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Editorial NeuroAIDS review

Shapshak, Paula,b; Kangueane, Pandjassaramec,d; Fujimura, Robert Ke; Commins, Deborahf; Chiappelli, Francescog; Singer, Elyseh; Levine, Andrew Jh; Minagar, Alirezai; Novembre, Francis Jj; Somboonwit, Charuruta,k; Nath, Avindral; Sinnott, John Ta,k

doi: 10.1097/QAD.0b013e328340fd42
Editorial Review

aDivision of Infectious Disease, Department of Internal Medicine, Tampa General Hospital, USA

bDepartment of Psychiatry and Behavioral Medicine, University of South Florida, College of Medicine, Tampa, Florida, USA

cBiomedical Informatics, 17A lrulan Sundai Annex, Pondicherry, India

dAIMST University, Kedha, Malaysia

eGeriatric Research Education and Clinical Centers, Veterans Administration, Puget Sound Healthcare System, Seattle, Washington, USA

fDepartment of Pathology, University of Southern California Keck School of Medicine, USA

gDivision of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, USA

hDepartment of Neurology and National Neurological AIDS Bank, UCLA School of Medicine, Westwood, California, USA

iDepartment of Neurology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA

jYerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA

kClinical Research Unit, Hillsborough Health Department, Tampa, Florida, USA

lDepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Received 9 December, 2009

Revised 15 September, 2010

Accepted 17 September, 2010

Correspondence to Paul Shapshak, PhD, Division of Infectious Disease, University of South Florida Health, Tampa General Hospital, 2 Columbia Drive, Tampa, FL 33606, USA. Tel: +1 843 754 0702; fax: +1 813 844 8013; e-mail:

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NeuroAIDS is a disease that incorporates both infectious and degenerative pathophysiologic pathways. It has a known cause, has several animal models, and is under investigation and treatment using multiple avenues, in vivo and in vitro [1–7]. Select highlights from the spectrum of NeuroAIDS research predominantly related to human immunodeficiency virus-1 clade B (HIV-1B) are reviewed below.

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Diagnosis, neurology, and neuroimaging

HIV-1 invades the central nervous system (CNS) early and can cause persistent infection and inflammation. Although early infection is typically asymptomatic, cerebrospinal fluid (CSF) analysis and magnetic resonance spectroscopy (MRS) imaging can detect CNS abnormalities during this period [8–11].

Chronic HIV-1 infection can result in neurodegenerative disease, overall termed NeuroAIDS. The clinical expression of this process includes neurocognitive impairments such as decreased attention/concentration, psychomotor speed, memory, learning, information processing, and executive function. There is also motor slowing, incoordination, and tremor, that may progress to disabling weakness, spasticity, extrapyramidal movement disorders, and paraparesis [12,13]. In addition, there may be behavioral effects such as apathy and irritability. Psychomotor retardation (associated with damage to the frontal-striatal systems) also may occur [14,15]. The clinical severity of this process ranges from asymptomatic neurocognitive impairment (ANI), to a mild neurocognitive disorder (MND), to full-blown HIV-associated dementia (HAD) [16]. The clinical nosology applied to this process has evolved, from the original AIDS dementia complex (ADC) [13], to HIV-associated cognitive-motor complex (HIVCMC) [17], and most recently to HIV-associated neurocognitive disorders (HAND) [16].

HIV-associated neurocognitive disorders were first identified in individuals with advanced AIDS, who had for example opportunistic infections, high viral loads, and elevated markers of immune activation. The development of HAND is influenced by host and viral characteristics, comorbid factors, substance abuse, and antiretroviral therapy. Although older literature focuses on HAD, milder forms of HAND (MND, ANI) were recently reported to be common in highly active antiretroviral therapy (HAART)-treated individuals with partial immune reconstitution, higher CD4+ cell counts, and suppressed viral loads. This is consistent with the decline in the incidence per 1000 person-years of HAD from 6.49 in 1997 to 0.66 2006 and associated with the introduction of HAART in 1996 [18]. More recently, HAND showed decreased association with immune activation and had a more diffuse range of neuropsychological deficits that may overlap with other brain diseases [18–21].

In-vivo studies of HAND have utilized neuroimaging techniques including MRS, functional MRI (fMRI), and morphometry. MRS measures brain biochemistry, fMRI measures changes in blood flow related to neural activity in the brain, and morphometry models quantitative changes in neuroanatomical structures. These techniques also have been used to detect changes in the brains of asymptomatic HIV-1-positive patients [10,14,22].

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Aging and neuropathology

In the US, the percentage of HIV-1-positive individuals, 50 years of age and older, increased from 19% to more than 25% between 2001 and 2005, primarily due to HAART-related increased survival. Seniors often present with advanced HIV-1 disease because an AIDS diagnosis was overlooked [18]. Aging adversely affects both cell-mediated and humoral immunity. Older HIV-1-positive persons tend to progress to AIDS and to die more rapidly, and increased age is a strong risk factor for HAND. Comorbid conditions, the cognitive changes that occur in ‘normal’ aging, and the increased risk for neurodegenerative diseases all present major difficulties in the assessment of neurocognitive impairment in older HIV-1-positive adults [23,24]. The diagnostic and neuropathological characteristics of some of these conditions and those of HAND are summarized in Table 1 [25–44].

Immune dysfunction, inflammation, and hyperlipidemia are features of HIV-1 infection (and its treatment) and are risk factors for Alzheimer's disease in the elderly. Likewise, increased amyloid has been reported in HIV-1-positive brain tissue (Fig. 1), possibly because HIV-1 Tat protein inhibits amyloid degradation. Moreover, Tat production, HAART, and aging may also result in increased phosphorylation of tau protein in the hippocampus. Expression of alpha-synuclein is increased in the substantia nigra of some HIV-positive brains. In the setting of HIV-1, these findings of the accumulation of abnormal proteins may point to common pathways activated in multiple brain diseases, possibly by brain inflammation [45–50].

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Drug abuse

Drug abusers with HIV-1 infection have higher viral loads, increased immunosuppression, more severe cognitive impairment, and neuropathological changes. However, causality is difficult to ascertain because drug abusers (commonly poly-drug abusers) are often noncompliant with medications and ambiguous in self-report [51,52].

In-vitro studies show that opiates, cocaine, and methamphetamine potentiate HIV-1 replication and synergize with HIV-1 proteins to cause glial cell activation, neurotoxicity, and breakdown of the blood–brain barrier [53]. The opioid system has dichotomous effects on HIV-1 replication. Mu receptor stimulation increases HIV-1 infection via increased expression of chemokine receptors (CCR3, CCR5, and CXCR4), that are also co-receptors for HIV-1 [54], whereas kappa receptor activation decreases CCR5 expression [55]. Opiates activate HIV-1 replication in latently infected macrophages and cocaine increases HIV-1 replication in macrophages via production of IL-10 [56,57]. In addition, cocaine increases HIV-1 replication in astrocytes and in dendritic cells (by up-regulation of DC-SIGN) [58,59] and methamphetamine increases HIV-1 infection via dopamine receptor signaling leading to up-regulation of CCR5 [60]. Moreover, cocaine and methamphetamine may both accelerate the development of HAND through increased dopamine, macrophage infiltration, and HIV-1 replication [61].

Cocaine and methamphetamine enhance monocyte migration across the blood–brain barrier involving disruption of endothelial cell tight junctions. Cocaine increases adhesion molecule expression [53], whereas methamphetamine up-regulates inflammatory genes in endothelial cells [62]. Morphine alone does not alter the blood–brain barrier; however, in combination with HIV-1-Tat protein, it alters tight junction expression [63]. Morphine withdrawal and associated stress also damages the blood–brain barrier [64]. Morphine and cocaine separately are not toxic to striatal neurons, but they each substantially potentiate Tat neurotoxicity [65]. For example, in a Tat transgenic mouse model, morphine caused shortening of dendrites [66]. Cocaine potentiates Tat-mediated glial cell activation and oxidative stress [65,67]. In post-mortem human brains, selective degeneration of pyramidal neurons and interneurons in the neocortex and limbic system have been associated with cognitive alterations in methamphetamine and cocaine users [68]. Loss of calbindin and parvalbumin interneurons correlates with memory deficits in HIV-1-infected methamphetamine users [69].

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Goals for treatment of NeuroAIDS include suppressing HIV through optimizing HAART and treating associated psychiatric, neurological, and neuropsychological dysfunctions including mood disorders, substance abuse, and painful peripheral neuropathies. Whereas it is commonly accepted that antiretroviral therapy ameliorates HAND, there is debate about the best regimen for HAND. Moreover, whether brain and CSF penetration play a role in treatment efficacy is under investigation as well. One study reported that neuropsychological test scores improved after a HAART regimen with high penetration and another study indicated no improvement, irrespective of blood–brain barrier penetration [70,71]. Additional studies suggested antiretroviral drugs with better CSF penetration improved outcomes [72–76]. Such studies include brain assessment by examination of CSF when CNS proteins and metabolites can be found, as well as by direct imaging techniques including MRI [72,75].

Palliative and adjunctive therapy of HAND [palliative therapy ameliorates symptoms without affecting the disease and adjunctive therapy does not treat the known cause of HIV-1 by reducing viral replication, but treats the downstream effects (e.g. neurodegeneration)] may improve the patient's ability to function. For example, since depression may be an important confounder in the diagnosis of HAND and reduces quality of life, HIV-1-positive individuals should be screened for mood disorders, and these can be treated with antidepressants [3]. In addition, methylphenidate and other psychostimulants, often used for attention deficit disorders, may help to reduce apathy and improve psychomotor slowing in HAND. Several drugs were investigated as potential neuroprotective agents. In a phase II randomized controlled trial within the Adult AIDS Clinical Trials Group (ACTG), adults with mild to severe ADC, receiving stable antiretroviral therapy and memantine treatment, showed improvement of MRS parameters in the brain; however, there was no significant clinical improvement [77]. Likewise, a trial of selegiline, a monoamine oxidase (MAO)-B inhibitor with antioxidant and neurotrophic properties, passed safety assessment in phase II studies in cognitively impaired HIV-1-positive patients, but failed to demonstrate cognitive or functional improvement [78]. An anticonvulsant (and mood-stabilizing) drug, sodium valproate (VPA) inhibits the activity of the glycogen synthase kinase-3-beta (GSK-3β) pathway [79]. Preliminary clinical studies using VPA suggested this drug might treat symptoms related to HAND by reversing HIV-1-induced damage to gray matter. Patients treated with VPA showed improved neuropsychological function compared to placebo; however, there were concerns related to toxicity, drug interactions, and lack of long-term benefit to reduce the size of the latent HIV-1 reservoir [80–82].

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Brain virus load

Comprehensive quantification of HIV-1 load in brain parenchyma can utilize at least three different types of measurements: proviral DNA, unspliced viral RNA, and multispliced viral RNA (HIV-1-multispliced RNA indicates viral replication; unspliced HIV-1 RNA indicates persistence with incomplete or dysfunctional replication). In brain virus load studies, several brain regions generally are sampled with the underlying hypothesis that increased brain HIV-1 viral load should be associated with premortem neurocognitive impairment such as HAND or HAD. However, this is not always the case and may be associated with several factors including variations in previous duration of infection, sampling across brain regions, irreparable neuronal damage, persistence of inflammation, as well as variations in HAART [83–88]. However, HAART probably reduces RNA viral load more effectively than proviral DNA load. Indeed, in some studies the circulating peripheral HIV proviral DNA load in macrophage/monocytes (CD14/CD16) was associated with HAD and minor cognitive motor disorder, independent of HIV RNA levels; the majority of these patients were treated with HAART [89–91]. Additional factors that may require attention include HAART resistance mutations, the particular mutational profile of the peripheral and CSF viruses that may influence HIV-1 neurovirulence, epigenetic mechanisms, and micro-(mi-) RNA expression. Factors including elevated plasma lipo-polysaccharide (LPS) as well as co-infections including HCV may be important in groups such as injection drug and alcohol abusers [91–96].

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Brain virus evolution

In NeuroAIDS, HIV-1 evolution (HIV-1 evolution refers to the increased and wide phylogenetic and sequence diversity that occurs over time and place. The different groups of sequences are referred to as swarms or quasispecies. The term, HIV-1 evolution, is also used to typify their wide variations of sequence diversity and phylogenetically clustered groups in the human brain in NeuroAIDS [97–99]) is hypothesized to modulate HIV-1 neuroinvasiveness and subsequent pathogenesis, for example strains with increased neurovirulence may have specific changes in the Nef protein associated with neurodegeneration in vitro [100]. In corollary, HIV-1 evolution may occur separately in compartmentalized brain regions, CSF, blood, and spleen and this paradigm has stood the test of 12 years of research. Compartmentalization may also occur also at the cellular level in astrocytes, macrophages, and multinucleated giant cells. In addition, a feline model, using feline immunodeficiency virus (FIV) produced supporting evidence of this precept [97,98,101–107]. Overall, this paradigm has been demonstrated for several HIV-1 genes including Env, Pol, Gag, and Nef [108]. However, one phylogenetic study did not conform to the compartmentalization paradigm [109]. In such studies, the conclusions depend heavily on the reliability of the sequences analyzed. Moreover, maintaining criteria for sequence database veracity continues to be important but should be systematically applied [110–113].

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Genetics of susceptibility and progression

Genes associated with immune and neurobiological functioning may play a role in NeuroAIDS progression and susceptibility to HAND. Candidate gene studies have identified a number of polymorphisms that modify the function or expression of immunologic factors and neurotransmitters thought to be involved in HIV-1 infection and NeuroAIDS progression (Table 2) [114–128].

A deletion within the CCR5 gene, for example, confers resistance to HIV-1 infection and an early study found that a disproportionately small number of heterozygous carriers of this allele were detected among a sample of HAD patients [114,115]. Since those early studies, this and other polymorphisms within genes associated with immune functioning have been associated with risk for and progression to HAND [e.g. chemokine (C-C motif) receptor-2, chemokine (C-C motif) ligand-3, stromal cell-derived factor-1, monocyte chemo-attractant protein-1, and tumor necrosis factor-1 alpha (TNF-1α)] [116,117,119–121,125,129–132], although few findings have been replicated. The ϵ4 allele of apolipoprotein E (ApoE), long implicated in the pathogenesis of Alzheimer's disease, has been examined as a risk factor for HAND, also with equivocal findings thus far [24,117,123,124,126,133]. Notably, in addition to a greater incidence of HAND among ApoE-4 carriers, Spector et al. [117] found the mannose-binding lectin (protein C)-2 O/O genotype to be associated with increased risk for progressive cognitive decline over 12 months among a Chinese cohort, whereas none of the aforementioned immunologic factors were associated with incidence of HAND or cognitive decline.

Dopaminergic pathway genes including dopamine transporter and catechol-O-methyltransferase (COMT) are also of interest in the neuropathogenesis of HAND, as dopamine pathway dysfunction appears to underlie many neurobehavioral deficits seen in HIV-1-infected individuals [24,134,135]. Recent studies have begun to examine the role of COMT polymorphisms in HAND, although much work remains to determine if genotype and HIV confer an additive or synergistic effect on neurocognitive functioning. The recent application of genome-wide association studies may reveal previously unknown factors involved in HIV-1-related neuropathogenesis. This method, which requires very large cohorts, previously has been successful in revealing novel genes associated with viral set point and HIV-1 progression [118].

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Host gene expression

HIV-1 infection activates macrophage/microglia and astrocytes, which produces several neurotoxins including pro-inflammatory cytokines including TNF-α, IL-1β, and interferon (IFN)-γ. These inflammatory mediators promote inflammatory signaling cascades in NeuroAIDS with a cumulative result of neuronal toxicity [49,136–138]. TNF-α levels increase in the CNS of patients with HAND and in-vitro exposure of macrophages and microglia to gp120 or Tat induces TNF-1α expression [139]. TNF-1α up-regulates the expression of intercellular adhesion molecule-1 (ICAM-1), vascular endothelium adhesion molecule-1 (VCAM-1), and surface E-selectin on astrocytes and cerebral endothelial cells, with consequent transendothelial migration of activated macrophages from the periphery into the CNS. TNF-1α up-regulates monocyte chemoattractant-1 and fractalkine expression [140,141], and neuronal expression of genes for calbindin, macrophage and astrocyte expression of macrophage inflammatory protein (MIP)-1α, regulated on activation normal T cell expressed and secreted (RANTES), and MIP-1β. TNF-α also increases the release of glutamate by astrocytes and microglia [142], and decreases the uptake of neuro-toxic glutamate by macrophage/microglia [143]. These effects are mediated by over-stimulation of NMDA receptors, which results in excessive calcium influx and generation of nitric oxide and superoxide anions, which are neurotoxic [144]. In human neuron cultures, exposure to gp120 and Tat causes increased expression of sphingomyelin and ceramide that is likely mediated by TNF-α and IL-1β. In human astrocyte cultures, activation of indoleamine-2,3-dioxygenase (IDO) results in elevation of tryptophan catabolism and the production of neurotoxins including kynurenine due to Tat protein for HIV-1B and not C. The authors conclude from the latter experiment that the prevalence of HAD may correlate with epidemiological differences in HIV-1B vs. C [139,145–148]. Finally, microarray technology has been applied to NeuroAIDS to measure simultaneous expression of large numbers of genes including recently discovered micro-(mi)-RNAs, as reviewed in detail elsewhere (Table 3) [49,50,96,136,138,140,141,145–154].

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Promising modes of therapeutic gene delivery

Few drugs treat NeuroAIDS effectively in part because of incomplete CNS penetration. However, noninvasive intra-nasal delivery of therapeutic drugs to the CNS can bypass the blood–brain barrier via the olfactory nerve [155]. Novel CNS delivery systems can blunt induction of apoptosis by using recombinant SV40-derived vectors to deliver antioxidant enzymes [e.g. Cu/Zn-superoxide dismutase (SOD1) and glutathione peroxidase (GPx1)]. This protects cells from free radical-mediated gp120-induced apoptosis by detoxifying oxygen free radicals, and leads to a 10-fold reduction of neuronal apoptosis. Further testing in animal models and in clinical trials for treatment of HAND is now needed [156,157]. However, these protocols carry safety concerns because of the direct connection of olfactory nerves into the brain.

Transgene expression, another brain-targeted treatment, is improved with the systemic injection of the polyol sugar, mannitol. Mannitol, though not as well tolerated as originally thought, opens the blood–brain barrier transiently, with a concomitant increase in the number of brain cells exposed to experimental treatments. Thus, mannitol can be used for delivery of vectors (to produce trangenes) and the amyloid-beta homologue (Gd-DTPA-K6Abeta1–30) to image plaques [158–160].

Adenoviruses, lentiviruses, onco-retroviruses, and herpes simplex virus serve as transgene vectors, but often are associated with inflammation that reduces the effectiveness of the gene transfer. Adeno-associated virus (AAV) causes a mild immune response while it incorporates its genome in dividing and nondividing cells, and AAV-2 strains carry extensive gene loads with enhanced infectivity of neurons via axonal entry and retrograde transport [161]. AAV yields successful gene transfer in animal models of Alzheimer's disease, PD, and other CNS disorders [162], and in phase I trials for PD. However, the use of AAV is not without caveats as AAV-mediated gene transfer can induce tumors in animal models [163].

Lentiviruses have a long incubation period and delayed immunogenicity. They deliver a significant quantity of genetic material into the host cell's DNA, and can infect neighboring cells, without producing extracellular particles. The efficiency of their CNS uptake was enhanced with mannitol and the vasodilator, bradykinin. However, lentiviruses have distinct immune and biologic properties that need further investigation (Tables 4 and 5 and Fig. 2) [53,137,155–189].

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Vaccines: classical and nonclassical

To produce a vaccine against NeuroAIDS, an effective HIV-1 vaccine must first be developed and the design and development of HIV-1 vaccines is still in progress [190]. The STEP HIV vaccine trial failure [STEP, an international HIV-1 vaccine clinical trial that commenced in 2004, is also known as the HVTN 502 or Merck V520-023 study, cosponsored by NIAID and Merck Corp. The trial tests three recombinant adenovirus-5 (rAD5) vectors, each expressing an HIV-1 gene: Ad5-gag, Ad5-pol and Ad5-Nef (] and this led to further intense debate related to the utility of the vaccine approach [191]. Some of the major concerns associated with the development of HIV/AIDS vaccines are viral diversity (viral mutation), HIV-1-host molecular mimicry (sequence level homology among viral and human genes), and HLA polymorphism among ethnic groups (including Black, Hispanic, Oriental, Pacific Islander, American Indian, Australian aboriginal, and Caucasian). The latest IMGT/HLA database ( update (as of 3-06-2010) has 4447 HLA alleles displaying sequence polymorphisms among these ethnicities. Nevertheless, efforts are underway using a multifaceted strategy for vaccine development. Four priming injections of a recombinant canary pox vector (ALVAC-HIV) and two booster injections of gp120 subunit (AIDSVAX-B/E) in a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial (NCT00223080) in Thailand, showed some encouraging results for future research in that there was a trend (P = 0.08) to prevent HIV-1 infection among vaccine recipients (efficacy 26.4%). However, the vaccine did not affect the degree of viremia or the CD4+ T-cell count in patients who later seroconverted [192]. Nonetheless, recent data from sequence to structure relationship studies [193–195] with corresponding immunological findings [196] to HIV-1 gp120 provide encouraging insights to continue use HIV-1 Env as a potential target for vaccine development.

A novel approach uses population-specific HLA sequences to design short HIV-1 oligopeptide-specific T-cell-based epitopes in the context of NeuroAIDS [197]. An HIV/AIDS oligopeptide vaccine consists of a cocktail of short synthetic antigenic oligopeptides (8–20 residues) [197,198]. These oligopeptides exhibit either CD8+ or CD4+ T-cell immunity by specifically binding to respective class I or class II HLA alleles (that is illustrated in Fig. 3) [199]. The LANL/HIV database ( documents a range of HIV-1-specific oligopeptides exhibiting T-cell immunity, with known HLA specificity. Cocktails of these oligopeptides are administered in conjunction with incomplete Freund's adjuvant (water-in-oil emulsion) to stimulate specific T-cell response [197,198]. Moreover, short oligopeptides are more capable of entering the brain than larger envelope and other viral proteins and hence are promising vaccine paradigm candidates for HIV/AIDS and NeuroAIDS [197].

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Animal models

Several animal model systems have been developed to investigate HIV-1-induced CNS disease. Transgenic mice were utilized to generate strains expressing HIV-1-encoded neurotoxic proteins, including Tat, under the control of a doxycycline promoter, HIV-1 gp120 under control of the glial fibrillary acidic protein (GFAP) promoter (for expression in astrocytes), and gp160 under the control of neurofilament promoters (for expression in neurons), to investigate the role of these HIV-1 proteins in neuropathogenesis. Additional technologies exploited the severe combined immune deficient/human (SCID/hu) mouse system when SCID mice were inoculated intracranially with HIV-1-infected human monocytes. FIV (FIV is a cat lentivirus related to HIV-1) infection was also utilized as a model for HIV-1 infection and this FIV/cat system proved useful to investigate cognitive and behavioral deficits in an infection-based model [200–206].

Simian immunodeficiency virus (SIV) is also known to induce neuropathologic changes in infected macaques [207]; however, several approaches were developed to circumvent the relatively low incidence of neuropathogenic infection. Passage in microglial cell culture generated a virus that replicates more efficiently within the CNS and results in increased incidence of neuropathological infection [208]. A multivirus combination (pathogenic and neurovirulent viruses together) yields a significant increase in the incidence of CNS disease in macaques. For example, co-inoculation of the SIV/DeltaB670 and SIV/17E-Fr precipitated neuropathogenic infection in pigtailed macaques [209]. Subsequently, a single virus system induced neuropathogenic infection in greater than 90% of infected pigtailed macaques [210]. The latter two systems offer the desired high incidence of neuropathogenesis and disease pattern that are remarkably similar to NeuroAIDS. Depletion of CD8+ T cells increased the incidence of CNS disease for more traditional SIV isolates (Table 6) [200–206,208–211]. These model systems help demonstrate pathogenic mechanisms in HIV-1-induced CNS disease. Continued improvements should enable a comprehensive understanding of HIV-1-induced neurological disease and the development of effective therapies.

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Since the earliest studies in NeuroAIDS, nearly 30 years ago, many different approaches and models for NeuroAIDS evolved. We conclude with key current issues dealt with in this review. CNS infection by HIV-1 can result in NeuroAIDS. The infection is chronic and subsequent neurodegeneration leads to several domains of neurocognitive impairment. NeuroAIDS is increased in older HIV-1+ adults and associated drug abuse exacerbates these impairments, synergizes with virus replication, and increases virus load and immunosuppression. In the brain, HIV-1 load and evolution affect these outcomes. However, HAART greatly reduces virus load by decreasing viral replication but has little effect on the viral reservoirs in the brain. Despite the use of HAART, milder forms of HAND are present in nearly 50% of HIV-1-positive adults. Thus palliative and adjunctive therapy are necessary to improve the patient's ability to function, although to date most clinical trials with such approaches have shown minimal or no efficacy. At the genetic level, immunologic, neurotransmitter host gene polymorphisms, and perturbed gene expression may influence NeuroAIDS progression and susceptibility; however, these tests currently lack the sensitivity and specificity for use in clinical practice for prediction of susceptibility of NeuroAIDS. Novel therapies that deliver genes into the CNS using AAV and other viruses as vectors may be a potential therapeutic approach to combat destructive processes such as apoptosis and inflammation thereby reducing brain damage in NeuroAIDS. Great dexterity is provided by animal models including transgenic mice, felines, and nonhuman primates to investigate all these aspects of viral infection and disease. These animal models also have great potential for the development of therapeutics for NeuroAIDS. Finally, HIV/AIDS therapeutic vaccines still require development for overall use and effectiveness let alone for the brain. The obstacles to vaccines include viral diversity, HIV-1-host molecular mimicry, and HLA polymorphism among ethnic groups. The use of oligopeptide vaccines is a step in a more effective direction. Directions of future studies that attack HIV/NeuroAIDS include greater sophistication in manipulation to target specific signaling and molecular processes. Specific developments in medications and vaccines that cross the blood–brain barrier are crucial as well.

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Raisa Avezova (Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California, USA) and Philippe Grisel, MD, PhD (Cardiology Service, University Hospital of Geneva, Geneva, Switzerland) are credited as co-authors, as there is a limitation of 12 authors.

We apologize to our colleagues in that although there is a wealth of critical contributions to NeuroAIDS research, many could not be included because of limitations in the scope of this review. We also wish to express our appreciation to the Editors for their advice. Gopichandran Sowmya (Biomedical Informatics Society, India) is acknowledged for her assistance. Support for this work included NIH Grants: F.C. – Alzheimer Association, University of California Senate, NIH AI07126, CA16042, DA07683, and DA10442; E.S., A.L., D.C., and P.S. –NIH NS038841, ES-NIH MH083500, AL-NIH DA026099.

The authors report no financial conflicts.

Authors and contributions: P.S. – introduction, brain virus load and evolution, Conclusion, editing manuscript, and corresponding author.

P.K. – vaccines, Figure 3.

R.K.F. – brain virus load.

D.C. – diagnosis, neurology, and neuroimaging; aging and neuropathology, Figure 1, Table 1.

F.C. – gene therapy, Table 4.

E.S. – diagnosis, neurology, and neuroimaging, Table 1.

A.J.L. – genetics, Table 2.

A.M. – gene expression, Figure 2, Table 3.

F.J.N. – animal models, Table 6.

C.S. – treatment, Table 5.

A.N. – drug abuse.

J.T.S. – treatment, Table 5.

In addition, all authors contributed to correcting and editing the text.

Raisa Avezova and Philippe Grisel, MD, PhD contributed to gene therapy.

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1. Singer EJ, Valdes-Sueiras M, Commins D, Levine AJ. Neurologic presentations of AIDS. Neurol Clin 2010; 28:253–275, doi: 10.1016/j.ncl.2009.09.018.
2. Minagar A, Shapshak P. HIV associated dementia: clinical features and pathogenesis. In Minagar A, Shapshak P, editors. NEURO-AIDS. Hauppauge, New York: Nova Science Publ; 2006.
3. Fernandez F, Ruiz P, editors. Psychiatric aspects of HIV/AIDS. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.
4. Goodkin K. Virology, Immunology, Transmission, and disease stage. In Fernandez F, Ruiz P, editors. Psychiatric aspects of HIV/AIDS. Philadelphia, PA: Lippincott Williams and Wilkins; 2006. pp. 11–22.
5. Goodkin K, Verma A, Shapshak P, editors. The spectrum of NeuroAIDS disorders: pathophysiology, diagnosis, and treatment. Washington, DC: ASM Press; 2008.
6. Petito C, Kerza-Kwiatecki AP, Gendelman HE, McCarthy M, Nath A, Podack ER, et al. Neuronal injury in HIV infection. J Neurovirol 1999; 5:327–341.
7. Ironson G, Weiss SM, Lydston D, Tobin J, Lechner S, Ishii M, et al. The impact of improved self-efficacy on viral-load in culturally diverse women living with AIDS: the SMART/EST Women's Project. AIDS Care 2005; 17:222–236.
8. Resnick L, Berger JR, Shapshak P, Tourtellotte WW. Early penetration of the blood-brain-barrier by HTLV-III/LAV. Neurology 1988; 38:9–15.
9. Arendt G, Nolting T, Frisch C, Husstedt IW, Gregor N, Koutsilieri E, et al. Intrathecal viral replication and cerebral deficits in different stages of human immunodeficiency virus disease. J Neurovirol 2007; 13:225–232.
10. Tarasów E, Wiercińska-Drapało A, Kubas B, Dzienis W, Orzechowska-Bobkiewicz A, Prokopowicz D, et al. Cerebral MR spectroscopy in neurologically asymptomatic HIV-infected patients. Acta Radiol 2003; 44:206–212.
11. Minagar A, Commins D, Alexander JS, Hoque R, Chiappelli F, Singer EJ, et al. Diagnostics for NeuroAIDS: present and future. Molec Diagn Ther 2008; 12:25–43.
12. Power C, Boissé L, Rourke S, Gill MJ. NeuroAIDS: an evolving epidemic. Can J Neurol Sci 2009; 36:285–295.
13. Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. Clinical features. Ann Neurol 1986; 19:517–524.
14. Klunder AD, Chiang MC, Dutton RA, Lee SE, Toga AW, Lopez OL, et al. Mapping cerebellar degeneration in HIV/AIDS. Neuroreport 2008; 19:1655–1659.
15. Cole MA, Castellon SA, Perkins AC, Ureno OS, Robinet MB, Reinhard MJ, et al. Relationship between psychiatric status and frontal-subcortical systems in HIV-infected individuals. J Int Neuropsychol Soc 2007; 13:549–554.
16. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69:1789–1799. Epub 2007 Oct 3.
17. AAN (American Academy Neurology). Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology 1991; 41:778–785.
18. Bhaskaran K, Mussini C, Antinori A, Walker AS, Dorrucci M, Sabin C, et al. Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Ann Neurol 2008; 63:213–221.
19. McArthur JC, McDermott MP, McClernon D, C St. Hillaire, K, Conant K, Marder, et al. Attenuated central nervous system infection in advanced HIV/AIDS with combination antiretroviral therapy. Arch Neurol 2004; 61:1687–1696.
20. Cysique LA, Maruff P, Brew BJ. Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus-infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre and posthighly active antiretroviral therapy eras: a combined study of two cohorts. J Neurovirol 2004; 10:350–357.
21. Simioni S, Cavassini M, Annoni JM, Rimbault A, Abraham AR, Isabelle Bourquin, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 2010; 24:1243–1250.
22. Descamps M, Hyare H, Stebbing J, Winston A. Magnetic resonance imaging and spectroscopy of the brain in HIV disease. J HIV Ther 2008; 13:55–58.
23. Babiker AG, Peto T, Porter K, Walker AS, Darbyshire JH. Age as a determinant of survival in HIV infection. J Clin Epidemiol 2001; 54(Suppl 1):S16–S21.
24. Valcour VC, Shikuma C, Shiramizu G, Watters M, Poff P, Selnes O, et al. Age, Apolipoprotein E4, and the risk of HIV dementia: the Hawaii Aging with HIV cohort. J Neuroimmunol 2004; 157:197–202.
25. Woods SP, Rippeth JD, Frol AB, Levy JK, Ryan E, Soukup VM, et al. Inter-rater reliability of clinical ratings and neurocognitive diagnoses in HIV. J Clin Exp Neuropsychol 2004; 26:759–778.
26. Everall I, Vaida F, Khanlou N, Lazzaretto D, Achim C, Letendre S, et al. Clinico-neuropathologic correlates of human immunodeficiency virus in the era of antiretroviral therapy. J Neurovirol 2009; 15:360–370.
27. Petersen RC, Morris JC. Mild cognitive impairment as a clinical entity and treatment target. Arch Neurol 2005; 62:1160–1163.
28. Petersen RC, Parisi JE, Dickson DW, Johnson KA, Knopman DS, Boeve BF, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006; 63:665–672, doi: 10.1001/archneur.63.5.665. PMID 16682536.
29. Saito Y, Murayama S. Neuropathology of mild cognitive impairment. Neuropathology 2007; 6:58–84.
30. Whitwell JL, Shiung MM, Przybelski SA, Weigand SD, Knopman DS, Boeve BF, et al. MRI patterns of atrophy associated with progression to AD in amnestic mild cognitive impairment. Neurology 2008; 70:512–520, doi: 10.1212/01.wnl.0000280575.77437.a2. PMID 17898323.
31. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer's disease': revising the NINCDS-ADRDA criteria. Lancet Neurol 2007; 6:734–746.
32. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, et al. Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65:1863–1872.
33. Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993; 43:250–260.
34. Wiederkehr S, Simard M, Fortin C, van Reekum R. Validity of the clinical diagnostic criteria for vascular dementia: a critical review. Part II. J Neuropsychiatry Clin Neurosci 2008; 20:162–177.
35. Marra CM, Critchlow CW, Hook EW 3rd, Collier AC, Lukehart SA. Cerebrospinal fluid treponemal antibodies in untreated early syphilis. Arch Neurol 1995; 52:68–72.
36. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009; 58:1–207, quiz CE1-4.
37. Portegies P, Solod L, Cinque P, Chaudhuri A, Begovac J, Everall I, et al. Guidelines for the diagnosis and management of neurological complications of HIV infection. Eur J Neurol 2004; 11:297–304.
38. Petito CK. Neuropathology of acquired immunodeficiency syndrome. In Nelson JS, Mena H, Parisi JS, Schochet SS, editors. The principles, practice of neuropathology. 2nd ed. New York: Oxford University Press; 2003. pp. 95–111.
39. Wang Y, Kirby JE, Qian Q. Effective use of JC virus PCR for diagnosis of progressive multifocal leukoencephalopathy. J Med Microbiol 2009; 58:253–255.
40. Cinque P, Bossolasco S, Bestetti A, Sala S, Pierotti C, Lazzarin A. Molecular studies of cerebrospinal fluid in human immunodeficiency virus type 1-associated opportunistic central nervous system diseases–: an update. J Neurovirol 2002; 8(Suppl 2):122–128.
41. Cash WJ, McConville P, McDermott E, McCormick PA, Callender ME, McDougall NI. Current concepts in the assessment and treatment of hepatic encephalopathy. QJM 2010; 103:9–16.
42. Harper C, Butterworth R. Nutritional and metabolic disorders. In Graham DI, Lantos PL, editors. Greenfield's neuropathology. 7th ed. London: Arnold Publishing; 2002. pp. 607–651.
43. Dreibelbis JE, Jozefowicz RF. Neurologic complications of respiratory disease. Neurol Clin 2010; 28:37–43.
44. Auer RN, Sutherland GR. Hypoxia and related conditions. In Graham DI, Lantos PL, editors. Greenfield's neuropathology. 7th ed. London: Arnold Publishing; 2002. pp. 233–280.
45. Xu J, Ikezu T. The comorbidity of HIV-associated neurocognitive disorders and Alzheimer's disease: a foreseeable medical challenge in post-HAART era. J Neuroimmune Pharmacol 2009; 4:200–212.
46. Pulliam L. HIV regulation of amyloid beta production. J Neuroimmune Pharmacol 2009; 4:213–217.
47. Anthony IC, Ramage SN, Camie FW, Simmonds P, Bell JE. Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active antiretroviral therapy. Acta Neuropathol 2006; 111:529–538.
48. Khanlou N, Moore DJ, Chana G, Cherner M, Lazzaretto D, Dawes S, et al. Increased frequency of alpha-synuclein in the substantia nigra in human immunodeficiency virus infection. J Neurovirol 2009; 15:131–138.
49. Minagar A, Shapshak P, Duran EM, Kablinger AS, Alexander JS, Kelley RE, et al. HIV-associated dementia, Alzheimer's disease, multiple sclerosis, and schizophrenia: gene expression review. J Neurol Sci 2004; 224(1–2):3–17.
50. Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C. The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 2002; 202(1–2):13–23.
51. Bell JE, Brettle RP, Chiswick A, Simmonds P. HIV encephalitis, proviral-load, and dementia in drug users and homosexuals with AIDS. Effect of neocortical involvement. Brain 1998; 121:2043–2052.
52. Kim MT, Hill MN. Validity of self-report of illicit drug use in young hypertensive urban African-American males. Addict Beh 2003; 28:795–802, doi: 10.1016/S0306-4603(01)00277-5.
53. Fiala M, Eshleman AJ, Cashman J, Lin J, Lossinsky AS, Suarez V, et al. Cocaine increases human immunodeficiency virus type 1 neuroinvasion through remodeling brain microvascular endothelial cells. J Neurovirol 2005; 11:281–291.
54. Peterson PK, Gekker G, Hu S, Lokensgard J, Portoghese PS, Chao CC. Endomorphin-1 potentiates HIV-1 expression in human brain cell cultures: implication of an atypical mu-opioid receptor. Neuropharmacology 1999; 38:273–278.
55. Rogers TJ, Peterson PK. Opioid G protein-coupled receptors: signals at the crossroads of inflammation. Trends Immunol 2003; 24:116–121.
56. Li Y, Wang X, Tian S, Guo CJ, Douglas SD, Ho WZ. Methadone enhances human immunodeficiency virus infection of human immune cells. J Infect Dis 2002; 185:118–122.
57. Dhillon NK, Williams R, Peng F, Tsai YJ, Dhillon S, Nicolay B, et al. Cocaine-mediated enhancement of virus replication in macrophages: implications for human immunodeficiency virus-associated dementia. J Neurovirol 2007; 13:483–495.
58. Nair MP, Mahajan SD, Schwartz SA, Reynolds J, Whitney R, Bernstein Z, et al. Cocaine modulates dendritic cell-specific C type intercellular adhesion molecule-3-grabbing nonintegrin expression by dendritic cells in HIV-1 patients. J Immunol 2005; 174:6617–6626.
59. Reynolds JL, Mahajan SD, Bindukumar B, Sykes D, Schwartz SA, Nair MP. Proteomic analysis of the effects of cocaine on the enhancement of HIV-1 replication in normal human astrocytes (NHA). Brain Res 2006; 1123:226–236.
60. Liang H, Wang X, Chen H, Song L, Ye L, Wang SH, et al. Methamphetamine enhances HIV infection of macrophages. Am J Pathol 2008; 172:1617–1624.
61. Gaskill PJ, Calderon TM, Luers AJ, Eugenin EA, Javitch JA, Berman JW. Human immunodeficiency virus (HIV) infection of human macrophages is increased by dopamine: a bridge between HIV-associated neurologic disorders and drug abuse. Am J Pathol 2009; 175:1148–1159, doi: 10.2353/ajpath.2009.081067.
62. Lee YW, Hennig B, Yao J, Toborek M. Methamphetamine induces AP-1 and NF-kappaB binding and transactivation in human brain endothelial cells. J Neurosci Res 2001; 66:583–591.
63. Mahajan SD, Aalinkeel R, Sykes DE, Reynolds JL, Bindukumar B, Fernandez SF, et al. Tight junction regulation by morphine and HIV-1 tat modulates blood-brain barrier permeability. J Clin Immunol 2008; 28:528–541.
64. Sharma HS, Ali SF. Alterations in blood-brain barrier function by morphine and methamphetamine. Ann N Y Acad Sci 2006; 1074:198–224.
65. Turchan J, Anderson C, Hauser KF, Sun Q, Zhang J, Liu Y, et al. Estrogen protects against the synergistic toxicity by HIV proteins, methamphetamine and cocaine. BMC Neurosci 2001; 2:3–11.
66. Bruce-Keller AJ, Turchan-Cholewo J, Smart EJ, Geurin T, Chauhan A, Reid R, et al. Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV-1 Tat transgenic mice. Glia 2008; 56:1414–1427.
67. Harrod SB, Mactutus CF, Fitting S, Hasselrot U, Booze RM. Intra-accumbal Tat1-72 alters acute and sensitized responses to cocaine. Pharmacol Biochem Behav 2008; 90:723–729.
68. Kuczenski R, Everall IP, Crews L, Adame A, Grant I, Masliah E. Escalating dose-multiple binge methamphetamine exposure results in degeneration of the neocortex and limbic system in the rat. Exp Neurol 2007; 207:42–51.
69. Chana G, Everall IP, Crews L, Langford D, Adame A, Grant I, et al. Cognitive deficits and degeneration of interneurons in HIV+ methamphetamine users. Neurology 2006; 67:1486–1489.
70. Sacktor N, Tarwater PM, Skolasky RL, McArthur JC, Selnes OA, Becker J, et al. CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing. Neurology 2001; 57:542–555.
71. Marra CM, Zhao Y, Clifford DB, Letendre S, Evans S, Henry K, et al, and AIDS Clinical Trials Group 736 Study Team. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 2009; 23:1359–1366.
72. Marra CM, Lockhart D, Zunt JR, Perrin M, Coombs RW, Collier AC. Changes in CSF and plasma HIV-1 RNA and cognition after starting highly active antiretroviral therapy. Neurology 2003; 60:1388–1395.
73. Foudraine NA, Hoetelmans RM, Lange JM, de Wolf F, van Benthem BH, Maas JJ, et al. Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine. Lancet 1998; 351:1547–1550.
74. Antinori A, Perno CF, Giancola ML, Forbici F, Ippolito G, Hoetelmans RM, et al. Efficacy of Cerebrospinal fluid (CSF)-penetrating antiretroviral drugs against HIV in the neurological compartment: different patterns of phenotypic resistance in CSF and plasma. Clin Infect Dis 2005; 41:1787–1793.
75. Letendre SL, van den Brande G, Hermes A, Woods SP, Durelle J, Beck JM, et al. Lopinavir with ritonavir reduces the HIV RNA level in cerebrospinal fluid. Clin Infect Dis 2007; 45:1511–1517.
76. Couzigou C, Seang S, Morand-Joubert L, Roque-Afonso AM, Escaut L, Vittecoq D. Efficacy of etravirine for treatment of acute HIV meningoencephalitis. Clin Infect Dis 2009; 48:e62–e65.
77. Schifitto G, Navia BA, Yiannoutsos CT, Marra CM, Chang L, Ernst T, et al. Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study. AIDS 2007; 21:1877–1886.
78. Schifitto G, Zhang J, Evans SR, Sacktor N, Simpson D, Millar LL, et al. A multicenter trial of selegiline transdermal system for HIV-associated cognitive impairment. Neurology 2007; 69:1314–1321.
79. Dewhurst S, Maggirwar SB, Schifitto G, Gendelman HE, Gelbard HA. Glycogen synthase kinase 3 beta (GSK-3 beta) as a therapeutic target in NeuroAIDS. J Neuroimmune Pharmacol 2007; 2:93–96.
80. Schifitto G, Peterson DR, Zhong J, Ni H, Cruttenden K, Gaugh M, et al. Valproic acid adjunctive therapy for HIV-associated cognitive impairment: a first report. Neurology 2006; 66:919–921. Epub 2006 Mar 1.
81. Lee K, Vivithanaporn P, Siemieniuk RA, Krentz HB, Maingat F, Gill MJ, et al. Clinical outcomes and immune benefits of antiepileptic drug therapy in HIV/AIDS. BMC Neurol 2010; 10:44–48.
82. Sagot-Lerolle N, Lamine A, Chaix ML, Boufassa F, Aboulker JP, Costagliola D, et al. ANRS EP39 study. Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS 2008; 22:1125–1129.
83. Fujimura RK. Viral-load and HIV-l associated dementia: neuropathology and drug efficacy. In Minagar A, Shapshak P, editors. Chapter 5 in NeuroAIDS. 2005. pp. 101–119 [ISBN: 1-59454-610-X].
84. Fujimura RK, Goodkin K, Petito C, Douyon R, Feaster DJ, Concha M, et al. HIV-1 proviral DNA load across neuroanatomic regions of individuals with evidence for HIV-1-associated dementia. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 16:146–152.
85. Fujimura RK, Khamis I, Shapshak P, Goodkin K. Regional quantitative comparison of multispliced to unspliced ratios of HIV-1 RNA copy number in infected human brain. J NeuroAIDS 2004; 2:45–60.
86. Zhao L, Galligan DC, Lamers SL, Yu S, Shagrun L, Salemi M, et al. High-level HIV-1 DNA concentrations in brain tissues differentiate patients with post-HAART AIDS dementia complex or cardiovascular disease from those with AIDS. Sci China C Life Sci 2009; 52:651–656.
87. Petito C, Hexin C, Angeline RM, Torres-Munoz J, Roberts B, Wood C. HIV infection of choroid plexus in AIDS and asymptomatic HIV-infected patients suggests that the choroid plexus may be a reservoir of productive infection. J NeuroVirol 1999; 5:670–677.
88. Zhou L, Ng T, Yuksel A, Wang B, Dwyer DE, Saksena NK. Short communication: absence of HIV infection in the choroid plexus of two patients who died rapidly with HIV-associated dementia. AIDS Res Hum Retroviruses 2008; 24:839–843.
89. Shiramizu B, Gartner S, Williams A, Shikuma C, Ratto-Kim S, Watters M, et al. Circulating proviral HIV DNA and HIV-associated dementia. AIDS 2005; 19:45–52. PubMed: 15627032.
90. Shiramizu B, Williams AE, Shikuma C, Valcour V. Amount of HIV DNA in peripheral blood mononuclear cells is proportional to the severity of HIV-1-associated neurocognitive disorders. J Neuropsychiatry Clin Neurosci 2009; 21:68–74, doi: 10.1176/appi.neuropsych.21.1.68.
91. Valcour VG, Shiramizu BT, Sithinamsuwan P, Nidhinandana S, Ratto-Kim S, Ananworanich J, et al. HIV DNA and cognition in Thai longitudinal HAART initiation cohort: SEARCH 001 cohort study. Neurol 2009; 72:992–998, doi: 10.1212/01.wnl.0000344404.12759.83.
92. Hightower GK, Letendre SL, Cherner M, Gibson SA, Ellis RJ, Wolfson TJ, et al. Select resistance-associated mutations in blood are associated with lower CSF viral-loads and better neuropsychological performance. Virology 2009; 394:243–248. Sep 15 [Epub ahead of print].
93. Ancuta P, Kamat A, Kunstman KJ, Kim E-Y, Autissier P, Wurcel A, et al. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS ONE 2008; 3:e2516, doi: 10.1371/journal.pone.0002516.
94. Chiappelli F, Shapshak P, Commins D, Singer E, Minagar A, Oluwadara O, et al. Molecular epigenetics, chromatin, and NeuroAIDS/HIV. I. Immunopathological implications. Bioinformation 2008; 3:47–52. PMID: 19052666.
95. Shapshak P, Chiappelli F, Commins D, Singer E, Levine AJ, Somboonwit C, et al. Molecular epigenetics, chromatin, and NeuroAIDS/HIV. II. Translational implications. Bioinformation 2008; 3:53–57. PMID: 19052667.
96. Tatro ET, Scott ER, Nguyen TB, Salaria S, Banerjee S, Moore DJ, et al. Evidence for alteration of gene regulatory networks through microRNAs of the HIV-infected brain: novel analysis of retrospective cases. PLoS One 2010; 5:e10337 [doi:10.1371/journal.pone.0010337] (
97. Zárate S, Kosakovsky-Pond SL, Shapshak P, Frost SDW. A comparative study of methods for detecting sequence compartmentalization in HIV-1. J Virol 2007; 61:6643–6651.
98. Smit TK, Brew BJ, Tourtellotte W, Morgello S, Gelman BB, Saksena NK. Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIV-infected patients, with and without dementia, on antiretroviral treatment. J Virol 2004; 78:10133–10148.
99. Burkala EJ, He J, West JT, Wood C, Petito C. Compartmentalization of HIV-1 in the central nervous system: role of the choroid plexus. AIDS 2005; 19:675–684.
100. van Marle G, Henry S, Todoruk T, Sullivan A, Silva C, Rourke SB, et al. Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10. Virology 2004; 329:302–318.
101. Chang J, Jozwiak R, Wang B, Ng T, Ge YC, Bolton W, et al. Unique HIV type 1 V3 region sequences derived from six different regions of brain: region-specific evolution within host-determined quasispecies. AIDS Res Hum Retr 1998; 14:25–30.
102. Shapshak P, Segal DM, Crandall K, Fujimura RK, Zhang BT, Xin KQ, et al. Independent evolution of HIV-1 in different brain regions. AIDS Res Hum Retr 1999; 15:811–820.
103. Caragounis EC, Gisslén M, Lindh M, Nordborg C, Westergren S, Hagberg L, et al. Comparison of HIV-1 pol and env sequences of blood, CSF, brain and spleen isolates collected ante-mortem and postmortem. Acta Neurol Scand 2008; 117:108–116.
104. Pillai SK, Pond SL, Liu Y, Good BM, Strain MC, Ellis RJ, et al. Genetic attributes of cerebrospinal fluid-derived HIV-1 env. Brain 2006; 129(Pt 7):1872–1883. Epub 2006 May 30.
105. Salemi M, Lamers SL, Yu S, de Oliveira T, Fitch WM, McGrath MS. Phylodynamic analysis of human immunodeficiency virus type 1 in distinct brain compartments provides a model for the neuropathogenesis of AIDS. J Virol 2005; 79:11343–11352.
106. Liu P, Hudson LC, Tompkins MB, Vahlenkamp TW, Meeker RB. Compartmentalization and evolution of feline immunodeficiency virus between the central nervous system and periphery following intracerebroventricular or systemic inoculation. J Neurovirol 2006; 12:307–321.
107. Thompson KA, Churchill MJ, Gorry PR, Sterjovski J, Oelrichs RB, Wesselingh SL, et al. Astrocyte specific viral strains in HIV dementia. Ann Neurol 2004; 56:873–877.
108. Agopian K, Wei BL, Garcia JV, Gabuzda D. CD4 and MHC-I downregulation are conserved in primary HIV-1 Nef alleles from brain and lymphoid tissues, but Pak2 activation is highly variable. Virology 2007; 358:119–135.
109. Ohagen A, Devitt A, Kunstman KJ, Gorry PR, Rose PP, Korber B, et al. Genetic and functional analysis of full-length human immunodeficiency virus type 1 env genes derived from brain and blood of patients with AIDS. J Virol 2003; 77:12336–12345.
110. Korber BT, Learn GH Jr, Mullins JI, Hahn BH, Wolinsky S. Protecting HIV databases. Nature 1995; 378:242–244.
111. Learn GH Jr, Korber BT, Foley B, Hahn BH, Wolinsky SM, Mullins JI. Maintaining the integrity of human immunodeficiency virus sequence databases. J Virol 1996; 70:5720–5730.
112. Herbeck JT, Nickle DC, Learn GH Jr, Gottlieb GS, Curlin ME, Heath L, et al. Human immunodeficiency virus type 1 env evolves toward ancestral states upon transmission to a new host. J Virol 2006; 80:1637–1644.
113. Mefford ME, Gorry PR, Kunstman K, Wolinsky SM, Gabuzda D. Bioinformatic prediction programs underestimate the frequency of CXCR4 usage by R5X4 HIV type 1 in brain and other tissues. AIDS Res Hum Retroviruses 2008; 24:1215–1220.
114. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382:722–725.
115. Boven LA, van der Bruggen T, van Asbecka BS, Marxa JJM, Nottet HSLM. Potential role of CCR5 polymorphism in the development of AIDS dementia complex. FEMS Immunol Med Microbiol 1999; 26(3–4):243–247.
116. Singh KK, Barroga CF, Hughes MD, Chen J, Raskino C, McKinney RE, Spector SA. Genetic influence of CCR5, CCR2, and SDF1 variants on human immunodeficiency virus 1 (HIV-1)-related disease progression and neurological impairment, in children with symptomatic HIV-1 infection. J Infect Dis 2003; 188:1461–1472.
117. Spector SA, Singh KK, Gupta S, Cysique LA, Jin H, Letendre S, et al, Heaton RK; HNRC Group. APOE epsilon4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors. AIDS 2010; 24:1471–1479.
118. Fellay J, Ge D, Shianna KV, Colombo S, Ledergerber B, Cirulli ET, et al. Immunology NCfHAV. Common genetic variation and the control of HIV-1 in humans. PLoS Genet 2009; 5:e1000791.
119. Singh KK, Ellis RJ, Letendre S, Heaton R, Grant I, Spector SA. CCR2 polymorphisms affect neuropsychological impairment in HIV-1-infected adults. J Neuroimmunol 2004; 157(1–2):185–192.
120. Diaz-Arrastia R, Gong Y, Kelly CJ, Gelman BB. Host genetic polymorphisms in human immunodeficiency virus-related neurologic disease. J Neurovirol 2004; 10(Suppl 1):67–73.
121. Pemberton LA, Stone E, Price P, van Bockxmeer F, Brew BJ. The relationship between ApoE, TNFA, IL1a, IL1b and IL12b genes and HIV-1-associated dementia. HIV Med 2008; 9:677–680.
122. Corder EH, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J, et al. HIV-infected subjects with the (4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med 1998; 4:1182–1184.
123. Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, et al. Apolipoprotein (Apo) (4 enhances HIV-1 cell entry in vitro, and the APOE (4/(4 genotype accelerates HIV disease progression. Proc Natl Acad Sci US 2008; 105:8718–8723.
124. Dunlop O, Goplen AK, Liestøl K, Myrvang B, Rootwelt H, Christophersen B, et al. HIV dementia and apolipoprotein E. Acta Neurol Scand 1997; 95:315–318.
125. Levine AJ, Singer EJ, Sinsheimer JS, Hinkin CH, Papp J, Dandekar S, et al. CCL3 genotype and current depression increase risk of HIV-associated dementia. Neurobeh HIV Med 2009; 1:1–7.
126. Gonzalez E, Rovin BH, Sen L, Cooke G, Dhanda R, Mummidi S, et al. HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proc Natl Acad Sci USA 2002; 99:13795–13800.
127. Singh KK, Hughes MD, Chen J, Spector SA. Impact of MCP-1-2518-G allele on the HIV-1 disease of children in the United States. AIDS 2006; 20:475–478.
128. Quasney MW, Zhang Q, Sargent S, Mynatt M, Glass J, McArthur J. Increased frequency of the tumor necrosis factor-alpha-308 A allele in adults with human immunodeficiency virus dementia. Ann Neurol 2001; 50:157–162.
129. Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 1998; 279:389–393.
130. Shrestha S, Strathdee SA, Galai N, Oleksyk T, Fallin MD, Mehta S, et al. Behavioral risk exposure and host genetics of susceptibility to HIV-1 infection. J Infect Dis 2006; 193:16–26.
131. Price P, James I, Fernandez S, French MA. Alleles of the gene encoding IL-1alpha may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy. AIDS 2004; 18:1495–1501.
132. Levine AJ, Singer EJ, Shapshak P. The role of host genetics in the susceptibility for HIV-associated neurocognitive disorders. AIDS Behav 2009; 13:118–132.
133. Pomara N, Belzer KD, Silva R, Cooper TB, Sidtis JJ. The apolipoprotein E (4 allele and memory performance in HIV-1 seropositive subjects: differences at baseline but not after acute oral lorazepam challenge. Psychopharmacology 2008; 201:125–135.
134. Ferris MJ, Mactutus CF, Booze RM. Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: current status of dopamine system vulnerability in NeuroAIDS. Neurosci Biobehav Rev 2008; 32:883–909.
135. Bousman CA, Cherner M, Atkinson JH, Grant I, Tsuang MT, Everall IP. Impact of the catechol-O-methyl-transferase Val158Met polymorphism on executive functioning in the context of HIV-infection and methamphetamine dependence. Neurobehav HIV Med 2010; 2:1–11. PMCID: PMC2804107.
136. Borjabad A, Brooks AI, Volsky DJ. Gene expression profiles of HIV-1-infected glia and brain: toward better understanding of the role of astrocytes in HIV-1-associated neurocognitive disorders. J Neuroimmune Pharmacol 2009 [Epub ahead of print] PubMed PMID: 19697136.
137. Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 2001; 410:988–994.
138. Shapshak P, Duncan D, Minagar D, Rodriguez de la Vega P, Stewart R, Petito CK. Elevated expression of IFN-γ in the HIV-1 infected brain. Front Biosci 2004; 9:1073–1081.
139. Nicolini A, Ajmone-Cat MA, Bernardo A, Levi G, Minghetti L. Human immunodeficiency virus type-1 Tat protein induces nuclear factor (NF)-kappaB activation and oxidative stress in microglial cultures by independent mechanisms. J Neurochem 2001; 79:713–716.
140. Hurwitz AA, Lyman WD, Berman JW. Tumor necrosis factor alpha and transforming growth factor beta upregulated astrocyte expression of monocyte chemo-attractant protein-1. J Neuroimmunol 1995; 57:193–198.
141. Erichsen D, Lopez AL, Peng H, Niemann D, Williams C, Bauer M, et al. Neuronal injury regulates fractalkine: relevance for HIV-1 associated dementia. J Neuroimmunol 2003; 138:144–155.
142. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, et al. CXCR-4 activated astrocyte glutamate release via TNF-alpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 2001; 4:702–710.
143. Fine SM, Angel RA, Perry SW, Epstein LG, Rothstein JD, Dewhurst S, et al. Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes. Implications for pathogenesis of HIV-1 dementia. J Biol Chem 1996; 271:15303–15306.
144. Yeh MW, Kaul M, Zheng J, Nottet HS, Thylin M, Gendelman HE, et al. Cytokine-stimulated, but not HIV-infected, human monocyte-derived macrophages produce neurotoxic levels of L-cysteine. J Immunol 2000; 164:4265–4270.
145. Haughey NJ, Cutler RG, Tamara A, McArthur JC, Vargas DL, Pardo CA, et al. Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Ann Neurol 2004; 55:257–267.
146. Nath A, Conant K, Chen P, Scott C, Major EO. Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J Biol Chem 1999; 274:17098–17102.
147. Viviani B, Corsini E, Binaglia M, Galli CL, Marinovich M. Reactive oxygen species generated by glia are responsible for neuron death induced by human immunodeficiency virus-glycoprotein 120 in vitro. Neuroscience 2001; 107:51–58.
148. Samikkannu T, Saiyed ZM, Rao KV, Babu DK, Rodriguez JW, Papuashvili MN, et al. Differential regulation of indoleamine-2,3-dioxygenase (IDO) by HIV type 1 clade B and C Tat protein. AIDS Res Hum Retroviruses 2009; 25:329–335.
149. Geschwind DH. DNA microarrays: translation of the genome from laboratory to clinic. Lancet Neurol 2003; 2:275–282.
150. Shapshak P, Minagar A, Duran EM, Ziegler F, Davis W, Seth R, et al. Gene expression in HIV associated dementia. In: Minagar A, Alexander JS, editors. Inflammatory disorders of the nervous system, clinical aspects, pathogenesis, and management. Totowa, NJ: Humana Press; 2005.
151. Albright AV, González-Scarano F. Microarray analysis of activated mixed glial (microglia) and monocyte-derived macrophage gene expression. J Neuroimmunol 2004; 157:27–38. PubMed PMID: 15579277.
152. Galey D, Becker K, Haughey N, Kalehua A, Taub D, Woodward J, et al. Differential transcriptional regulation by human immunodeficiency virus type 1 and gp120 in human astrocytes. J Neurovirol 2003; 9:358–371. PubMed PMID: 12775419.
153. Roberts ES, Zandonatti MA, Watry DD, Madden LJ, Henriksen SJ, Taffe MA, et al. Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS. Am J Pathol 2003; 162:2041–2057. PubMed PMID: 12759259; PubMed Central PMCID: PMC1868118.
154. Masliah E, Robert ES, Langford D, Everall I, Crews L, Adame A, et al. Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis. J Neuroimmun 2004; 157:163–175.
155. Hanson LR, Frey WH. Strategies for intranasal delivery of therapeutics for the prevention and treatment of NeuroAIDS. J Neuroimmune Pharmacol 2007; 2:81–86.
156. Agrawal L, Louboutin JP, Reyes BA, Van Bockstaele EJ, Strayer DS. Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis. Gene Ther 2006; 13:1645–1656.
157. Zink MC. Translational research models and novel adjunctive therapies for NeuroAIDS. J Neuroimmune Pharmacol 2007; 2:14–19.
158. Louboutin JP, Agrawal L, Reyes BA, Van Bockstaele EJ, Strayer DS. Protecting neurons from HIV-1 gp120-induced oxidant stress using both localized intracerebral and generalized intraventricular administration of antioxidant enzymes delivered by SV40-derived vectors. Gene Ther 2007; 14:1650–1661.
159. Infanti JL. Challenging the gold standard: should mannitol remain our first-line defense against intracranial hypertension? J Neurosci Nurs 2008; 40:362–368.
160. Sigurdsson EM, Wadghiri YZ, Mosconi L, Blind JA, Knudsen E, Asuni A, et al. T. A nontoxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice. Neurobiol Aging 2008; 29:836–847.
161. Xu J, Ma C, Bass C, Terwilliger EF. A combination of mutations enhances the neurotropism of AAV-2. Virology 2005; 341:203–214.
162. Terzi D, Zachariou V. Adeno-associated virus-mediated gene delivery approaches for the treatment of CNS disorders. Biotechnol J 2008; 3:1555–1563.
163. Romano G. Current development of adeno-associated viral vectors. Drug News Perspect 2005; 18:311–316.
164. Lu Y. GFP-lentiviral vectors targeting for NeuroAIDS. Methods Mol Biol 2009; 515:177–197.
165. Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, et al. CHARTER Group. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008; 65:65–70.
166. Letendre S, Ellis R, Ances B, McCutchan. Neurologic complications if HIV disease and their treatment. Topics HIV Med 2010; 18:45–55.
167. DeLuca A, Ciancio B, Larussa D, Murri R, Cingolani A, Rizzo MG, et al. Correlates of independent HIV-1 replication in the CNS and of its control by antiretrovirals. Neurology 2002; 59:342–347.
168. Gollapudi S, Gupta S. Human immunodeficiency virus I-induced expression of P-glycoprotein. Biochem Biophys Res Commun 1990; 171:1002–1007.
169. Yao SY, Ng AM, Sundaram M, Cass CE, Baldwin SA, Young JD. Transport of antiviral 3'-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitro-benzyl-thio-inosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. Mol Membr Biol 2001; 18:161–167.
170. Minuesa G, Purcet S, Erkizia I, Molina-Arcas M, Bofill M, Izquierdo-Useros N, et al. Expression and functionality of antihuman immunodeficiency virus and anticancer drug uptake transporters in immune cells. J Pharmacol Exp Ther 2008; 324:558–567. Epub 2007 Nov 27.
171. Sturmer E, von Moltke LL, Perloff MD, Greenblatt DJ. Differential modulation of P-glycoprotein expression and activity by nonnucleoside HIV-1 reverse transcriptase inhibitors in cell culture. Pharm Res 2002; 19:1038–1045.
172. Gibbs JE, Jayabalan P, Thomas SA. Mechanisms by which 2',3'-dideoxyinosine (ddI) crosses the guinea-pig CNS barriers; relevance to HIV therapy. J Neurochem 2003; 84:725–734.
173. Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD. The equilibrative nucleoside transporter family, SLC29. Pflugers Arch 2004; 447:735–743. Epub 2003 Jun 28.
174. Jung N, Lehmann C, Rubbert A, Knispel M, Hartmann P, van Lunzen J, et al. Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab Dispos 2008; 36:1616–1623. Epub 2008 May 19.
175. Kim AE, Dintaman JM, Waddell DS, Silverman JA. Saquinavir, an HIV protease inhibitor, is transported by P-glycoprotein. J Pharmacol Exp Ther 1998; 286:1439–1445.
176. Lee LS, Soon GH, Shen P, Yong EL, Flexner C, Pham P. Darunavir/ritonavir and Efavirenz exert differential effects on MRP1 transporter expression and function in healthy volunteers. Antivir Ther 2010; 15:275–279.
177. Fujimoto H, Higuchi M, Watanabe H, Koh Y, Ghosh AK, Mitsuya H, et al. P-glycoprotein mediates efflux transport of darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell lines. Biol Pharm Bull 2009; 32:1588–1593.
178. Vierling P, Greiner J. Prodrugs of HIV protease inhibitors. Curr Pharm Des 2003; 9:1755–1770.
179. Eilers M, Roy U, Mondal D. MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, Saquinavir and zidovudine, from human endothelial cells. Exp Biol Med (Maywood) 2008; 233:1149–1160. Epub 2008 Jun 5.
180. Zastre JA, Chan GN, Ronaldson PT, Ramaswamy M, Couraud PO, Romero IA, et al. Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line. J Neurosci Res 2009; 87:1023–1036.
181. Gupta A, Zhang Y, Unadkat JD, Mao Q. HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther 2004; 310:334–341. Epub 2004 Mar 8.
182. Perloff MD, von Moltke LL, Fahey JM, Greenblatt DJ. Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells. J Pharm Pharmacol 2007; 59:947–953.
183. Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien HC, White N, et al. A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clin Pharmacol Ther 2010; 87:735–742. Epub 2010 Feb 10.
184. Walker DK, Bowers SJ, Mitchell RJ, Potchoiba MJ, Schroeder CM, Small HF. Preclinical assessment of the distribution of Maraviroc to potential human immunodeficiency virus (HIV) sanctuary sites in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT). Xenobiotica 2008; 38:1330–1339.
185. Price RW, Parham R, Kroll JL, Wring SA, Baker B, Sailstad J, et al. Enfuvirtide cerebrospinal fluid (CSF) pharmacokinetics and potential use in defining CSF HIV-1 origin. Antivir Ther 2008; 13:369–374.
186. Morris KA, Davies NWS, Brew BJ. A guide to interpretation of neuroimmunological biomarkers in the combined antiretroviral therapy-era of HIV central nervous system disease. Neurobehav HIV Med 2010; 2:59–72, doi: 10.2147/NBHIV.S7167.
187. Diesing TS, Swindells S, Gelbard H, Gendelman HE. HIV-1-associated dementia: a basic science and clinical perspective. AIDS Read 2002; 12:358–368.
188. Smits HA, Boven LA, Pereira CF, Verhoef J, Nottet HS. Role of macrophage activation in the pathogenesis of Alzheimer's disease and human immunodeficiency virus type 1-associated dementia. Eur J Clin Invest 2000; 30:526–535.
189. Ghafouri M, Amini S, Khalili K, Sawaya BE. HIV-1 associated dementia: symptoms and causes. Retrovirology 2006; 3:28–35.
190. Alter G, Ananworanich J, Pantophlet R, Rybicki EP, Buonaguro L. Report on the AIDS vaccine 2008 conference. Hum Vaccine 2009; 5:119–125.
191. Bass E, Feuer C, Warren M. AIDS vaccine research and advocacy: an update. BETA 2009; 21:24–30.
192. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009; 361:2209–2220.
193. Koff WC, Berkley SF. The renaissance in HIV vaccine development–: future directions. N Engl J Med 2010.
194. Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 2010.
195. Zolla-Pazner S, Cardozo T. Structure–function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design. Nature Rev Immunol 2010; 10:527–535, doi: 10.1038/nri2801.
196. Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, et al. Rational design of envelope surface identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 2010; 329:856–861, doi: 10.1126/science.1187659.
197. Kangueane P, Kayathri R, Kishore M, Flower DR, Sadler K, Chiappelli F, et al. Designing HIV gp120 peptide vaccines: rhetoric or reality for NeuroAIDS, Chapter 9. In Goodkin K, Shapshak P, Verma A, editors. The spectrum of NeuroAIDS disorders: pathophysiology, diagnosis, and treatment. Washington, DC: ASM Press; 2008. pp. 105–119.
198. DeGroot AS, Marcon L, Bishop EA, Rivera D, Kutzler M, Weiner DB, et al. HIV vaccine development by computer-assisted design: the GAIA vaccine. Vaccine 2005; 23:2136–2148.
199. Mohanapriya A, Nandagond S, Shapshak P, Kangueane U, Kangueane P. A HLA-DRB supertype chart with potential overlapping peptide binding function. Bioinformation 2010; 4:300–309.
200. Toggas SM, Masliah E, Rockenstein EM, Rall GF, Abraham CR, Mucke L. Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 1994; 367:188–193.
201. Michaud J, Fajardo R, Charron G, Sauvageau A, Berrada F, Ramla D, et al. Neuropathology of NFHgp160 transgenic mice expressing HIV-1 env protein in neurons. J Neuropathol Exp Neurol 2001; 60:574–587.
202. Kim BO, Liu Y, Ruan Y, Xu ZC, Schantz L, He JJ. Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline. Am J Pathol 2003; 162:1693–1707.
203. Tyor WR, Power C, Gendelman HE, Markham RB. A model of human immunodeficiency virus encephalitis in SCID mice. PNAS, USA 1993; 90:8658–8662.
204. Hartman K. Feline immunodeficiency virus infection: an overview. Vet J 1998; 155:123–137.
205. Fox HS, Phillips TR. FIV and NeuroAIDS. J Neurovirol 2002; 8:155–157.
206. Manigat F, Vivithanaporn P, Zhu Y, Taylor A, Baker G, Pearson K, et al. Neurobehavioral performance in feline immunodeficiency virus infection: integrated analysis of viral burden, neuroinflammation, and neuronal injury in cortex. J Neurosci 2009; 29:8429–8437.
207. Ward JM, O'Leary TJ, Baskin GB, Benveniste R, Harris CA, Nara PL, et al. Immunohistochemical localization of human and simian immunodeficiency viral antigens in fixed tissue sections. Am J Pathol 1987; 127:199–205.
208. Watry D, Lane TE, Streb M, Fox HS. Transfer of neuropathogenic simian immunodeficiency virus with naturally infected microglia. Am J Pathol 1995; 146:914–923.
209. Zink MC, Suryanarayana K, Mankowski JL, Shen A, Piatak M Jr, Spelman JP, et al. High viral-load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis. J Virol 1999; 73:10480–10488.
210. Novembre FJ, DeRosayro J, O'Neil SP, Anderson DC, Klumpp SA, McClure HM. Isolation and characterization of a neuropathogenic simian immunodeficiency virus derived from a sooty mangabey. J Virol 1998; 72:8841–8851.
211. Williams K, Westmoreland S, Greco J, Ratai E, Lentz M, Kim WK, et al. Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV NeuroAIDS. J Clin Invest 2005; 115:2534–2545.

animal models; evolution; gene expression; genetics; HIV-associated neurocognitive disorder; HIV-1; molecular therapy; NeuroAIDS; vaccines; virus load

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