Methamphetamine Enhances HIV-Induced Aberrant Proliferation of Neural Progenitor Cells via the FOXO3-Mediated Mechanism.

Maintaining an intact pool of neural progenitor cells (NPCs) is crucial for generating new and functionally active neurons. Methamphetamine (METH) can exacerbate the HIV-induced deficit of adult neurogenesis; however, potential mechanisms of this influence are still poorly understood. In the present study, we present evidence that chronic exposure to METH combined with brain infection by EcoHIV results in enhanced proliferation of NPCs in the subventricular zone (SVZ) in mice. This effect was long-lasting as it was preserved ex vivo in NPCs isolated from the exposed mice over several passages in the absence of additional treatments. Increased proliferation in response to METH plus HIV was associated with dysregulation of cyclin B1 and cyclin D. Transcriptomic studies indicated that 27 out of the top 30 differentially expressed genes in response to METH plus EcoHIV were targets of the forkhead box O transcriptional factor (FOXO) and primarily FOXO3. Additional ex vivo studies and in vitro experiments using human NPCs exposed to METH and infected with HIV revealed upregulation of the CXCL12-CXCR4 axis, leading to activation of downstream pAkt and pErk, the pathways that can phosphorylate FOXO3 and force its exports from the nuclei into the cytoplasm. Indeed, nuclear expulsion of FOXO3 was demonstrated both in mice exposed to METH and infected with EcoHIV and in cell cultures of human NPCs. These results provide novel information that exposure to METH combined with HIV infection can induce aberrant proliferation of SVZ-derived NPCs and identifies CXCL12-CXCR4-Akt-1-mediated phosphorylation of FOXO3 as the mechanism responsible for this effect.

Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review.

Despite evidence of premature, accentuated and accelerated aging for some age-related conditions such as cardiovascular diseases in people living with HIV (PLHIV), the evidence for these abnormal patterns of aging on neurocognition remains unclear. Further, no systematic review has been dedicated to this issue. Using PRISMA guidelines, we searched standard databases (PubMed, EMBASE, CINAHL and PsycINFO). Articles were included if they analyzed and reported the effect of age on neurocognition among PLHIV as one of their major findings, if they were conducted in the combination anti-retroviral therapy era (after 1996) and published in a peer-reviewed journal in English. Quality appraisal was conducted using the Joanna Briggs Institute (JBI) appraisal tools. To systematically target the abnormal patterns of neurocognitive aging, we define premature cognitive aging as significant interaction effect of HIV status and age on cross-sectional neurocognitive test performance covering both the normal and abnormal performance range; accentuated cognitive aging as significant interaction effect of HIV status and age on cross-sectional neurocognitive impairment (NCI) rate, thus covering the abnormal performance range only; accelerated cognitive aging as significant interaction effect of HIV status and age on longitudinal neurocognitive test performance or incidence of NCI. Because these definitions require an age-comparable HIV-negative (HIV-) control group, when no controls were included, we determined the range of the age effect on neurocognitive test performance or NCI among PLHIV. A total of 37 studies originating from the US (26), UK (2), Italy (2), Poland (2), China (2), Japan (1), Australia (1), and Brazil (1) were included. Six studies were longitudinal and 14 included HIV- controls. The quality appraisal showed that 12/37 studies neither used an age-matched HIV- controls nor used demographically corrected cognitive scores. A meta-analysis was not possible because study methods and choice of neurocognitive measurement methods and outcomes were heterogeneous imposing a narrative synthesis. In studies with an HIV- control sample, premature neurocognitive aging was found in 45% of the cross-sectional analyses (9/20), while accelerated neurocognitive aging was found in 75% of the longitudinal analyses (3/4). There was no evidence for accentuated aging, but this was tested only in two studies. In studies without an HIV- control sample, the age effect was always present but wide (NCI OR = 1.18-4.8). While large sample size (> 500) was associated with abnormal patterns of cognitive aging, most of the studies were under powered. Other study characteristics such as longitudinal study design and higher proportion of older participants were also associated with the findings of abnormal cognitive aging. There is some support for premature and accelerated cognitive aging among PLHIV in the existing literature especially among large and longitudinal studies and those with higher proportion of older samples. Future HIV and cognitive aging studies need to harmonize neuropsychological measurement methods and outcomes and use a large sample from collaborative multi-sites to generate more robust evidences.

Validation of a rapid and easy-to-perform screening test for neurocognitive impairment in HIV+ patients.

OBJECTIVE: Information Processing Speed (IPS) is one of the earliest cognitive domains impaired in both multiple sclerosis (MS) and HIV-infected patients. Our aim was to study whether the Computerized Speed Cognitive Test (CSCT), an ultra-rapid tool which detects IPS impairment and is already used in MS subjects, could also be useful to screen for HIV-associated neurocognitive disorders (HAND). METHODS: The Neuracog study was an open-label prospective trial conducted in Nice and Cannes hospitals. Each patient performed a wide range of neuropsychological (NP) tests. Patients were defined as no-HAND or HAND. Groups were compared to measure sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CSCT for detecting HAND. RESULTS: Eighty-six subjects were included (26 women, 60 men, mean age: 53.1 years). HAND was diagnosed in 67/86 patients. The CSCT z-score showed a highly significant difference between the no-HAND and the HAND groups (No HAND mean: -0.1, SD: 1.0 versus HAND mean: -1.1, SD: 1.6; p = .002). The sensitivity, specificity, PPV and NPV were 81%, 53%, 86% and 43%, respectively. CONCLUSIONS: The CSCT is an easy-to-perform test allowing detection of mild forms of HAND, to be considered among screening tools for neurocognitive impairment.

Proceedings of the 2017 ISEV symposium on "HIV, NeuroHIV, drug abuse, & EVs".

Despite the success of combination antiretroviral therapy (cART), there is increased prevalence of HIV-associated neurocognitive disorders (HAND) in HIV-1-infected individuals on cART, which poses a major health care challenge. Adding further complexity to this long-term antiretroviral use is the comorbidity with drugs of abuse such as morphine, cocaine, and methamphetamine, which can in turn, exacerbate neurologic and cognitive deficits associated with HAND. Furthermore, HIV proteins, such as the transactivator of transcription (Tat) and the envelope protein (gp120), as well as antiretrovirals themselves can also contribute to the progression of neurodegeneration underlying HAND. In the field of NeuroHIV and drug addiction, EVs hold the potential to serve as biomarkers of cognitive dysfunction, targets of therapy, and as vehicles for therapeutic delivery of agents that can ameliorate disease pathogenesis. Based on the success of a previous Satellite Symposium in 2015 at the ISEV meeting in Washington, experts again expanded on their latest research findings in the field, shedding light on the emerging trends in the field of Extracellular Vesicle (EV) biology in NeuroHIV and drug abuse. The satellite symposium sought to align experts in the fields of NeuroHIV and drug abuse to share their latest insights on the role of EVs in regulating neuroinflammation, neurodegeneration, peripheral immune response, and HIV latency in HIV-infected individuals with or without the comorbidity of drug abuse.

HIV and drug abuse mediate astrocyte senescence in a ß-catenin-dependent manner leading to neuronal toxicity.

Emerging evidence suggests that cell senescence plays an important role in aging-associated diseases including neurodegenerative diseases. HIV leads to a spectrum of neurologic diseases collectively termed HIV-associated neurocognitive disorders (HAND). Drug abuse, particularly methamphetamine (meth), is a frequently abused psychostimulant among HIV+ individuals and its abuse exacerbates HAND. The mechanism by which HIV and meth lead to brain cell dysregulation is not entirely clear. In this study, we evaluated the impact of HIV and meth on astrocyte senescence using in vitro and several animal models. Astrocytes constitute up to 50% of brain cells and play a pivotal role in marinating brain homeostasis. We show here that HIV and meth induce significant senescence of primary human fetal astrocytes, as evaluated by induction of senescence markers (ß-galactosidase and p16INK4A ), senescence-associated morphologic changes, and cell cycle arrest. HIV- and meth-mediated astrocyte senescence was also demonstrated in three small animal models (humanized mouse model of HIV/NSG-huPBMCs, HIV-transgenic rats, and in a meth administration rat model). Senescent astrocytes in turn mediated neuronal toxicity. Further, we show that ß-catenin, a pro-survival/proliferation transcriptional co-activator, is downregulated by HIV and meth in human astrocytes and this downregulation promotes astrocyte senescence while induction of ß-catenin blocks HIV- and meth-mediated astrocyte senescence. These studies, for the first time, demonstrate that HIV and meth induce astrocyte senescence and implicate the ß-catenin pathway as potential therapeutic target to overcome astrocyte senescence.

Emerging roles of extracellular vesicles in neurodegenerative disorders: focus on HIV-associated neurological complications.

Exosomes are membrane-enriched extracellular vesicles with a proposed diameter in the range of 30-100 nm. They are released during both normal homeostasis as well as under pathological conditions by most cell types. In recent years, there has been robust interest in the study of these vesicles as conduits for the delivery of information between cells in both analogous as well as disparate tissues. Their ability to transport specialized cargo including signaling mediators, proteins, messenger RNA and miRNAs characterizes these vesicles as primary facilitators of cell-to-cell communication and regulation. Exosomes have also been demonstrated to have important roles in the field of cancer biology and metastasis. More recently, their role in several neurodegenerative disorders has been gaining increased momentum as these particles have been shown to promote the spread of toxic factors such as amyloid beta and prions, adding further validity to their role as important regulators of disease pathogenesis. This review briefly summarizes current findings and thoughts on exosome biology in the context of neurodegenerative disorders and the manipulation of these particles for the development of potential therapeutic strategies.

Depression and diagnosis of neurocognitive impairment in HIV-positive patients.

Neurocognitive impairment (NCI) is frequently observed in patients infected with human immunodeficiency virus (HIV) and results from the compromise of subcortical brain structures by the virus. The manifestations of NCI range from asymptomatic impairment to dementia. In addition to cognitive impairment resulting from HIV infection, other factors such as depression are associated with the loss of cognitive functions. The aim of this study was to estimate the prevalence of NCI in HIV-positive patients in a city in southern Brazil and to establish possible associations for the prevalence of NCI with HIV-related and other risk factors. This cross-sectional study of HIV-positive outpatients was conducted in a specialized care service in the city of Pelotas in Southern Brazil. Sociodemographic data and HIV-related information were collected, and all patients underwent psychiatric and neurocognitive evaluations. The prevalence of NCI among the 392 patients was 54.1% when tracked using the IHDS (International HIV Dementia Scale) and 36.2% when the IHDS was associated with a battery of complementary tests. A bivariate analysis suggested an association of NCI with gender, age, educational level, depression, current CD4 count and lowest CD4 count. The association of NCI with depression remained in the Poisson regression (PR=1.96, 95%CI=1.12-3.42). The prevalence of cognitive impairment in HIV-positive patients estimated in this study is in accordance with international and Brazilian data. Of the factors analyzed, depression showed the greatest evidence of association with neurocognitive loss. Based on our findings, the inclusion of instruments to evaluate depression in our services for patients with HIV and acquired immunodeficiency syndrome (AIDS) is recommended.

Macrophage secretome from women with HIV-associated neurocognitive disorders.

PURPOSE: Thirty to 50% of HIV patients develop HIV-associated neurocognitive disorders (HANDs) despite combined antiretroviral therapy. HIV-1-infected macrophages release viral and cellular proteins that induce neuronal degeneration and death. We hypothesize that changes in the macrophage secretome of HIV-1 seropositive patients with HAND may dissect proteins related to neurotoxicity. EXPERIMENTAL DESIGN: Monocyte-derived macrophages (MDMs) were isolated from the peripheral blood of 12 HIV+ and four HIV- women characterized for neurocognitive function. Serum-free MDM supernatants were collected for protein isolation and quantification with iTRAQ® labeling. Protein identification was performed using a LTQ Orbitrap Velos mass spectrometer and validated in MDM supernatants and in plasma using ELISA. RESULTS: Three proteins were different between normal cognition (NC) and asymptomatic neurocognitive disorders (ANI), six between NC and HIV-associated dementia (HAD), and six between NC and HAD. Among these, S100A9 was decreased in plasma from patients with ANI, and metalloproteinase 9 was decreased in the plasma of all HIV+ patients regardless of cognitive status, and was significantly reduced in supernatant of MDM isolated from patients with ANI. CONCLUSIONS AND CLINICAL RELEVANCE: S100A9 and metalloproteinase 9 have been associated with inflammation and cognitive impairment, and therefore represent potential targets for HAND treatment.

Depression and diagnosis of neurocognitive impairment in HIV-positive patients

Neurocognitive impairment (NCI) is frequently observed in patients infected with human immunodeficiency virus (HIV) and results from the compromise of subcortical brain structures by the virus. The manifestations of NCI range from asymptomatic impairment to dementia. In addition to cognitive impairment resulting from HIV infection, other factors such as depression are associated with the loss of cognitive functions. The aim of this study was to estimate the prevalence of NCI in HIV-positive patients in a city in southern Brazil and to establish possible associations for the prevalence of NCI with HIV-related and other risk factors. This cross-sectional study of HIV-positive outpatients was conducted in a specialized care service in the city of Pelotas in Southern Brazil. Sociodemographic data and HIV-related information were collected, and all patients underwent psychiatric and neurocognitive evaluations. The prevalence of NCI among the 392 patients was 54.1% when tracked using the IHDS (International HIV Dementia Scale) and 36.2% when the IHDS was associated with a battery of complementary tests. A bivariate analysis suggested an association of NCI with gender, age, educational level, depression, current CD4 count and lowest CD4 count. The association of NCI with depression remained in the Poisson regression (PR=1.96, 95%CI=1.12-3.42). The prevalence of cognitive impairment in HIV-positive patients estimated in this study is in accordance with international and Brazilian data. Of the factors analyzed, depression showed the greatest evidence of association with neurocognitive loss. Based on our findings, the inclusion of instruments to evaluate depression in our services for patients with HIV and acquired immunodeficiency syndrome (AIDS) is recommended.

An unusual and challenging case of HIV-associated primary CNS Lymphoma with Hodgkin-like morphology and HIV encephalitis.

HIV-associated primary CNS lymphomas are well-recognized, almost exclusively EBV-driven neoplasms with poor clinical prognosis. We report a challenging, atypical case of an HIV-associated lymphoproliferative disorder with unusual morphologic features reminiscent of Hodgkin Lymphoma, accompanied by HIV encephalitis. A 52-year-old male presented with acute seizures after seven months of progressive neurocognitive decline that was clinically diagnosed as progressive supranuclear palsy. Clinical work-up revealed HIV infection along with two ring-enhancing lesions in the brain on MRI, and negative CSF EBV testing. Subsequent biopsy showed well-demarcated hypercellular regions in the brain comprised of scattered Reed-Sternberg-like cells in a background of small to medium-sized lymphocytes exhibiting focal angiocentricity and geographic necrosis. The atypical cells were positive for CD20, EBV, and CD79a, and negative for CD45, GFAP, CD15, CD30, and p24. These cells were admixed with numerous CD68-positive cells. The adjacent brain showed classic features of HIV encephalitis with perivascular, CD68 and p24-positive multinucleated giant cells. This case illustrates several diagnostic pitfalls in the work-up of HIV-associated brain lesions, as well as reporting a unique histomorphology for an HIV-related primary CNS lymphoproliferative disorder.

Interdisciplinary Differential Diagnosis and Care of a Patient with Atypical Delusional Parasitosis due to early HIV-related Dementia.

OBJECTIVE: To provide a differential diagnosis and recommendations for care for an individual with suspected delusional parasitosis secondary to human immunodeficiency virus (HIV). METHOD: A 62-year-old male with sexually acquired, chronic, and well-managed HIV infection was referred for neuropsychological evaluation and treatment recommendations following extensive self-manipulation of a sternoclavicular cystic mass and superficial skin lesions over most of his body. The patient reported that he had pulled long calcified tendrils out of the mass over a period of several weeks and that "encapsulated fat" was flowing beneath his skin. RESULTS: Numerous lab panels were negative for any acute medical pathology. Clinical neuroimaging was unremarkable. Neuropsychological evaluation revealed a profile consistent with mild neurocognitive disorder due to HIV. Medical and behavioral recommendations were made for the management of delusional thought processes consistent with atypical delusional parasitosis and other symptoms. The patient was responsive to carefully crafted provider feedback and his delusional and somatic symptoms decreased significantly with risperidone. CONCLUSIONS: This case illustrates the utility of neuropsychological assessment and provider feedback in the diagnosis and care of HIV-related neurocognitive disorder, the context of a delusional disorder.

Cortical neurons are a prominent source of the proinflammatory cytokine osteopontin in HIV-associated neurocognitive disorders.

The proinflammatory cytokine osteopontin (OPN) is elevated in the cerebrospinal fluid (CSF) in individuals with HIV-associated neurocognitive disorders (HAND) and remains so in those on suppressive antiretroviral therapy. To understand the pathophysiological significance of elevated OPN in the CNS, we sought to determine the cellular source of this cytokine. As HIV-1 replicates productively in macrophages/microglia, we tested whether these cells are the predominant producers of OPN in the brain. Stringent patient selection criteria, which excluded brain tissues from those with evidence of drug abuse and dependence, were used. Uninfected normal controls, amyotrophic lateral sclerosis (ALS), HIV+ asymptomatic neurocognitive impairment (ANI), and HIV+ mild neurocognitive disorder (MND)/HIV-associated dementia (HAD) groups were included. Double-label immunohistochemistry for CNS cells and OPN was used to quantify OPN expression in astrocytes, macrophages/microglia, and neurons. While resident macrophages/microglia expressed OPN, astrocytes and unexpectedly neurons were also a major source of OPN. OPN levels in ionized Ca(2+)-binding adapter 1 (Iba1)/allograft inflammatory factor-1 (AIF-1)+ microglia in HIV+ ANI and MND/HAD exceeded those of HIV-negative controls and were comparable to expression seen in ALS. Moreover, in neurons, OPN was expressed at the highest levels in the HIV+ ANI group. These findings suggest that while infiltrating HIV-infected macrophages are most likely the initial source of OPN, resident CNS cells become activated and also express this inflammatory cytokine at significant levels. Moreover, as OPN levels are elevated compared to uninfected individuals and increases with the severity of impairment, it appears that the expression of OPN is persistent and sustained within the brain parenchyma in those that progress to HAND.

Demencia en pacientes adultos con síndrome de inmunodeficiencia adquirida, atendidos en el Hospital Mario Catarino Rivas / Dementia in adult patients with acquired immunodeficiency syndrome treated at Hospital Mario Catarino Rivas

Introducción: La demencia asociada al virus de inmunodeficiencia humana (D-VIH) es un tipo de demencia subcortical debido a infecciones crónicas por VIH; y combina alteraciones cognitivas, motoras y conductuales, afectando del 20 al 30% de los pacientes adultos que sufren esta enfermedad. La Escala de Demencia por VIH (EDV) es una herramienta sensible que se utiliza para tamizaje de pacientes infectados por VIH y con riesgo de desarrollar demencia. Objetivos. Aplicar la EDV en pacientes con infección avanzada por VIH que asistían al Centro de Atención Integral (CAI) del Hospital Mario Catarino Rivas (HMCR) y analizar su relación con el conteo de células TCD4 <200. Metodología. Se trata de un estudio cuantitativo, descriptivo, de corte transversal con un muestreo intencionado. En el estudio se incluyó pacientes mayores de 18 años con VIH confirmado, quienes asisten al CAI, alfabetos, con conteo reciente de linfocitos CD4 menor de 200 células y que consintieron participar en el estudio. Se les aplicó la EDV como tamizaje para evaluar su función mental. Resultados. El 81% de los pacientes entrevistados presentaron riesgo de D-VIH con un rango de edad de mayor prevalencia entre 38 y 57 años, siendo el género femenino el de mayor riesgo. Conclusión de acuerdo a los resultados obtenidos, la EDV es una herramienta costo-efectiva para determinar la función cognitiva en los pacientes...(AU)

Neurologic diseases in HIV-infected patients.

Since the introduction of highly active antiretroviral therapy there has been an improvement in the quality of life for people with HIV infection. Despite the progress made, about 70% of HIV patients develop neurologic complications. These originate either in the central or the peripheral nervous system (Sacktor, 2002). These neurologic disorders are divided into primary and secondary disorders. The primary disorders result from the direct effects of the virus and include HIV-associated neurocognitive disorder (HAND), HIV-associated vacuolar myelopathy (VM), and distal symmetric polyneuropathy (DSP). Secondary disorders result from marked immunosuppression and include opportunistic infections and primary central nervous system lymphoma (PCNSL). A differential diagnosis which can be accomplished by detailed history, neurologic examination, and by having a good understanding of the role of HIV in various neurologic disorders will help physicians in approaching these problems. The focus of this chapter is to discuss neuropathogenesis of HIV, the various opportunistic infections, primary CNS lymphoma, neurosyphilis, CNS tuberculosis, HIV-associated peripheral neuropathies, HIV-associated neurocognitive disorder (HAND), and vacuolar myelopathy (VM). It also relies on the treatment recommendations and guidelines for the above mentioned neurologic disorders proposed by the US Centers for Disease Control and Prevention (CDC) and the Infectious Diseases Society of America.

Routine detection and management of neurocognitive impairment in HIV-positive patients in a UK centre.

We estimated the burden of HIV-associated neurocognitive disorders (HAND) in a UK clinic. From a random sample, and referrals to specialist services over one year (neurology, clinical psychology, hospital admissions), we determined whether patients were diagnosed with HIV-associated dementia (HAD) and whether they reported symptoms suggesting neurocognitive impairment (NCI). In the first sample, 2/150 (prevalence 1.3%; 95% confidence interval [CI] 0.2-4.7%) had documented HAD. Eleven patients (7.3%; CI 3.7-12.7%) reported recent symptoms suggesting NCI; most of these individuals were diagnosed with a psychiatric or substance-use disorder. Among specialist referrals with symptoms suggesting NCI, 11 were diagnosed with HAD from a clinic population of 3129 individuals (annual incidence 0.4%; CI 0.2-0.6%). No patients with mildly symptomatic or asymptomatic HAND were identified in either sample, suggesting that such patients remain undetected in current clinical practice. Evidence-based screening for HAND in HIV clinics may be needed.

Genome-wide association study of neurocognitive impairment and dementia in HIV-infected adults.

The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. Candidate gene studies have implicated genetic susceptibility loci within immune-related genes; however, these have not been reliably validated. Here, we employed genome-wide association (GWA) methods to discover novel genetic susceptibility loci associated with HAND, and validate susceptibility loci implicated in prior candidate gene studies. Data from 1,287 participants enrolled in the Multicenter AIDS Cohort Study between 1985 and 2010 were used. Genotyping was conducted with Illumina 1M, 1MDuo, or 550K platform. Linear mixed models determined subject-specific slopes for change over time in processing speed and executive functioning, considering all visits including baseline and the most recent study visit. Covariates modeled as fixed effects included: time since the first visit, depression severity, nadir CD4+ T-cell count, hepatitis C co-infection, substance use, and antiretroviral medication regimen. Prevalence of HIV-associated dementia (HAD) and neurocognitive impairment (NCI) was also examined as neurocognitive phenotypes in a case-control analysis. No genetic susceptibility loci were associated with decline in processing speed or executive functioning among almost 2.5 million single nucleotide polymorphisms (SNPs) directly genotyped or imputed. No association between the SNPs and HAD or NCI were found. Previously reported associations between specific genetic susceptibility loci, HIV-associated NCI, and HAD were not validated. In this first GWAS of HAND, no novel or previously identified genetic susceptibility loci were associated with any of the phenotypes examined. Due to the relatively small sample size, future collaborative efforts that incorporate this dataset may still yield important findings.

Impact of HIV and aging on neuropsychological function.

Cognitive efficiency decreases with age, and advancing age is the leading risk factor for most neurodegenerative disorders that result in dementia. In HIV infection, risk for cognitive impairment is consistently linked to advancing chronological age. As the HIV epidemic enters its fourth decade in the USA, extended life expectancy will likely result in an increased prevalence of cognitive disorders by virtue of these factors. However, it is less clear if HIV potentiates or accelerates the risk for cognitive impairment given that most reports are mixed or demonstrate only a small interaction effect. More critically, it is unclear if HIV will modulate the neuropathology associated with non-HIV cognitive disorders in a manner that will increase risk for diseases such as cerebrovascular and Alzheimer's disease. In the coming years, with increasing numbers of HIV+ patients entering their 60s and 70s, background risk for neurodegenerative disorders will be sufficiently high as to inform this issue on clinical grounds. This review summarizes knowledge of cognition in HIV as it relates to age and presents some emerging controversies.

Rodent models of HAND and drug abuse: exogenous administration of viral protein(s) and cocaine.

Humans and chimpanzees are the natural hosts for HIV. Non-human primate models of SIV/SHIV infection in rhesus, cynomologus and pigtail macaques have been used extensively as excellent model systems for pathogenesis and vaccine studies. However, owing to the variability of disease progression in infected macaques, a phenomenon identical to humans, coupled with their prohibitive costs, there exists a critical need for the development of small-animal models in which to study the untoward effects of HIV-1 infection. Owing to the fact that rodents are not the natural permissive hosts for lentiviral infection, development of small animal models for studying virus infection has used strategies that circumvent the steps of viral entry and infection. Such strategies involve overexpression of toxic viral proteins, SCID mice engrafted with the human PBLs or macrophages, and EcoHIV chimeric virus wherein the gp120 of HIV-1 was replaced with the gp80 of the ecotropic murine leukemia virus. Additional strategy that is often used by investigators to study the toxic effect of viral proteins involves direct stereotactic injection of the viral protein(s) into specific brain regions. The present report is a compilation of the applications of direct administration of Tat into the striatum to mimic the effects of the viral neurotoxin in the CNS. Added advantage of this model is that it is also amenable to repeated intraperitoneal cocaine injections, thereby allowing the study of the additive/synergistic effects of both the viral protein and cocaine. Such a model system recapitulates aspects of HAND in the context of drug abuse.

Role of obesity, metabolic variables, and diabetes in HIV-associated neurocognitive disorder.

OBJECTIVE: To evaluate relationships between HIV-associated neurocognitive disorder and metabolic variables in a subgroup of HIV+ participants examined in a prospective, observational, multicenter cohort study. METHODS: In a cross-sectional substudy of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, 130 HIV+ participants provided fasting blood samples. Neurocognitive impairment (NCI) was defined by performance on neuropsychological tests adjusting for age, education, gender, and race/ethnicity. Global ratings and global deficit scores were determined. Demographics, biomarkers of HIV disease, metabolic variables, combination antiretroviral therapy (CART) history, other drug exposures, and self-reported diabetes were examined in multivariate models predicting NCI. Separate models were used for body mass index (BMI) alone (n = 90) and BMI and waist circumference (WC) together (n = 55). RESULTS: NCI (global impairment rating ≥5) was diagnosed in 40%. In univariate analyses, age, longer duration of HIV infection, obesity, and WC, but not BMI, were associated with NCI. Self-reported diabetes was associated with NCI in the substudy and in those >55 in the entire CHARTER cohort. Multivariate logistic regression analyses demonstrated that central obesity (as measured by WC) increased the risk of NCI and that greater body mass may be protective if the deleterious effect of central obesity is accounted for. CONCLUSIONS: As in HIV-uninfected persons, central obesity, but not more generalized increases in body mass (BMI), was associated with a higher prevalence of NCI in HIV+ persons. Diabetes appeared to be associated with NCI only in older patients. Avoidance of antiretroviral drugs that induce central obesity might protect from or help to reverse neurocognitive impairment in HIV-infected persons.

Reliability of the lay adherence counsellor administered substance abuse and mental illness symptoms screener (SAMISS) and the International HIV Dementia Scale (IHDS) in a primary care HIV clinic in Cape Town, South Africa.

HIV infection is associated with an increased prevalence of common mental disorders and with the development of HIV associated neurological disorders (HAND). The aim of this research was to determine the reliability of lay adherence counsellors in the administration of the substance abuse and mental illness symptom screener (SAMISS) for common mental disorders and International HIV Dementia Scale (IHDS) for HAND in a South African sample of 269 people living with HIV/AIDS and on HAART in a primary healthcare setting. We used a cross-sectional design with each patient assessed by a mental health nurse and counsellor, 1 week apart. Reliability was fair for the SAMISS overall (κ = 0.39, CI(95) 0.29-0.49, P < 0.01), but was higher for the substance abuse component compared to the mental illness component. Reliability for the IHDS between counsellors and nurses was slight (κ = 0.11, CI(95) 0.00-0.27, P < 0.02). Counsellors tended not to miss symptoms, and detected symptoms more often than nurses for the both the SAMISS and IHDS. Strategies to improve the ability of primary healthcare providers to screen for neurocognitive disorders as well as avoiding over-detection of mental illness and substance abuse symptoms need to be developed and implemented for the primary healthcare setting.