant
                                                                               women from Tanzania followed over a 5- to 7-year period
Table 1                                                                        [83]. Vitamin C suppress the replication of HIV by
Changes in antioxidant levels in patients with HIV-1
                                                                               reduction of reverse transcriptase activity [58], and vitamin
Evidence                  Body site/cell type            Reference             E suppresses the activation of NF-nB [69]. Supplementa-
GSH and                   Plasma, blood, liver, CNS      [18,31,36,43,         tion of vitamin E and vitamin C was found to reduce
  cysteine depletion                                     45,56,148,149]        oxidative stress in HIV infection and produced a down-
GSH depletion/            Peripheral blood T cells       [8,94,147]
  GSSG elevation
                                                                               ward trend in HIV viral load in a blind HIV study [3].
TRX depletion             Plasma                         [102]                 HIV-infected patients supplemented with vitamins A, C,
TRX elevation             Peripheral blood T cells,      [79,97,113]           and E had significantly decreased levels of oxidized DNA
                          monocytes, plasma                                    bases and lipid peroxidation, and had increased activity of
Selenium decreased        Blood                          [123]                 antioxidant enzymes superoxide dismutase and catalase
                                    C.B. Pocernich et al. / Brain Research Reviews 50 (2005) 14 – 26                                17


[71]. Recently, Tanzanian women who received vitamins                  5. Tat
B, C, and E supplementation were less likely to have
progression to advanced stages of HIV disease, had better                  In patients with HIV-1 infection, significant neuronal loss
preservation of CD4+ T-cell counts and lower viral loads,              and dysfunction occur even though, ironically, neurons are
and had lower HIV-related morbidity and mortality rates                rarely infected [121]. In brain, microglia, macrophages, and
than women who received placebo [52]. HIV-infected Thai                astrocytes are the most commonly infected cell types
adults who received multivitamins also had decreased                   [80,84,137]. Uninfected cell death can be induced by viral
mortality rates [72]. Fawzi and colleagues have previously             proteins released from nearby HIV-1-infected cells and host-
shown that multivitamin use is associated with improved                derived toxins. Toxic viral proteins released from HIV-1-
pregnancy outcomes, including reduced rates of low birth               infected proteins include Tat and gp120.
weight, prematurity, and fetal death in HIV women [50].                    Tat is a nonstructural HIV protein of 86 –101 amino acids
Vitamin A supplementation has reportedly been followed                 that is formed from 2 exons. The first exon contributes to
by increased rates of mother-to-child transmission of                  the first 72 amino acids and acts as a transacting nuclear
infection [51]. Supplementation of lipoic acid (thioctic               regulatory protein essential for viral replication. Tat can be
acid), a sulfur containing antioxidant, in patients with HIV-          transported efficiently across the intact blood –brain barrier
associated cognitive impairment, did not improve cognitive             [141]. In HIV-infected astrocytes, the regulatory gene tat is
function [1]. Several reports have shown that h-carotene               overexpressed [117], and mRNA levels for Tat are elevated
supplementation has no significant effect in HIV-infected              in brain extracts from individuals with HIV-1 dementia
individuals [38,39]. The above results suggest that HIV-               [68,164]. The Tat sequences from brains of patients with
infected people can benefit from selected antioxidant                  HIV-dementia are mutated with glutamate substitutions in
treatment. In fact, a clinical trial using minocycline is              the second exon [15], which may decrease its ability to be
being initiated in patients with HIVD, which has both                  taken up by cells, thus increasing its extracellular concen-
antioxidant and anti-inflammatory effects (Sacktor, Johns              trations and possibly neurotoxicity effects on the cell. Brain
Hopkins University, personal communication).                           regions particularly susceptible to Tat toxicity, i.e., striatum
   Many clinical trials on HIV-dementia have centered on               [63], hippocampal dentate gyrus, and the CA3 region of the
drugs that block receptors or are antagonists to the neuro-            hippocampus [99], parallel those significantly affected in
toxic chemokines and cytokines released from activated                 Alzheimer’s disease. Tat has been hypothesized by many as
microglia, macrophages, and astrocytes. These drugs                    a potential contributor to HIV-dementia [59].
indirectly act as antioxidants by blocking the downstream
effects of these neurotoxic agents that usually result in an
increase in reactive oxygen species and neuronal death.                6. Tat-induced neurotoxicity
HIV-dementia clinical trials to date include nimodipine (L-
type calcium channel antagonist), peptide T (possible                     Tat is a mediator of neurotoxicity. Tat transactivates viral
chemokine receptor blocker), selegiline (monoamine oxi-                and cellular gene expression, is actively secreted into the
dase-B inhibitor), deprenyl (monoamine oxidase-B inhib-                extracellular environment mainly from astrocytes, micro-
itor), lexipafant (platelet-activating factor antagonist),             glia, and macrophages, and is taken up by neighboring
memantine (NMDA antagonist), and CPI-1189 (TNF                         uninfected cells such as neurons [32,46,81,135]. The HIV-1
antagonist). Most of these drugs displayed a trend for                 protein Tat released from astrocytes reportedly produces
improvement (for review, see [160]).                                   trimming of neurites, mitochondrial dysfunction, and cell
   Memantine is an NMDA receptor antagonist that blocks                death in neurons [33]. A single injection of full-length
the receptor’s ion pore, but has a low affinity for the                Tat(1 –86), Tat(1 – 72), or the short basic domain of Tat(48 –
NMDA receptor, allowing it to disassociate readily from the            57) into the hippocampus or thalamus resulted in glial cell
channel [124]. Memantine is currently used to treat                    activation, influx of inflammatory cells, induction of in-
Alzheimer’s disease, another dementing disorder [20]. In               ducible nitric oxide synthase, and neurotoxicity [73,125]. In
vitro, HIV-1 proteins gp120 and Tat activate NMDA                      vivo measurements of Tat are difficult because Tat anti-
receptors, and this activation is blocked by memantine                 bodies have weak affinity and are poorly standardized from
[90,120]. Transgenic mice expressing the HIV-1 protein                 laboratory to laboratory [37]. HIV-Tat has been detected in
gp120, also benefited from memantine treatment [156].                  sera of HIV-infected patients at the low nanomolar level
Recently, memantine has been demonstrated to attenuate                 [163,167], a value that may be underestimated since Tat can
hippocampal synaptic impairment in murine HIVE [5].                    be trapped by heparan sulfate, which is widely expressed on
Memantine is currently in a phase II study for HIV-                    cell surfaces [134,171]. Furthermore, this concentration
associated dementia.                                                   would be higher near productively infected cells. In vitro
   HIV-infected individuals supplemented with deprenyl, a              systems test Tat toxicity between 100 and 500 nM
monoamine oxidase B inhibitor and putative anti-apoptotic              concentration.
agent, displayed significant improvement on tests of verbal               Tat-induced neurotoxicity is thought to be mediated
memory compared with patients not taking deprenyl [1].                 through excitotoxic mechanisms involving calcium. Tat is
18                                   C.B. Pocernich et al. / Brain Research Reviews 50 (2005) 14 – 26


capable of depolarizing rat CA1 hippocampal neurons and                 anatomical pathways from the dentate gyrus to the CA3/4
human cortical neurons [95], increasing intracellular Ca2+              region of the hippocampus and from the striatum to the
[118], and inducing neuronal death [63,95,155]. The                     substantia nigra, resulting in behavioral abnormalities,
increases of cytosolic calcium are followed by mitochon-                neurotoxicity, and reactive gliosis [17]. This finding
drial calcium uptake, generation of ROS, activation of                  demonstrates the ability of Tat to cause neuroglial dysfunc-
caspases, and eventually apoptosis [82]. Cleavage of                    tion at sites distant from that of viral replication by neuronal
phosphatidylinositol (PI) by phospholipase C (PLC) to                   transport and supports the participation of Tat in HIVD.
produce diacylglycerol (DAG) and inositol triphosphate                     The CSF has three main functions: to cushion the brain,
(IP3) has been implicated as an important signaling pathway             deliver nutrients through out, and remove waste from the
for Tat. In neurons, Tat activates phosphatidylinositol 3-              brain. CSF is produced in the choroid plexus in the lateral
kinase [110], increases levels of IP3, releases calcium from            ventricles in the middle of the brain. It flows from the lateral
IP3-sensitive endoplasmic reticulum (ER) internal stores                ventricles through the interventricular foramen to the third
[60], and increases activity of the protein kinase C isoforms           ventricle through the cerebral aqueduct to the fourth
a, (, and s [13], all precursors of oxidative stress. Tat-              ventricle. It exits the fourth ventricle into the spinal cord
induced neurotoxicity is prevented by antagonists of                    and subarachnoid space, which cushions the outside of the
phospholipase C and IP3-sensitive ER calcium release                    brain, and is drained by series of sinuses into the venous
[60]. This evidence suggests that Tat activates a metabo-               bloodstream. Extracellular Tat can be cleared from the brain
tropic receptor and that inositol signaling is central to Tat-          extracellular fluid by the CSF. The movement of the CSF
induced neurotoxicity. However, Tat toxicity is also related            throughout the brain and into the spinal cord offers another
to glutamate receptor activation, since antagonists of                  explanation of how Tat can cause neurotoxicity and
NMDA and non-NMDA receptors partially protect neurons                   dysfunction at sites remote from viral replication, although
from the toxic effects of Tat [62,63,95,118]. Neurotoxic                significant neuronal death in HIVD patients is not found
effects of Tat are in part mediated by direct interactions              throughout the brain, but concentrated in the hippocampus
with a polyamine-sensitive site on the NMDA receptor                    and striatum. Extracellular Tat also causes microglia and
[131,142].                                                              microphage activation and migration, resulting in neuro-
    Tat can induce markers of oxidative stress. Striatal                toxicity by cytokine and chemokine dysfunction. The ability
injections of Tat caused an increase in protein carbonyl                of Tat to cause neuroglial dysfunction at sites distant
formation, preceded Tat-mediated astrogliosis [2], and                  from that of viral replication can occur by many different
caused a loss of striatal tissue in rats [10]. We have shown            pathways.
Tat induced protein and lipid peroxidation in synaptosomal
membranes and neuronal cell cultures [128].
    Tat-induced neurotoxicity requires interaction of Tat with          7. Indirect neurotoxicity of Tat
the neuronal cell membrane [35]. Tat specifically binds to
rat brain synaptosomal membranes with moderate affinity                    Tat stimulates the production of the cytokines, tumor
(Kd of 2 AM) [135]. When Tat is introduced intracellularly              necrosis factor (TNF-a), interleukin 6 (IL-6), IL-8, and IL-
into neurons through patch recording pipettes, it does not              10, in glial cells and macrophages [34,119]. These cytokines
alter neuronal membrane potentials [35]. Tat has been                   are released extracellularly and can trigger degenerative
shown to bind to the low-density lipoprotein receptor                   processes and apoptosis in neurons. TNF-a has been
related-protein (LRP) on neurons, internalized, and trans-              implicated in stimulation of HIV-1 replication in chronically
ported into the neuronal nuclei in a biologically active form           infected cells [166]. TNF-a releases the excitatory amino
[92]. We demonstrated that after cleaving heparin sulfate, a            acid glutamate from astrocytes [12] and restricts glutamate
protein required for Tat uptake by the LRP receptor [92],               uptake by astrocytes [54]. This leads to accumulation of
Tat-induced oxidative stress, as measured by protein and                glutamate in the vicinity of neurons, hyperactivation of
lipid oxidation, increased in synaptosomal membranes                    NMDA receptors, influx of calcium, and subsequent cell
[128]. Tat-mediated, HIV-infected neurotoxicity is directly             death. Recently, HIV-1 and gp120 have been shown to
evident from a study that demonstrated cell death was                   impair the ability of astrocytes to transport glutamate related
completely prevented when the supernatant from HIV-                     to a defect that inhibits transcription of the EAAT2
infected monocytes was first immunoabsorbed with anti-                  glutamate transporter gene [161]. Glutamate levels are
serum to Tat and the HIV-1 protein gp120 [158]. The above               increased in CSF and plasma of patients with HIVD
findings suggest that Tat is capable of directly exciting               compared with HIV patients without dementia and gluta-
neurons and causing excitotoxicity.                                     mate levels correlate with cognitive decline and brain
    Neurodegeneration in HIVD occurs in uninfected neu-                 atrophy [53], although, others did not find any correlation
rons at sites that are often distant from the site of viral             between glutamate levels in CSF and HIVD or HIV
replication. C6 rat glioma cells stably producing Tat were              infection [47].
injected into rat striatum or hippocampus. Bruce-Keller and                Tat activates astrocytes and induces the expression of
colleagues demonstrated that Tat could be transported along             inducible nitric oxide synthase (iNOS) [93], leading to the
                                           C.B. Pocernich et al. / Brain Research Reviews 50 (2005) 14 – 26                                        19


overproduction of nitric oxide (NO), which can react with                     differentiation [86]. The brain is a major site of synthesis for
                      À
superoxide anion (O2 ) to form neurotoxic peroxynitrite                       apoE, produced primarily by astrocytes.
         À
(ONOO ). TNF-a, which is induced by Tat, also induces                            In humans, three predominant isoforms of the apoE
iNOS leading to increased production of NO in HIV-                            protein exists, apoE2, apoE3, and apoE4, and are thought to
infected macrophages [19]. Excess NO also enhances                            have varying degrees of antioxidant properties [87,111].
glutamate release from astrocytes [9], adding to NMDA                         The three alleles for human APOE have differential
excitotoxicity. Overproduction of NO is proposed to                           antioxidant capabilities, E2 > E3 > E4 [87,111], and the
increase HIV-1 replication, as reported in many studies,                      reverse order displays increased injury from stroke, head
while low levels of NO inhibit HIV-1 replication [157].                       injury, and amyloid h-peptide-induced toxicity in brain
   Tat and TNF-a, which is induced by Tat, can stimulate                      [34,87,143]. Inheritance of the e4 allele of the APOE gene
the production of quinolinic acid (QUIN) from macrophages                     has been implicated as a major genetic risk factor for late-
[65,146]. QUIN is a neurotoxin that activates the NMDA                        onset Alzheimer’s disease [100,152]. There are conflicting
receptor raising intracellular calcium and leading to cell                    reports concerning the inheritance of APOE4 and the
death [151]. Elevated concentrations of QUIN are found in                     development of HIV-dementia. Twice as many HIV patients
the CSF and brains of HIVD patients [65].                                     that carry the apoE4 protein were demented or had
   Tat induces interleukin-10 (IL-10) production from                         peripheral neuropathy compared to apoE4-negative HIV
monocytes [11] and increases mRNA levels of IL-6 [170]                        patients. In contrast, Dunlop and colleagues reported no
by a PKC-dependent pathway. IL-10 is a highly immuno-                         correlation in HIV-dementia or encephalitis in relation to
suppressive cytokine that is associated with the disease                      APOE genotypes [44]. Recently, it has been demonstrated
progression toward AIDS, and IL-6 is increased in HIVD                        that there are increased HNE levels, a marker of lipid
brain [144,162].                                                              peroxidation, in brain and CSF of HIV patients with
   A schematic drawing of some of the potential direct and                    dementia vs. HIV patients without dementia [159], and this
indirect neurotoxic pathways of Tat is shown in Fig. 1.                       finding correlates with the e4 allele of APOE (A. Nath,
                                                                              Department of Neurology, Johns Hopkins University,
                                                                              personal communication). Further, elevations of sphingo-
8. Tat and apolipoprotein E                                                   myelin, ceramide, and cholesterol was found in the medial
                                                                              frontal cortex, parietal cortex, and cerebellum of HIVD
   Apolipoprotein E (apoE) is a small secreted protein of                     patients with an APOE3/4 or APOE4/4 genotype compared
¨34 kDa and a component of several different types of                         with HIVD patients with an APOE3/3 genotype. There was
lipoproteins [96]. ApoE is well known for its role in lipid                   no difference in the number of astrocytes or activated
and cholesterol homeostasis, but has also been demonstrated                   microglia in any brain region of the two patient populations,
to have immunomodulatory properties in vitro and may                          suggesting that modification of lipid metabolism in HIVD
regulate smooth muscle and endothelial cell growth and                        patients with an APOE4 genotype was not the result of




Fig. 1. Schematic drawing of potential neurotoxic mechanisms involving the HIV protein Tat. Activated microglia and macrophages release Tat, cytokines
TNF-a, IL-6, IL-8, and IL-10, and excitotoxins quinolinic acid, which have neurotoxic effects on neurons and activate astrocytes.
20                                          C.B. Pocernich et al. / Brain Research Reviews 50 (2005) 14 – 26


increased CNS inflammation [40]. We have shown that
human apoE3 acts as an antioxidant, whereas, human
apoE4 and mouse apoE, which is similar to human apoE4,
do not provide protection against Tat-induced toxicity
[128].


9. Antioxidants and Tat

   Glutathione (GSH) is the major cellular thiol participat-
ing in the maintenance of cellular redox status of the neuron
and neuronal mitochondria [28]. A decreased level of GSH
may severely impair normal cellular functions. The biosyn-
thesis of glutathione may be compromised by Tat. Tat plays
                                                                               Fig. 3. Tat-induced increase of lipid oxidation was protected by pre-
a major role in the glutathione system as evidenced by                         treatment with D609 and BaptaAM. Pretreatment with 25 AM D609 or 2
downregulation in the liver of tat-transgenic mice expres-                     AM BaptaAM, an intracellular calcium chelator, protected primary
sion of the g-glutamylcysteine synthetase regulatory sub-                      cortical rat neurons from increased HNE, a lipid peroxidation product.
unit, driving the glutathione cycle towards feedback                           N = 4, *P < 0.015.
inhibition, stopping glutathione synthesis, and downregulat-
ing the activity of glutathione synthetase [36]. We hypothe-                   reported to protect against oxidative damage induced by
size that chronic inflammation of the CNS, activation of                       ionizing radiation [169]. A recent study from our labo-
microglia, and increased lipid and protein oxidation, all                      ratory reported the glutathione-mimetic properties of D609
observed in HIV-infected individuals, can lead to the                          [88]. D609, like glutathione, prevented acrolein-induced
decrease of glutathione levels and potentially HIV-dementia.                   alterations of synaptosomal membrane proteins, formed a
In vitro, GSH inhibits viral replication in human monocyte-                    disulfide (a dixanthate) upon oxidation, and the dixanthate
derived macrophages and lymphocytes [66,74,109]. HeLa                          was reduced back to xanthate by glutathione reductase, an
cells expressing Tat were found to have decreased gluta-                       enzyme that converts oxidized glutathione to GSH [88].
thione peroxidase activity and mRNA levels [133], and                          Moreover, D609 completely protected neurons against the
expression and mRNA of Mn superoxide dismutase [55].                           oxidative stress and neurotoxic properties of amyloid h-
Protein oxidation was increased and total cellular sulfhydryl                  peptide(1 – 42) [154]. We demonstrated that primary
content was decreased in HeLa-Tat cells reflecting ongoing                     cortical rat neurons pretreated 1 h with 25 AM D609 and
oxidative stress [55].                                                         then treated with 500 nM Tat were completely protected
   D609 (tricyclodecan-9-yl-xanthogenate) is a selective                       against protein and lipid oxidation as measured by protein
inhibitor of phosphotidylcholine-specific phospholipase C                      carbonyls and HNE levels, respectively (Figs. 2 and 3).
[112,139]. D609 also displays antiviral activity by inhibit-                   D609 also protected against Tat-induced TNF-a production
ing the shedding of infectious HIV into tissue culture                         (Fig. 4), a cytokine, which is also toxic to neurons, as
medium from chronically infected lymphoma cells and                            mentioned above. We also showed that by sequestering
inhibiting HIV replication, although HIV-specific pro-                         intracellular calcium with BaptaAM, Tat-induction of lipid
teins accumulated intracellularly [4,106]. D609 has been




                                                                               Fig. 4. Tat-induction of TNF-a is blocked by D609 and BaptaAM.
Fig. 2. D609 attenuates Tat-induced increased protein oxidation. Pretreat-     Pretreatment of neuronal cell cultures with 25 AM D609 or 2 AM BaptaAM
ment with 25 AM D609 protected primary cortical rat neurons from 500 nM        protected primary cortical rat neurons from Tat-induced increase of TNF-
Tat-induced increased protein oxidation. N = 4, *P < 0.01.                     levels. N = 4, *P < 0.03.
                                     C.B. Pocernich et al. / Brain Research Reviews 50 (2005) 14 – 26                              21


peroxidation and TNF-a was abolished. D609 may be                           The HIV-1 protein Tat released from astrocytes report-
blocking Tat-induced toxicity, by inhibiting the PC-PLC-                edly produces trimming of neurites, mitochondrial dysfunc-
specific pathway and/or by acting as a GSH-like antiox-                 tion, and cell death in neurons [33]. Intracellular Tat is not
idant to block the toxic effects Tat induces through other              toxic to astrocytes. In fact, Tat produced in astrocytic cell
signaling pathways. Potentially, D609 may be a novel                    lines was able to protect astrocytes from cellular injury
treatment for HIVD.                                                     induced by 3-nitroproprionic acid (3-NP), a mitochondrial
    Estrogen deficiency has been implicated as a risk factor            toxin; whereas, HeLa cells expressing Tat were not
in the development of several neurodegenerative diseases                protected [33]. This finding demonstrates that Tat is a
[98,145], and estrogen replacement may result in improve-               neurotoxin at distant sites while protecting the environment
ment of cognitive function [7]. Plasma estradiol levels are             where it is produced.
lower in HIV-infected women [57]. Estrogen has been                         We treated human astocytes expressing Tat (SVGA-Tat)
demonstrated to be protective against oxidative stressors.              and vector controls (SVGA-pcDNA) with the irreversible
Pretreatment with 17 beta-estradiol dramatically blocked                mitochondrial complex II inhibitor 3-NP. Proteomics anal-
the activation of NF-nB in human endothelial cells                      ysis was utilized to identify changes in protein expression
exposed to Tat [89]. In addition, 17 beta-estradiol                     levels. Actin, heat shock protein 90, and mitochondrial
selectively inhibited the Tat-induced expression of IL-                 single-stranded DNA binding protein were identified as
1beta. These results suggest that estrogen may protect                  proteins with increased expression, while lactate dehydro-
against Tat-induced inflammatory reactions in human                     genase had decreased protein expression levels in SVGA-
vascular endothelium via blocking NF-kappaB-mediated                    Tat cells treated with 3-NP compared to SVGA-pcDNA
molecular signaling pathways. Estradiol can also suppress               cells treated with 3-NP [130]. We found h-actin, calreticulin
the proinflammatory effects of HIV proteins [16]. Plant                 precursor protein, and synovial sarcoma X breakpoint 5
estrogens, favinoids, are another attractive possibility as a           isoform A to have increased oxidation in control SVGA-
potential treatment modality for HIVD. We have shown                    pcDNA cells treated with 3-NP compared to SVGA-Tat
that diosgenin, found in fenugreek and yams, can block                  cells treated with 3-NP[130].
both Tat-induced and CSF-induced neurotoxicity [158,                        We also utilized proteomics to investigate protein
159]. An advantage of plant estrogens is that they do not               expression changes in human astrocytes intracellularly
have the same feminizing and cancer promoting side                      expressing Tat (SVGA-Tat). We identified phosphatase 2
effects as estrogens, yet maintain the antioxidant proper-              A, isocitrate dehydrogenase, nuclear ribonucleoprotein A1,
ties. For example, diosgenin has a long carbon chain                    Rho GDP dissociation inhibitor alpha, beta-tubulin, crocal-
attached to the sterol ring that cannot be metabolized in               bin-like protein/calumenin, and vimentin/alpha-tubulin to
humans to form estrogen. Other plant estrogens worthy of                have decreased protein expression levels in SVGA-Tat cells
further investigation include resveratrol, found in grape               compared to the SVGA-pcDNA cells. Heat shock protein
skins, peanuts, and red wine, and genistein, daidzein and               70, heme oxygenase-1, and inducible nitric oxide synthase
quercetin, compounds all found in soybeans.                             were found to have increased protein expression in SVGA-
    Other widely available drugs with free radical scaveng-             Tat cells compared to controls by slotblot technique [129].
ing properties include diethyldithiocarbamate [91], a Chi-              These proteins may be critical in understanding how HIV
nese herbal medicine BG-104 [6], ferulic acid [77], 3-[4-               utilizes astrocytes as hosts, without destruction of the host.
(N,N-dimethylamino)benzenetellurenyl]propanesulfonic
acid sodium salt (NDBT) [75], 5-aminosalicylic acid [76],
and S-nitrosoglutathione [132].                                         11. Conclusions

                                                                           The HIV-1 protein Tat directly and indirectly induces
10. Protection of astrocytes overexpressing Tat                         oxidative stress in neurons, which may be correlated with
                                                                        the dementia observed in some HIV patients [128,159]. That
   In patients with HIV-1 infection, significant neuronal loss          selected antioxidants are neuroprotective against oxidative
and dysfunction occurs even though neurons are rarely                   stress inducers, including Tat, suggests a therapeutic
infected [101,104,121]. The most commonly infected cell                 strategy for treatment of HIV-dementia that involves
types in brain are microglia, macrophages, and to some                  elevation of intracellular GSH levels. Studies to test this
extent astrocytes, although limited viral replication is                notion in model systems are underway.
produced in astrocytes [80,84,101,121,137]. Astrocytes
may serve as a reservoir for the virus inducing neuronal
damage by releasing cellular and viral products or loss of              Acknowledgments
neuronal support functions. In HIV-infected astrocytes, the
regulatory gene tat is overexpressed [117] and mRNA levels                This work was supported in part by grants from NIH
for Tat are elevated in brain extracts from individuals with            (MH64409; AG-10836; AG-05119) to D.A.B. and (RO1
HIV-1 dementia [164].                                                   NS39253; P20 RR15592) to A.N.
22                                            C.B. Pocernich et al. / Brain Research Reviews 50 (2005) 14 – 26


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