Cognitive impairment among older adults with HIV: a systematic review protocol of cohort studies / Transtornos cognitivos em idosos vivendo com HIV: protocolo de revisão sistemática com estudos de coorte

OBJECTIVES: This review will determine whether the incidence of cognitive impairment in HIV patients aged ≥ 50 years is greater than that of their HIV-negative peers. METHODS: The MEDLINE, EMBASE, LILACS, Web of Science, and Scopus databases will be searched for studies with a sample of individuals aged ≥ 50 years or a mixed population with ≥ 50% aged ≥ 50 years). It will include studies that evaluate seropositive patients compared to and an unexposed control group. STUDY DESIGN: Cohort studies with follow-up ≥ 24 months will be included. Three reviewers will independently screen for eligibility criteria, extract data, and assess the risk of bias in the included studies, as well as evaluate the overall quality of evidence. A narrative synthesis will be prepared according to synthesis without meta-analysis guidelines. EXPECTED RESULTS: We expect to find correlations between older age, HIV, and cognitive impairment. RELEVANCE: The association of geriatric syndromes and HIV is becoming an important field of study. Increased life expectancy accompanied by an active sex life is contributing to this public health problem. This protocol is reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols and is registered in PROSPERO (CRD42022321914). This study was financed in part by the CAPES foundation (financial code: 001)

OBJETIVOS: Esta revisão abordará o questionamento: a incidência de comprometimento cognitivo é maior em pacientes com 50 anos ou mais com o vírus da imunodeficiência humana do que em idosos soronegativos? METODOLOGIA: As bases de dados Medical Literature Analysis and Retrieval System Online (MEDLINE), EMBASE, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Web of Science e Scopus serão pesquisadas. A estratégia de busca considerará estudos com amostra de 50 anos ou mais e população mista (pelo menos 50% com 50 anos ou mais). Incluirá estudos que avaliam pacientes soropositivos, e o controle considerará pesquisas que abordem pessoas não expostas. DESENHO DO ESTUDO: Serão incluídos estudos de coorte com seguimento de pelo menos 24 meses. Três revisores, de forma independente, farão a triagem dos artigos quanto aos critérios de elegibilidade, extrairão dados, avaliarão o risco de viés dos trabalhos e avaliarão a qualidade geral das evidências. Uma síntese narrativa será preparada de acordo com a diretriz SWiM. RESULTADOS ESPERADOS: Esperamos encontrar maior incidência de comprometimento cognitivo em idosos que vivem com o vírus da imunodeficiência humana. RELEVÂNCIA: As síndromes geriátricas associadas ao HIV tornam-se um importante escopo de estudo, uma vez que, o aumento da expectativa de vida acompanhado de uma vida sexual ativa sustenta o ciclo de contaminação desse problema de saúde pública. Este protocolo é relatado de acordo com os Itens Preferenciais de Relatórios para Protocolos de Revisão Sistemática e Metanálise e está registrado no International Prospective Register of Systematic Reviews ­ PROSPERO (CRD42022321914). Este estudo foi parcialmente financiado pela Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ­ Brasil ­ Código de financiamento: 001

Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders.

HIV-associated neurocognitive disorders (HAND) have been linked to dysregulation of glutamate metabolism in the central nervous system (CNS) culminating in elevated extracellular glutamate and disrupted glutamatergic neurotransmission. Increased glutamate synthesis via upregulation of glutaminase (GLS) activity in brain immune cells has been identified as one potential source of excess glutamate in HAND. However, direct evidence for this hypothesis in an animal model is lacking, and the viability of GLS as a drug target has not been explored. In this brief report, we demonstrate that GLS inhibition with the glutamine analogue 6-diazo-5-oxo-L-norleucine (DON) can reverse cognitive impairment in the EcoHIV-infected mouse model of HAND. However, due to peripheral toxicity DON is not amenable to clinical use in a chronic disease such as HAND. We thus tested JHU083, a novel, brain penetrant DON prodrug predicted to exhibit improved tolerability. Systemic administration of JHU083 reversed cognitive impairment in EcoHIV-infected mice similarly to DON, and simultaneously normalized EcoHIV-induced increases in cerebrospinal fluid (CSF) glutamate and GLS activity in microglia-enriched brain CD11b + cells without observed toxicity. These studies support the mechanistic involvement of elevated microglial GLS activity in HAND pathogenesis, and identify JHU083 as a potential treatment option. Graphical Abstract Please provide Graphical Abstract caption.Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders .

The impact of homocysteine, B12, and D vitamins levels on functional neurocognitive performance in HIV-positive subjects.

BACKGROUND: The correlation among high levels of total homocysteine, low levels of B12vitamin, and neurocognitive impairment in HIV negative patients has been the main research topic in some of the latest reviews. The aim of this study was to examine if the alteration of homocysteine, B12 vitamin, and D vitamins plasma levels was present in HIV-positive, and their relationship with cognitive function. METHODS: 57 HIV infected were enrolled and underwent the serum measurement of homocysteine, B12, and D vitamins. The neurocognitive evaluation investigated 5 cognitive domains, through a neuropsychological battery test RESULTS: Homocysteine was found to be elevated in 70.2% of cases, B12 vitamin mean levels were low in 8 participants (14.0%), and 8 patients had D hypovitaminosis (14.0%). Abnormal homocysteine levels were associated with worse performance of verbal fluency (p = 0.003) and worse executive function (Stroop E test p = 0.040). The 25-OH D hypovitaminosis was associated with worse performances in executive functions in three different tests: Stroop E (p = 0.049), Trail B (p = 0.035), and Wais Digit Span (p = 0.042). Pathological levels of B12 Vitamin were also associated to worse performances in executive functions (Trail B Test and Wais Digit Span respectively p = 0.002 and 0.029) and with a lower speed in psychomotor processing (Peg Board Test on dominant hand, p = 0.014). CONCLUSIONS: In this study serum homocysteine, B12, and D vitamin levels are associated with neurocognitive performances; in fact low performance neurocognitive was correlated with hyperhomocysteine and low B12vitamin, and D vitamin levels. Evidence of the alteration of these parameters could facilitate the early identification of a neurocognitive impairment.

Effects of HIV on executive function and verbal fluency in Cameroon.

HIV-associated neurocognitive disorders (HAND) are frequently associated with impaired executive function and verbal fluency. Given limited knowledge concerning HAND in Sub-Saharan-Africa and lack of Cameroonian adult neuropsychological (NP) test norms, we administered four executive function [Halstead Category Test (HCT), Wisconsin Card Sorting Test (WCST), Color Trails-II (CTT2), and Stroop Color-Word-Interference (SCWT)] and three verbal fluency (Category, Action, and Letter Fluency) tests to 742 adult Cameroonians (395 HIV-, 347 HIV+). We developed demographically-corrected NP test norms and examined the effects of HIV and related variables on subjects' executive function and verbal fluency. HIV+ subjects had significantly lower T-scores on CTT2 (P = 0.005), HCT (P = 0.032), WCST (P < 0.001); lower executive function composite (P = 0.002) and Action Fluency (P = 0.03) T-scores. ART, viremia, and CD4 counts did not affect T-scores. Compared to cases harboring other viral subtypes, subjects harboring HIV-1 CRF02_AG had marginally higher CTT2 T-scores, significantly higher SCWT (P = 0.015) and executive function (P = 0.018) T-scores. Thus, HIV-1 infection in Cameroon is associated with impaired executive function and some aspects of verbal fluency, and viral genotype influenced executive function. We report the first normative data for assessing executive function and verbal fluency in adult Cameroonians and provide regression-based formulas for computing demographically-adjusted T-scores. These norms will be useful for investigating HIV/AIDS and other diseases affecting cognitive functioning in Cameroon.

Changes in resting-state functional brain activity are associated with waning cognitive functions in HIV-infected children.

Delayed brain development in perinatally HIV-infected children may affect the functional brain activity and subsequently cognitive function. The current study evaluated the functional brain activity in HIV-infected children by quantifying the amplitude of low frequency fluctuations (ALFF) and functional connectivity (FC). Additionally, correlation of ALFF and FC with cognitive measures was performed. Twenty-six HIV-infected children and 20 control children underwent neuropsychological (NP) assessment and resting-state functional magnetic resonance imaging (rs-fMRI). ALFF and FC maps were generated and group differences were analyzed using two-sample t-test. Furthermore, ALFF and FC showing significant group differences were correlated with NP scores using Pearson's correlation. Significantly lower ALFF in the left middle temporal gyrus, precentral and post central gyrus was observed in HIV-infected children compared to controls. FC was significantly reduced in the right inferior parietal, vermis, middle temporal and left postcentral regions, and significantly increased in the right precuneus, superior parietal and left middle frontal regions in HIV-infected children as compared to control. HIV-infected children showed significantly lower NP scores in various domains including closure, exclusion, memory, verbal meaning, quantity and hidden figure than controls. These waning cognitive functions were significantly associated with changes in ALFF and FC in HIV-infected children. The findings suggest that abnormal ALFF and FC may responsible for cognitive deficits in HIV-infected children. ALFF and FC in association with cognitive evaluation may provide a clinical biomarker to evaluate functional brain activity and to plan neurocognitive intervention in HIV-infected children undergoing standard treatment.

Neurological manifestations, laboratory and neuroimaging features in HIV-infected patients.

OBJECTIVE: To present detailed information regarding these aspects in Human Immunodeficiency Virus (HIV)-infected patients making an effort to improve the recognition of neurological complications of HIV infection. METHODS: This retrospective study analyzed the clinical manifestations, laboratory and neuroimaging results of HIV-infected patients with neurological complications at Xuanwu hospital, Beijing, China from January 2011 to December 2014, one of top-rated hospitals in Beijing, China. RESULTS: A diverse range of clinical diagnoses was identified, including encephalopathy, meningoencephalitis, peripheral neuropathy, multiple sclerosis, cerebral infarction and lymphoma associated with HIV infection. The mostly observed neurological disorders were motor/sensory deficits in the limbs (75%), cognitive impairments (42%) and fever (33%). Non-specific results of laboratory tests, including elevated erythrocyte sedimentation rate (ESR), cerebrospinal fluid (CSF) protein concentration and IgG, were found. Brain Magnetic Resonance Imaging (MRI) abnormalities displayed a variety of patterns and distributions due to diverse clinical profiles. CONCLUSION: The clinical scenarios of HIV-infected patients are remarkably diverse and complex. Etiological tests would be cardinal to make more definitive diagnosis for HIV-infected patients. Prospective studies with follow-up were needed to bring more accurate information.

Brief Report: Peripheral Monocyte/Macrophage Phenotypes Associated With the Evolution of Cognitive Performance in HIV-Infected Patients.

BACKGROUND: The contribution of monocyte activation in the development of HIV-associated neurocognitive disorders is not completely understood. This study aimed to explore the predictive value of peripheral monocyte/macrophage (M/M) phenotypes on the evolution of cognitive performance in a population of virologically suppressed HIV-infected patients. SETTING: Prospective, observational, longitudinal study. METHODS: HIV-1-infected patients with HIV-RNA <50copies/mL for >12 months underwent neuropsychological examination at baseline and after 1 year. Cognitive performance was evaluated using Z-transformed scores, and neurocognitive impairment (NCI) was defined according to Frascati criteria. Peripheral M/M phenotypes (classic CD14CD16, intermediate CD14CD16, and nonclassic CD14CD16) and specific surface activation markers (eg, CD163, CD11b, and CD38) were evaluated using flow cytometry at baseline. Predictive value of peripheral M/M phenotypes on the evolution of cognitive performance over 1-year follow-up was also evaluated. RESULTS: Overall, 54 patients [85.2% men, median age 50 years (range 27-60 years), 27.8% hepatitis C virus coinfected, 48.1% with past AIDS-defining events, median nadir CD4 83 cells/µL (range 1-334), median baseline CD4 547 cells/µL (range 136-1652)] were enrolled. Proportion of patients with NCI was low, accounting for 13% at baseline and 16.5% after 1 year (P = 0.687). Memory was the only single domain in which decreased performance after 1 year was observed (-0.25 Z-score, P = 0.025). In patients with significant decrease (≥0.5 SD) in memory performance (n = 20), significantly lower CD14CD16CD163 (% CD14CD16) (P = 0.038) and higher CD14CD38 (% CD14) (P = 0.030) levels were observed. CONCLUSIONS: In virologically suppressed HIV-infected patients, the evolution of memory performance could be linked to the expression of certain peripheral activated M/M phenotypes. Such associations should be verified in larger populations over the long term.

Cognitive impairment is frequent among symptomatic carriers of human T-cell lymphotropic virus type 1 (HTLV-1), regardless of their clinical status.

The main goal of this study was to investigate the presence of cognitive impairment in patients infected with HTLV-1 presenting or not TSP/HAM. METHODS: Cross-sectional study including 104 participants: 37 asymptomatic HTLV-1 carriers, 37 patients diagnosed with TSP/HAM and 30 HTLV-1 negative control patients. Within the HTLV-1 positive group, 53 were female and 21 were male, the average age was 46 (SD=13.5) and the average schooling time was 7.7years (SD=3.3).The sociodemographic variables (genre, age and education) were compared between the three groups. The assessment tools used were: Beck Depression Inventory, Lawton's Activities of Daily Life Scale and a complete neuropsychological battery. The application of these assessment tools was carried out in blind. Both HTLV-1 asymptomatic subjects and HAM/TSP patients showed a lower performance on neuropsychological tests and higher depression scores when compared to the control group. HTLV-1 patients performed poorly in several cognitive domains, but only fluid intelligence, estimated intellectual functioning, immediate and delayed recall of visual memory and information processing speed (in the specific case of patients with TSP/HAM) reached statistical significance when compared with controls. Depression was not associated with cognitive impairment. HTLV-1 carriers presented a higher frequency of cognitive impairment than normal controls.

Clinicopathological case: progressive cognitive decline with gait disturbance in a steel worker.

A 57-year-old male steel plant worker presented with fatigue and altered liver function tests. Over the next two years, he developed cognitive decline, parkinsonism and seizures. This paper reports the clinicopathological conference at the 37th Edinburgh Advanced Neurology Course 2015 and outlines what we can learn from this case.

Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression.

BACKGROUND: Cognitive impairment persists despite suppression of plasma human immunodeficiency virus (HIV) RNA. Monocyte-related immune activation is a likely mechanism. We examined immune activation and cognition in a cohort of HIV-infected and uninfected women from the Women's Interagency HIV Study (WIHS). METHODS: Blood levels of activation markers, soluble CD163 (sCD163), soluble CD14 (sCD14), CRP, IL-6, and a gut microbial translocation marker (intestinal fatty acid binding protein (I-FABP)) were measured in 253 women (73% HIV-infected). Markers were compared to concurrent (within ± one semiannual visit) neuropsychological testing performance. RESULTS: Higher sCD163 levels were associated with worse overall performance and worse verbal learning, verbal memory, executive function, psychomotor speed, and fine motor skills (P < .05 for all comparisons). Higher sCD14 levels were associated with worse verbal learning, verbal memory, executive function, and psychomotor speed (P < .05 for all comparisons). Among women with virological suppression, sCD163 remained associated with overall performance, verbal memory, psychomotor speed, and fine motor skills, and sCD164 remained associated with executive function (P < .05 for all comparisons). CRP, IL-6, and I-FABP were not associated with worse cognitive performance. CONCLUSIONS: Monocyte activation was associated with worse cognitive performance, and associations persisted despite viral suppression. Persistent inflammatory mechanisms related to monocytes correlate to clinically pertinent brain outcomes.

The association among smoking, HSV-1 exposure, and cognitive functioning in schizophrenia, bipolar disorder, and non-psychiatric controls.

Previous investigations have found that smokers with schizophrenia demonstrate reduced performance on cognitive tasks compared to non-smokers. However previous studies have not taken into account other environmental factors associated with cognitive functioning such as exposure to Herpes Simplex Virus type 1 (HSV-1). We examined these factors in a sample consisting of individuals with schizophrenia (n=773), bipolar disorder (n=493), or controls without a psychiatric disorders (n=548). Participants were assessed on a cognitive battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and had a blood sample drawn to measure seropositivity to HSV-1. Within each group linear regression models were constructed to determine whether cigarette smoking and HSV-1 seropositivity were jointly associated with cognitive functioning after adjusting for relevant covariates. Within the schizophrenia group, the effect size of lower total cognitive score was -0.279 (p<0.0001) for individuals who were both smokers and HSV-1 seropositive and a significant effect was found in all cognitive domains. The odds of being in the highest quartile of RBANS Total score were significantly lower for smokers (OR=0.58, 95% CI 0.41, 0.82, p=0.002). Smoking was not as consistently associated with levels of cognitive functioning in the bipolar disorder or the non-psychiatric control group. While experimental studies show that nicotine transiently improves functioning on sensory gating and attention tasks known to be deficient in schizophrenia, long-term nicotine exposure via smoking appears to have an adverse effect on cognitive functioning.

Facial Emotion Processing in Aviremic HIV-infected Adults.

The emotional processing in human immunodeficiency virus-seropositive individuals (HIV+) has been scarcely studied. We included HIV+ individuals (n = 107) on antiretroviral therapy (≥2 years) who completed 6 facial processing tasks and neurocognitive testing. We compared HIV+ and healthy adult (HA) participants (n = 40) in overall performance of each facial processing task. Multiple logistic regressions were conducted to explore predictors of poorer accuracy in those measures in which HIV+ individuals performed poorer than HA participants. We separately explored the impact of neurocognitive status, antiretroviral regimen, and hepatitis C virus (HCV) coinfection on the tasks performance. We found similar performance in overall facial emotion discrimination, recognition, and recall between HIV+ and HA participants. The HIV+ group had poorer recognition of particular negative emotions. Lower WAIS-III Vocabulary scores and active HCV predicted poorer accuracy in recognition of particular emotions. Our results suggest that permanent damage of emotion-related brain systems might persist despite long-term effective antiretroviral therapy.

HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration.

Monocyte Phenotype and Polyfunctionality Are Associated With Elevated Soluble Inflammatory Markers, Cytomegalovirus Infection, and Functional and Cognitive Decline in Elderly Adults.

Monocytes are mediators of the inflammatory response and include three subsets: classical, intermediate, and nonclassical. Little is known about the phenotypical and functional age-related changes in monocytes and their association with soluble inflammatory biomarkers, cytomegalovirus infection, and functional and mental decline. We assayed the activation ex vivo and the responsiveness to TLR2 and TLR4 agonists in vitro in the three subsets and assessed the intracellular production of IL1-alpha (α), IL1-beta (ß), IL-6, IL-8, TNF-α, and IL-10 of elderly adults (median 83 [67-90] years old;n= 20) compared with young controls (median 35 [27-40] years old;n= 20). Ex vivo, the elderly adults showed a higher percentage of classical monocytes that expressed intracellular IL1-α (p= .001), IL1-ß (p= .001), IL-6 (p= .002), and IL-8 (p= .007). Similar results were obtained both for the intermediate and nonclassical subsets and in vitro. Polyfunctionality was higher in the elderly adults. The functionality ex vivo was strongly associated with soluble inflammatory markers. The activation phenotype was independently associated with the anti-cytomegalovirus IgG levels and with functional and cognitive decline. These data demonstrate that monocytes are key cell candidates for the source of the high soluble inflammatory levels. Our findings suggest that cytomegalovirus infection might be a driving force in the activation of monocytes and is associated with the functional and cognitive decline.

Hepatitis C virus-associated neurocognitive and neuropsychiatric disorders: Advances in 2015.

Since its identification in 1989, hepatitis C virus (HCV) has emerged as a worldwide health problem with roughly 185 million chronic infections, representing individuals at high risk of developing cirrhosis and liver cancer. In addition to being a frequent cause of morbidity and mortality due to liver disease, HCV has emerged as an important trigger of lymphoproliferative disorders, owing to its lymphotropism, and of a wide spectrum of extra-hepatic manifestations (HCV-EHMs) affecting different organ systems. The most frequently observed HCV-EHMs include mixed cryoglobulinemia and cryoglobulinemic vasculitis, B-cell non-Hodgkin's lymphoma, nephropathies, thyreopathies, type 2 diabetes mellitus, cardiovascular diseases, and several neurological conditions. In addition, neuropsychiatric disorders and neurocognitive dysfunction are reported in nearly 50% of patients with chronic HCV infection, which are independent of the severity of liver disease or HCV replication rates. Fatigue, sleep disturbance, depression and reduced quality of life are commonly associated with neurocognitive alterations in patients with non-cirrhotic chronic HCV infection, regardless of the stage of liver fibrosis and the infecting genotype. These manifestations, which are the topic of this review, typically occur in the absence of structural brain damage or signal abnormalities on conventional brain magnetic resonance imaging (MRI), although metabolic and microstructural changes can be detected by in vivo proton magnetic resonance spectroscopy, perfusion-weighted and diffusion tensor MRI, and neurophysiological tests of cognitive processing. Several lines of evidence, including comparative and longitudinal neuropsychological assessments in patients achieving spontaneous or treatment-induced viral clearance, support a major pathogenic role for HCV in neuropsychiatric and neurocognitive disorders.

Response of Mammalian Macrophages to Challenge with the Chlorovirus Acanthocystis turfacea Chlorella Virus 1.

UNLABELLED: It was recently reported that 44% of the oropharyngeal samples from the healthy humans in a study cohort had DNA sequences similar to that of the chlorovirus ATCV-1 (Acanthocystis turfacea chlorella virus 1, family Phycodnaviridae) and that these study subjects had decreases in visual processing and visual motor speed compared with individuals in whom no virus was detected. Moreover, mice inoculated orally with ATCV-1 developed immune responses to ATCV-1 proteins and had decreases in certain cognitive domains. Because heightened interleukin-6 (IL-6), nitric oxide (NO), and ERK mitogen-activated protein (MAP) kinase activation from macrophages are linked to cognitive impairments, we evaluated cellular responses and viral PFU counts in murine RAW264.7 cells and primary macrophages after exposure to ATCV-1 in vitro for up to 72 h after a virus challenge. Approximately 8% of the ATCV-1 inoculum was associated with macrophages after 1 h, and the percentage increased 2- to 3-fold over 72 h. Immunoblot assays with rabbit anti-ATCV-1 antibody detected a 55-kDa protein consistent with the viral capsid protein from 1 to 72 h and increasing de novo synthesis of a previously unidentified 17-kDa protein beginning at 24 h. Emergence of the 17-kDa protein did not occur and persistence of the 55-kDa protein declined over time when cells were exposed to heat-inactivated ATCV-1. Moreover, starting at 24 h, RAW264.7 cells exhibited cytopathic effects, annexin V staining, and cleaved caspase 3. Activation of ERK MAP kinases occurred in these cells by 30 min postchallenge, which preceded the expression of IL-6 and NO. Therefore, ATCV-1 persistence in and induction of inflammatory factors by these macrophages may contribute to declines in the cognitive abilities of mice and humans. IMPORTANCE: Virus infections that persist in and stimulate inflammatory factors in macrophages contribute to pathologies in humans. A previous study showed that DNA sequences homologous to the chlorovirus ATCV-1 were found in a significant fraction of oropharyngeal samples from a healthy human cohort. We show here that ATCV-1, whose only known host is a eukaryotic green alga (Chlorella heliozoae) that is an endosymbiont of the heliozoon Acanthocystis turfacea, can unexpectedly persist within murine macrophages and trigger inflammatory responses including factors that contribute to immunopathologies. The inflammatory factors that are produced in response to ATCV-1 include IL-6 and NO, whose induction is preceded by the activation of ERK MAP kinases. Other responses of ATCV-1-challenged macrophages include an apoptotic cytopathic effect, an innate antiviral response, and a metabolic shift toward aerobic glycolysis. Therefore, mammalian encounters with chloroviruses may contribute to chronic inflammatory responses from macrophages.

A hitherto unrecognised case of progressive multifocal leukoencephalopathy.

A 65-year-old man presented with a 6-week history of increasing confusion with associated cognitive decline. Empirical antibiotic cover for a urinary tract infection was prescribed with no response. After exhaustive radiological and pathological investigations were carried out, a diagnosis of John Cunningham virus encephalopathy was made. This case report describes the varied clinical presentation of symptoms and their management options, along with the latest clinical opinions behind them.

HIV-associated neurocognitive disorders: A review for NPs.

This review discusses HIV-associated neurocognitive disorders. Practical screening methods are needed for the nurse practitioner to detect neurocognitive impairment in HIV-infected patients.

Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice.

BACKGROUND: Host-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rgcnull mice transplanted with human CD34+ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus. METHODS: Changes in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N-acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens. RESULTS: Behavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum. CONCLUSIONS: The findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease.

[HIV encephalopathy due to drug resistance despite 2-year suppression of HIV viremia by cART].

A 57-year-old man presented with subacute progression of cognitive impairment (MMSE 22/30). He had been diagnosed as AIDS two years before and taking atazanavir, abacavir, and lamivudine. HIV RNA of plasma had been negative. On admission, HIV RNA was 4,700 copy/ml and 5,200 copy/ml in plasma and in cerebrospinal fluid respectively, suggesting treatment failure of cART. The brain magnetic resonance imaging showed high intensity areas in the white matter of the both frontal lobes and brain stem. The drug-resistance test revealed the resistance of lamivudine and abacavir. We introduced the CNS penetration effectiveness (CPE) score to evaluate the drug penetration of HIV drugs. As the former regimen had low points (7 points), we optimized the regimen to raltegravir, zidovudine, and darunavir/ritonavir (scoring 10 points). His cognitive function improved as normal (MMSE 30/30) in 2 weeks and HIV-RNA became undetectable both in plasma and CSF in a month. In spite of the cognitive improvement, the white matter hyperintensity expanded. To rule out malignant lymphoma or glioblastoma, the brain biopsy was performed from the right frontal lobe. It revealed microglial hyperplasia and diffuse perivascular infiltration by CD8+/CD4-lymphocytes. No malignant cells were found and the polymerase chain reaction analyses excluded other viruses. Considering the drug penetration to the central nervous system is important for treating HIV encephalopathy.