Extracellular Vesicles and HIV-Associated Neurocognitive Disorders: Implications in Neuropathogenesis and Disease Diagnosis.

Extracellular vesicles are heterogeneous cell-derived membranous structures of nanometer size that carry diverse cargoes including nucleic acids, proteins, and lipids. Their secretion into the extracellular space and delivery of their cargo to recipient cells can alter cellular function and intracellular communication. In this review, we summarize the role of extracellular vesicles in the disease pathogenesis of HIV-associated neurocognitive disorder (HAND) by focusing on their role in viral entry, neuroinflammation, and neuronal degeneration. We also discuss the potential role of extracellular vesicles as biomarkers of HAND. Together, this review aims to convey the importance of extracellular vesicles in the pathogenesis of HAND and foster interest in their role in neuroinflammatory diseases.

Application of Data Mining Algorithms for Dementia in People with HIV/AIDS.

Dementia interferes with the individual's motor, behavioural, and intellectual functions, causing him to be unable to perform instrumental activities of daily living. This study is aimed at identifying the best performing algorithm and the most relevant characteristics to categorise individuals with HIV/AIDS at high risk of dementia from the application of data mining. Principal component analysis (PCA) algorithm was used and tested comparatively between the following machine learning algorithms: logistic regression, decision tree, neural network, KNN, and random forest. The database used for this study was built from the data collection of 270 individuals infected with HIV/AIDS and followed up at the outpatient clinic of a reference hospital for infectious and parasitic diseases in the State of Ceará, Brazil, from January to April 2019. Also, the performance of the algorithms was analysed for the 104 characteristics available in the database; then, with the reduction of dimensionality, there was an improvement in the quality of the machine learning algorithms and identified that during the tests, even losing about 30% of the variation. Besides, when considering only 23 characteristics, the precision of the algorithms was 86% in random forest, 56% logistic regression, 68% decision tree, 60% KNN, and 59% neural network. The random forest algorithm proved to be more effective than the others, obtaining 84% precision and 86% accuracy.

HIV-1 Vpr protein impairs lysosome clearance causing SNCA/alpha-synuclein accumulation in neurons.

Despite the promising therapeutic effects of combinatory antiretroviral therapy (cART), 20% to 30% of HIV/AIDS patients living with long term infection still exhibit related cognitive and motor disorders. Clinical studies in HIV-infected patients revealed evidence of basal ganglia dysfunction, tremors, fine motor movement deficits, gait, balance, and increased risk of falls. Among older HIV+ adults, the frequency of cases with SNCA/α-synuclein staining is higher than in older healthy persons and may predict an increased risk of developing a neurodegenerative disease. The accumulation of SNCA aggregates known as Lewy Bodies is widely described to be directly linked to motor dysfunction. These aggregates are naturally removed by Macroautophagy/autophagy, a cellular housekeeping mechanism, that can be disturbed by HIV-1. The molecular mechanisms involved in linking HIV-1 proteins and autophagy remain mostly unclear and necessitates further exploration. We showed that HIV-1 Vpr protein triggers the accumulation of SNCA in neurons after decreasing lysosomal acidification, deregulating lysosome positioning, and the expression levels of several proteins involved in lysosomal maturation. Viruses and retroviruses such as HIV-1 are known to manipulate autophagy in order to use it for their replication while blocking the degradative final step, which could destroy the virus itself. Our study highlights how the suppression of neuronal autophagy by HIV-1 Vpr is a mechanism leading to toxic protein aggregation and neurodegeneration.Abbreviations: BLOC1: Biogenesis of Lysosome-related Organelles Complex 1; CART: combinatory antiretroviral therapy; CVB: coxsackievirus; DAPI: 4',6-diamidino-2-phenylindole; DENV: dengue virus; GFP: green fluorescent protein; HCV: hepatitis C virus; HCMV: human cytomegalovirus; HIV: human immunodeficiency virus; Env: HIV-1 envelope glycoproteins; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; VSV: Indiana vesiculovirus; LTR: Long Terminal Repeat; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MLBs: multilamellar bodies; RIPA: Radioimmunoprecipitation assay buffer; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; Tat: transactivator of TAR; TEM: transmission electron microscope; Vpr: Viral protein R.

Reductions in Gray Matter Linked to Epigenetic HIV-Associated Accelerated Aging.

A growing literature suggests a relationship between HIV-infection and a molecular profile of age acceleration. However, despite the widely known high prevalence of HIV-related brain atrophy and HIV-associated neurocognitive disorder (HAND), epigenetic age acceleration has not been linked to HIV-related changes in structural MRI. We applied morphological MRI methods to study the brain structure of 110 virally suppressed participants with HIV infection and 122 uninfected controls age 22-72. All participants were assessed for cognitive impairment, and blood samples were collected from a subset of 86 participants with HIV and 83 controls to estimate epigenetic age. We examined the group-level interactive effects of HIV and chronological age and then used individual estimations of epigenetic age to understand the relationship between age acceleration and brain structure. Finally, we studied the effects of HAND. HIV-infection was related to gray matter reductions, independent of age. However, using epigenetic age as a biomarker for age acceleration, individual HIV-related age acceleration was associated with reductions in total gray matter. HAND was associated with decreases in thalamic and hippocampal gray matter. In conclusion, despite viral suppression, accentuated gray matter loss is evident with HIV-infection, and greater biological age acceleration specifically relates to such gray matter loss.

Cerebral Vascular Toxicity of Antiretroviral Therapy.

HIV infection is associated with comorbidities that are likely to be driven not only by HIV itself, but also by the toxicity of long-term use of antiretroviral therapy (ART). Indeed, increasing evidence demonstrates that the antiretroviral drugs used for HIV treatment have toxic effects resulting in various cellular and tissue pathologies. The blood-brain barrier (BBB) is a modulated anatomophysiological interface which separates and controls substance exchange between the blood and the brain parenchyma; therefore, it is particularly exposed to ART-induced toxicity. Balancing the health risks and gains of ART has to be considered in order to maximize the positive effects of therapy. The current review discusses the cerebrovascular toxicity of ART, with the focus on mitochondrial dysfunction. Graphical Abstract Graphical representation of the interactions between HIV, antiretroviral therapy (ART), and the blood-brain barrier (BBB).

Functional deficits and other psychiatric associations with abnormal scores on the Montreal Cognitive Assessment (MoCA) in older HIV-infected patients.

OBJECTIVE: The authors assessed the association of physical function, social variables, functional status, and psychiatric co-morbidity with cognitive function among older HIV-infected adults. DESIGN: From 2012-2014, a cross-sectional study was conducted among HIV-infected patients ages 50 or older who underwent comprehensive clinical geriatric assessment. SETTING: Two San Francisco HIV clinics. PARTICIPANTS: 359 HIV-infected patients age 50 years or older. MEASUREMENTS: Unadjusted and adjusted Poisson regression measured prevalence ratios and 95% confidence intervals for demographic, functional and psychiatric variables and their association with cognitive impairment using a Montreal Cognitive Assessment (MoCA) score < 26 as reflective of cognitive impairment. RESULTS: Thirty-four percent of participants had a MoCA score of < 26. In unadjusted analyses, the following variables were significantly associated with an abnormal MoCA score: born female, not identifying as homosexual, non-white race, high school or less educational attainment, annual income < $10,000, tobacco use, slower gait speed, reported problems with balance, and poor social support. In subsequent adjusted analysis, the following variables were significantly associated with an abnormal MoCA score: not identifying as homosexual, non-white race, longer 4-meter walk time, and poor social support. Psychiatric symptoms of depressive, anxiety, and post-traumatic stress disorders did not correlate with abnormal MoCA scores. CONCLUSIONS: Cognitive impairment remains common in older HIV-infected patients. Counter to expectations, co-morbid psychiatric symptoms were not associated with cognitive impairment, suggesting that cognitive impairment in this sample may be due to neurocognitive disorders, not due to other psychiatric illness. The other conditions associated with cognitive impairment in this sample may warrant separate clinical and social interventions to optimize patient outcomes.

White matter loss and oligodendrocyte dysfunction in HIV: A consequence of the infection, the antiretroviral therapy or both?

While the severe cognitive effects of HIV-associated dementia have been reduced by combined antiretroviral therapy (cART), nearly half of HIV-positive (HIV+) patients still suffer from some form of HIV-Associated Neurocognitive Disorders (HAND). While frank neuronal loss has been dramatically reduced in HAND patients, white matter loss, including dramatic thinning of the corpus callosum, and loss of volume and structural integrity of myelin persists despite viral control by cART. It remains unclear whether changes in white matter underlie the clinical manifestation seen in patients or whether they are the result of persistent viral reservoirs, remnant damage from the acute infection, the antiretroviral compounds used to treat HIV, secondary effects due to peripheral toxicities or other associated comorbid conditions. Both HIV infection itself and its treatment with antiretroviral drugs can induce metabolic syndrome, lipodystrophy, atherosclerosis and peripheral neuropathies by increased oxidative stress, induction of the unfolded protein response and dysregulation of lipid metabolism. These virally and/or cART-induced processes can also cause myelin loss in the CNS. This review aims to highlight existing data on the contribution of white matter damage to HAND and explore the mechanisms by which HIV infection and its treatment contribute to persistence of white matter changes in people living with HIV currently on cART.

Heterogeneity in neurocognitive change trajectories among people with HIV starting antiretroviral therapy in Rakai, Uganda.

Considerable heterogeneity exists in patterns of neurocognitive change in people with HIV (PWH). We examined heterogeneity in neurocognitive change trajectories from HIV diagnosis to 1-2 years post-antiretroviral therapy (ART). In an observational cohort study in Rakai, Uganda, 312 PWH completed a neuropsychological (NP) test battery at two-time points (ART-naïve, 1-2 years post-ART initiation). All NP outcomes were used in a latent profile analysis to identify subgroups of PWH with similar ART-related neurocognitive change profiles. In a subset, we examined subgroup differences pre-ART on cytokine and neurodegenerative biomarkers CSF levels. We identified four ART-related change subgroups: (1) decline-only (learning, memory, fluency, processing speed, and attention measures), (2) mixed (improvements in learning and memory but declines in attention and executive function measures), (3) no-change, or (4) improvement-only (learning, memory, and attention measures). ART-related NP outcomes that are most likely to change included learning, memory, and attention. Motor function measures were unchanged. Subgroups differed on eight of 34 pre-ART biomarker levels including interleukin (IL)-1ß, IL-6, IL-13, interferon-γ, macrophage inflammatory protein-1ß, matrix metalloproteinase (MMP)-3, MMP-10, and platelet-derived growth factor-AA. The improvement-only and mixed subgroups showed lower levels on these markers versus the no-change subgroup. These findings provide support for the need to disentangle heterogeneity in ART-related neurocognitive changes, to focus on higher-order cognitive processes (learning, memory, attention) as they were most malleable to change, and to better understand why motor function remained unchanged despite ART treatment. Group differences in pre-ART CSF levels provide preliminary evidence of biological plausibility of neurocognitive phenotyping.

Circulating LPS and (1→3)-ß-D-Glucan: A Folie à Deux Contributing to HIV-Associated Immune Activation.

Immune activation is the driving force behind the occurrence of AIDS and non-AIDS events, and is only partially reduced by antiretroviral therapy (ART). Soon after HIV infection, intestinal CD4+ T cells are depleted leading to epithelial gut damage and subsequent translocation of microbes and/or their products into systemic circulation. Bacteria and fungi are the two most abundant populations of the gut microbiome. Circulating lipopolysaccharide (LPS) and (1→3)-ß-D-Glucan (ßDG), major components of bacterial and fungal cell walls respectively, are measured as markers of microbial translocation in the context of compromised gut barriers. While LPS is a well-known inducer of innate immune activation, ßDG is emerging as a significant source of monocyte and NK cell activation that contributes to immune dysfunction. Herein, we critically evaluated recent literature to untangle the respective roles of LPS and ßDG in HIV-associated immune dysfunction. Furthermore, we appraised the relevance of LPS and ßDG as biomarkers of disease progression and immune activation on ART. Understanding the consequences of elevated LPS and ßDG on immune activation will provide insight into novel therapeutic strategies against the occurrence of AIDS and non-AIDS events.

Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer's disease?

HIV infection in the combination antiretroviral therapy (cART) era has become a chronic disease with a life expectancy almost identical to those free from this infection. Concomitantly, chronic diseases such as neurodegenerative diseases have emerged as serious clinical problems. HIV-induced cognitive changes, although clinically very diverse are collectively called HIV-associated neurocognitive disorder (HAND). HAND, which until the introduction of cART manifested clinically as a subcortical disorder, is now considered primarily cognitive disorder, which makes it similar to diseases like Alzheimer's (AD) and Parkinson's disease (PD). The pathogenesis involves either the direct effects of the virus or the effect of viral proteins such as Tat, Ggp120, and Nef. These proteins are either capable of destroying neurons directly by inducing neurotoxic mediators or by initiating neuroinflammation by microglia and astrocytes. Recently, it has become recognized that HIV infection is associated with increased production of the beta-amyloid peptide (Aß) which is a characteristic of AD. Moreover, amyloid plaques have also been demonstrated in the brains of patients suffering from HAND. Thus, the question arises whether this production of Aß indicates that HAND may lead to AD or it is a form of AD or this increase in Aß production is only a bystander effect. It has also been discovered that APP in HIV and its metabolic product Aß in AD manifest antiviral innate immune peptide characteristics. This review attempts to bring together studies linking amyloid precursor protein (APP) and Aß production in HIV infection and their possible impact on the course of HAND and AD. These data indicate that human defense mechanisms in HAND and AD are trying to contain microorganisms by antimicrobial peptides, however by employing different means. Future studies will, no doubt, uncover the relationship between HAND and AD and, hopefully, reveal novel treatment possibilities.

High prevalence of neurocognitive disorders observed among adult people living with HIV/AIDS in Southern Ethiopia: A cross-sectional study.

BACKGROUND: Comprehensive care given to people living with HIV/AIDS is improving over time; however, their concurrent cognitive illness is still ignored, under screened and treated particularly in developing countries. And this problem is also striking in Ethiopia. Therefore, the objective of this study was to assess HIV-associated neurocognitive disorders and associated factors among adult people living with HIV/AIDS. METHODS: An institution based cross sectional study was conducted from April to May, 2017 at Gamo Gofa zone public Hospitals. International HIV Dementia Scale was used to screen HIV associated neurocognitive disorders. Logistic regression analysis was used to assess predictors of neurocognitive disorders. RESULT: A total of 684 study participants were included in this study with a response rate of 98%. Among them, 56% were females while 44% were males. The mean (±SD) age of the participants was 38.8±8.8years. The screening prevalence of HIV-associated neurocognitive disorder was 67.1% (95% CI; 63.6, 70.5). Body mass index 16 kg/m2 (AOR 4.389 (1.603-12.016)), being married (AOR 0.377 (0.213-0.666), unemployment status (AOR 3.181 (1.752-5.777) and being in WHO clinical stage T3 category/advancing stages of the disease (AOR 3.558 (1.406-9.006) were the key predictors of HIV-associated neurocognitive disorders among people living with HIV/AIDS. CONCLUSION: In this study the screening prevalence of HIV-associated neurocognitive disorder is higher than the earlier reports in Ethiopia and Africa. This indicates that early screening strategies and policies for cognitive health in people living with HIV/AIDS should be given a top priority.

Chronic Intrahippocampal Infusion of HIV-1 Neurotoxic Proteins: A Novel Mouse Model of HIV-1 Associated Inflammation and Neural Stem Cell Dysfunction.

HIV-1 infection causes chronic neuroinflammation resulting in cognitive decline associated with diminution of survival of neural stem cells (NSC). In part, this is attributable to production of toxic viral proteins (gp120 and tat) by infected cells in the brain that can activate microglia. Here, we evaluated a novel model for HIV-1 neuropathogenesis by direct administration of viral proteins into the hippocampus. Chronic administration of either HIV-1 gp120 or tat over 14 days significantly decreased NSC proliferation, survival and neuroblast formation (by 32-37%) within the hippocampal subgranular zone as detected by doublecortin/BrdU or Ki67-positive cells. Intrahippocampal administration of gp120 or tat induced microglial activation within the hippocampus as determined by increases in microglial number and increases in the volume of the microglia (2.5-3-fold, evaluated by double IBA-1/CD68 staining). We further assessed inflammatory responses within the hippocampus by RNAseq and Ingenuity Pathway Analysis. There was a significant mRNA upregulation of numerous inflammatory mediators including Il1b, Icam1, Il12a, Ccl2, and Ccl4. These data suggest that chronic administration induces a prolonged inflammatory state within the hippocampus that negatively affects NSC survival potentially leading to cognitive dysfunction. Graphical Abstract.

Properties of a brief assessment tool for longitudinal measurement of cognition in people living with HIV.

BACKGROUND: Mild cognitive impairment is common in chronic HIV infection and there is concern that it may worsen with age. Distinguishing static impairment from on-going decline is clinically important, but the field lacks well-validated cognitive measures sensitive to decline and feasible for routine clinical use. Measures capable of detecting improvement are also needed to assess interventions. The objective of this study is to estimate the extent of change on repeat administration of three different forms of a brief computerized cognitive assessment battery (B-CAM) developed for assessing cognitive ability in the mildly-impaired to normal range in people living with HIV. We hypothesized no change over a six-month period in people on effective antiretroviral therapy. METHODS: 102 HIV+ individuals completed a set of computerized cognitive tasks on three occasions over a six-month period. Rasch analysis was used to determine if change over time (i.e. improvement due to practice) was uniform across tasks and to refine scoring in order to produce three forms of the B-CAM of equivalent level of difficulty. Group-based trajectory analysis (GBTA) was then applied to determine if performance at baseline influenced the magnitude of practice-related improvement on the battery as a whole over the course of follow-up. RESULTS: Two cognitive tasks (fluency and word recall) had different levels of difficulty across test sessions, related to the different forms of the tasks. These two items were split by testing session. For all other items, the level of difficulty remained constant across all three time points. GBTA showed that the sample was composed of three distinct groups of people with unique trajectories, defined mainly by level of cognitive ability at baseline. Only the highest group showed an apparent improvement over time, but this change fell within measurement error. CONCLUSIONS: Rasch analysis provides mathematical confirmation that these three forms of the B-CAM are of equivalent difficulty. GBTA demonstrates that no adjustment of the total score is required to correct for practice effects. Application of these modern statistical methods paves the way towards rapid and robust quantification of change in cognition.

Pathogenesis of age-related HIV neurodegeneration.

People over the age of 50 are the fastest growing segment of the HIV-infected population in the USA. Although antiretroviral therapy has remarkable success controlling the systemic HIV infection, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group, and cognitive deficits appear more severe in aged patients with HIV. The mechanisms of HAND in the aged population are not completely understood; a leading hypothesis is that aged individuals with HIV might be at higher risk of developing Alzheimer's disease (AD) or one of the AD-related dementias (ADRD). There are a number of mechanisms through which chronic HIV disease alone or in combination with antiretroviral therapy and other comorbidities (e.g., drug use, hepatitis C virus (HCV)) might be contributing to HAND in individuals over the age of 50 years, including (1) overlapping pathogenic mechanisms between HIV and aging (e.g., decreased proteostasis, DNA damage, chronic inflammation, epigenetics, vascular), which could lead to accelerated cellular aging and neurodegeneration and/or (2) by promoting pathways involved in AD/ADRD neuropathogenesis (e.g., triggering amyloid ß, Tau, or α-synuclein accumulation). In this manuscript, we will review some of the potential common mechanisms involved and evidence in favor and against a role of AD/ADRD in HAND.

Cognitive screening in treatment-naïve HIV-infected individuals in Hong Kong - a single center study.

BACKGROUND: HIV-associated neurocognitive disorder (HAND) remains prevalent in the era of combination antiretroviral therapy (cART). The prevalence of HAND in Hong Kong is not known. METHODS: Between 2013 and 2015, 98 treatment-naïve HIV-1-infected individuals were referred to and screened by the AIDS Clinical Service, Queen Elizabeth Hospital with (1) the International HIV Dementia Scale (IHDS), a screening tool that targets moderate to severe HAND, (2) the Montreal Cognitive Assessment (MoCA), a frequently used cognitive screening test and (3) the Patient Health Questionnare-9 (PHQ-9), a 9-item questionnaire that evaluates depression symptoms. Within the study period, 57 of them completed the second set of IHDS and MoCA at 6 months after baseline assessment. RESULTS: Most participants were male (94%), with a median age of 31 years. At baseline, 38 (39%) and 25 (26%) of them scored below the IHDS (≤10) and MoCA (25/26) cut-offs respectively. Poor IHDS performers also scored lower on MoCA (p = 0.039) but the correlation between IHDS and MoCA performance was weak (r = 0.29, p = 0.004). Up to a third of poor IHDS performers (13/38) showed moderate depression (PHQ-9 > 9). In the multivariable analysis, a lower education level (p = 0.088), a history of prior psychiatric illness (p = 0.091) and the presence of moderate depression (p = 0.079) tended to be significantly associated with poor IHDS performance. At follow-up, 54 out of 57 were on cART, of which 46 (85%) had achieved viral suppression. Their blood CD4+ T-lymphocytes and IHDS scores were higher at follow-up compared to baseline values (both p < 0.001) but their MoCA performance was similar at both assessments. Of note, 17 participants in this subgroup scored below the IHDS cut-off at both assessments. CONCLUSIONS: Poor IHDS performance, and likely cognitive impairment, was frequently observed in treatment-naïve HIV-infected individuals in our locality. A considerable proportion continued to score below the IHDS cut-off at 6 months after cART. Depression was frequently observed in this vulnerable population and was associated with poor IHDS performance.

Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics.

Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our current understanding is that HIV enters the central nervous system (CNS) during infection, persisting and replicating in resident immune and supporting cells, with the subsequent host immune response and inflammation likely adding to the development of HAND. Differences in host (human) genetics determine, in part, the effectiveness of the immune response and other factors that increase the vulnerability to HAND. This review describes findings from studies investigating the role of human host genetics in the pathogenesis of HAND, including potential risk factors for developing HAND. The similarities and differences between HAND and Alzheimer's disease are also discussed. While some specific variations in host genes regulating immune responses and neurotransmission have been associated with protection or risk of HAND development, the effects are generally small and findings poorly replicated. Nevertheless, a few specific gene variants appear to affect the risk for developing HAND and aid our understanding of HAND pathogenesis.

HIV and Aging - Perhaps Not as Dramatic as We Feared?

Ever since the introduction of highly active antiretroviral therapy (ART) in 1995, HIV infection has been linked to "metabolic" complications (insulin resistance, dyslipidemia, osteoporosis, and others). Studies suggested increased rates of myocardial infarction, renal insufficiency, neurocognitive dysfunction, and fractures in HIV-postitive patients. Even long-term suppression of HIV seemed to be accompanied by an excess of deleterious inflammation that could promote these complications. The aims of this viewpoint paper are to summarize recent data and to examine the possibility that the problem of aging-related morbidity in HIV might not be as dramatic as previously believed.

HIV Dementia with a Decreased Cardiac 123I-metaiodobenzylguanidine Uptake Masquerading as Dementia with Lewy Bodies.

Cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy is a promising biomarker for dementia with Lewy bodies (DLB). However, we experienced a patient with cognitive decline, parkinsonism, and a decreased MIBG uptake who turned out to have HIV dementia. Normal dopamine transporter single-photon emission computed tomography reduced the possibility of comorbid Lewy body pathology causing the patient' s parkinsonism. The decreased MIBG uptake was most likely due to postganglionic sympathetic nerve denervation, which can also be caused by HIV. This case further emphasizes the importance of excluding other causes of autonomic neuropathy, including HIV infection, before interpreting MIBG scans.

Dementia and behavioral disorders in progressive multifocal leukoencephalopathy (PML) ­ case report / Demência e alterações comportamentais na leucoencefalopatia multifocal progressive (LEMP) ­ relato de caso

Psychiatric disturbances in Progressive Multifocal Leukoencephalopathy (PML) are rarely adressed and its study can offer insights into the neurobiology of psychosis. The authors report a case of male patient, 42 years old, HIV positive, with PML and psychotic symptoms. The present case shows the need for regular neurological and neuropsychological evaluations of HIV positive patients and the importance of studying diseases that cause lesions in the white matter,such as PML, to elucidate the neurobiology of psychosis.(AU)

Os distúrbios psiquiátricos na Leucoencefalopatia Multifocal Progressiva (LEMP) raramente são abordados e seu estudo pode oferecer insights sobre a neurobiologia da psicose. Os autores relatam caso de paciente do sexo masculino, 42 anos, HIV positivo, com LEMP e sintomas psicóticos. O caso apresentado evidencia a necessidade de realização regular de avaliações neurológicas e neuropsicológicas de pacientes HIV positivos e a importância de se estudar doenças que causam lesões na substância branca, como a LEMP, para elucidar a neurobiologia da psicose.(AU)

Differential Effects of Antiretroviral Drugs on Neurons In Vitro: Roles for Oxidative Stress and Integrated Stress Response.

Mounting evidence suggests that antiretroviral drugs may contribute to the persistence of HIV-associated neurocognitive disorders (HAND), which impact 30%-50% of HIV-infected patients in the post-antiretroviral era. We previously reported that two first generation HIV protease inhibitors, ritonavir and saquinavir, induced oxidative stress, with subsequent neuronal death in vitro, which was reversed by augmentation of the endogenous antioxidant response by monomethyl fumarate. We herein determined whether two newer-generation PIs, darunavir and lopinavir, were deleterious to neurons in vitro. Further, we expanded our assessment to include three integrase strand transfer inhibitors, raltegravir, dolutegravir, and elvitegravir. We found that only lopinavir and elvitegravir were neurotoxic to primary rat neuroglial cultures as determined by the loss of microtubule-associated protein 2 (MAP2). Intriguingly, lopinavir but not elvitegravir led to oxidative stress and induced the endogenous antioxidant response (EAR). Furthermore, neurotoxicity of lopinavir was blocked by pharmacological augmentation of the endogenous antioxidant heme oxygenase-1 (HO-1), expanding our previous finding that protease inhibitor-induced neurotoxicity was mediated by oxidative stress. Conversely, elvitegravir but not lopinavir led to increased eIF2α phosphorylation, indicating the activation of a common adaptive pathway termed the integrated stress response (ISR), and elvitegravir-mediated neurotoxicity was partially alleviated by the ISR inhibitor trans-ISRIB, suggesting ISR as a promoter of elvitegravir-associated neurotoxicity. Overall, we found that neurotoxicity was induced only by a subset of protease inhibitors and integrase strand transfer inhibitors, providing evidence for class- and drug-specific neurotoxic effects of antiretroviral drugs. Future in vivo studies will be critical to confirm the neurotoxicity profiles of these drugs for incorporation of these findings into patient management. The EAR and ISR pathways are potential access points for the development of adjunctive therapies to complement antiretroviral therapies and limit their contribution to HAND persistence.