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doi: 10.1097/QAD.0b013e328340fd42
Editorial Review

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

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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: pshapshak@gmail.com

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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].

Table 1
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Table 1
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Table 1
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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].

Fig. 1
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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].

Table 2
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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].

Table 3
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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].

Table 4
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Table 5
Table 5
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Fig. 2
Fig. 2
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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 (http://www.hvtn.org/media/pr/step111307.html)] 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 (http://www.ebi.ac.uk/imgt/hla/) 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 (http://www.hiv.lanl.gov/content/immunology/index.html) 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].

Fig. 3
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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.

Table 6
Table 6
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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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animal models; evolution; gene expression; genetics; HIV-associated neurocognitive disorder; HIV-1; molecular therapy; NeuroAIDS; vaccines; virus load

© 2011 Lippincott Williams & Wilkins, Inc.


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