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HIV persistence in the brain is a barrier to cure, and potentially contributes to HIV-associated neurocognitive disorders. Whether HIV transcription persists in the brain despite viral suppression with antiretroviral therapy (ART) and is subject to the same blocks to transcription seen in other tissues and blood, is unclear. Here, we quantified the level of HIV transcripts in frontal cortex tissue from virally suppressed or non-virally suppressed people with HIV (PWH). HIV transcriptional profiling of frontal cortex brain tissue (and PBMCs where available) from virally suppressed (n = 11) and non-virally suppressed PWH (n = 13) was performed using digital polymerase chain reaction assays (dPCR). CD68+ myeloid cells or CD3+ T cells expressing HIV p24 protein present in frontal cortex tissue was detected using multiplex immunofluorescence imaging. Frontal cortex brain tissue from PWH had HIV TAR (n = 23/24) and Long-LTR (n = 20/24) transcripts. Completion of HIV transcription was evident in brain tissue from 12/13 non-virally suppressed PWH and from 5/11 virally suppressed PWH, with HIV p24+CD68+ cells detected in these individuals. While a block to proximal elongation was present in frontal cortex tissue from both PWH groups, this block was more extensive in virally suppressed PWH. These findings suggest that the brain is a transcriptionally active HIV reservoir in a subset of virally suppressed PWH., Competing Interests: SRL has received investigator-initiated grant funding from Gilead, Merck and ViiV Healthcare. She has participated as a paid member of scientific advisory boards to Abivax, Immunocore, Efsam, Abbvie and Gilead., (Copyright: © 2024 Jamal Eddine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Although previous studies have suggested that subtype B HIV-1 proviruses in the brain are associated with physiological changes and immune activation accompanied with microgliosis and astrogliosis, and indicated that both HIV-1 subtype variation and geographical location might influence the neuropathogenicity of HIV-1 in the brain. The natural course of neuropathogenesis of the most widespread subtype C HIV-1 has not been adequately investigated, especially for people living with HIV (PLWH) in sub-Saharan Africa. To characterize the natural neuropathology of subtype C HIV-1, postmortem frontal lobe and basal ganglia tissues were collected from nine ART-naïve individuals who died of late-stage AIDS with subtype C HIV-1 infection, and eight uninfected deceased individuals as controls. Histological staining was performed on all brain tissues to assess brain pathologies. Immunohistochemistry (IHC) against CD4, p24, Iba-1, GFAP, and CD8 in all brain tissues was conducted to evaluate potential viral production and immune activation. Histological results showed mild perivascular cuffs of lymphocytes only in a minority of the infected individuals. Viral capsid p24 protein was only detected in circulating immune cells of one infected individual, suggesting a lack of productive HIV-1 infection of the brain even at the late-stage of AIDS. Notably, similar levels of Iba-1 or GFAP between HIV + and HIV- brain tissues indicated a lack of microgliosis and astrogliosis, respectively. Similar levels of CD8 + cytotoxic T lymphocyte (CTL) infiltration between HIV + and HIV- brain tissues indicated CTL were not likely to be involved within subtype C HIV-1 infected participants of this cohort. Results from this subtype C HIV-1 study suggest that there is a lack of productive infection and limited neuropathogenesis by subtype C HIV-1 even at late-stage disease, which is in contrast to what was reported for subtype B HIV-1 by other investigators., (© 2024. The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc.)

Despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals' quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified. We investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n = 11), with or without CD8+ lymphocyte depletion, based on detectable (n = 6) or non-detectable (n = 5) presence of the virus in frontal cortex tissues. Significant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion. In addition, transcripts of four poly (ADP-ribose) polymerases (PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction. Our results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology.

Acute delirium and other neuropsychiatric symptoms have frequently been reported in COVID-19 patients and are variably referred to as acute encephalopathy, COVID-19 encephalopathy, SARS-CoV-2 encephalitis, or steroid-responsive encephalitis. COVID-19 specific biomarkers of cognitive impairment are currently lacking, but there is some evidence that SARS-CoV-2 could preferentially and directly target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET imaging. We suggest that an inflammatory parainfectious process targeting preferentially the frontal lobes (and/or frontal networks) could be the underlying cause of these shared clinical, neurophysiological, and imaging findings in COVID-19 patients. We explore the biological mechanisms and the clinical biomarkers that might underlie such disruption of frontal circuits and highlight the need of standardized diagnostic procedures to be applied when investigating patients with these clinical findings. We also suggest the use of a unique label, to increase comparability across studies.

The purpose of this study was to assess whole brain and regional patterns of cerebrovascular reactivity (CVR) abnormalities in HIV-infected women using quantitative whole brain arterial spin labeling (ASL). We hypothesized that HIV-infected women would demonstrate decreased regional brain CVR despite viral suppression. This cross-sectional study recruited subjects from the Bay Area Women's Interagency Health Study (WIHS)-a cohort study designed to investigate the progression of HIV disease in women. In addition to conventional noncontrast cerebral MRI sequences, perfusion imaging was performed before and after the administration of intravenous acetazolamide. CVR was measured by comparing quantitative ASL brain perfusion before and after administration of intravenous acetazolamide. In order to validate and corroborate ASL-based whole brain and regional perfusion, phase-contrast (PC) imaging was also performed through the major neck vessels. FLAIR and susceptibility weighted sequences were performed to assess for white matter injury and microbleeds, respectively. Ten HIV-infected women and seven uninfected, age-matched controls were evaluated. Significant group differences were present in whole brain and regional CVR between HIV-infected and uninfected women. These regional differences were significant in the frontal lobe and basal ganglia. CVR measurements were not significantly impacted by the degree of white matter signal abnormality or presence of microbleeds. Despite complete viral suppression, dysfunction of the neurovascular unit persists in the HIV population. Given the lack of association between CVR and traditional imaging markers of small vessel disease, CVR quantification may provide an early biomarker of pre-morbid vascular disease.

HIV-associated neuroinflammation is primarily driven by CNS macrophages including microglia. Regulation of these immune responses, however, remains to be characterized in detail. Using the SIV/macaque model of HIV, we evaluated CNS expression of triggering receptor expressed on myeloid cells 2 (TREM2) which is constitutively expressed by microglia and contributes to cell survival, proliferation, and differentiation. Loss-of-function mutations in TREM2 are recognized risk factors for neurodegenerative diseases including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Nasu-Hakola disease (NHD); recent reports have also indicated a role for TREM2 in HIV-associated neuroinflammation. Using in situ hybridization (ISH) and qRT-PCR, TREM2 mRNA levels were found to be significantly elevated in frontal cortex of macaques with SIV encephalitis compared with uninfected controls (P = 0.02). TREM2 protein levels were also elevated as measured by ELISA of frontal cortex tissue homogenates in these animals. Previously, we characterized the expression of CSF1R (colony-stimulating factor 1 receptor) in this model; the TREM2 and CSF1R promoters both contain a PU.1 binding site. While TREM2 and CSF1R mRNA levels in the frontal cortex were highly correlated (Spearman R = 0.79, P < 0.001), protein levels were not well correlated. In SIV-infected macaques released from ART to study viral rebound, neither TREM2 nor CSF1R mRNA increased with rebound viremia. However, CSF1R protein levels remained significantly elevated unlike TREM2 (P = 0.02). This differential expression suggests that TREM2 and CSF1R play unique, distinct roles in the pathogenesis of HIV CNS disease.

Neurologic sequelae can be devastating complications of respiratory viral infections. We report the presence of virus in neural and capillary endothelial cells in frontal lobe tissue obtained at postmortem examination from a patient infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Our observations of virus in neural tissue, in conjunction with clinical correlates of worsening neurologic symptoms, pave the way to a closer understanding of the pathogenic mechanisms underlying central nervous system involvement by SARS-CoV-2., (© 2020 Wiley Periodicals LLC.)

Although the reduction of viral loads in people with HIV undergoing combination antiretroviral therapy has mitigated AIDS-related symptoms, the prevalence of neurological impairments has remained unchanged. HIV-associated CNS dysfunction includes impairments in memory, attention, memory processing, and retrieval. Here, we show a significant site-specific increase in the phosphorylation of Syn I serine 9, site 1, in the frontal cortex lysates and synaptosome preparations of male rhesus macaques infected with simian immunodeficiency virus (SIV) but not in uninfected or SIV-infected antiretroviral therapy animals. Furthermore, we found that a lower protein phosphatase 2A (PP2A) activity, a phosphatase responsible for Syn I (S9) dephosphorylation, is primarily associated with the higher S9 phosphorylation in the frontal cortex of SIV-infected macaques. Comparison of brain sections confirmed higher Syn I (S9) in the frontal cortex and greater coexpression of Syn I and PP2A A subunit, which was observed as perinuclear aggregates in the somata of the frontal cortex of SIV-infected macaques. Synaptosomes from SIV-infected animals were physiologically tested using a synaptic vesicle endocytosis assay and FM4-64 dye showing a significantly higher baseline depolarization levels in synaptosomes of SIV + -infected than uninfected control or antiretroviral therapy animals. A PP2A-activating FDA-approved drug, FTY720, decreased the higher synaptosome depolarization in SIV-infected animals. Our results suggest that an impaired distribution and lower activity of serine/threonine phosphatases in the context of HIV infection may cause an indirect effect on the phosphorylation levels of essential proteins involving in synaptic transmission, supporting the occurrence of specific impairments in the synaptic activity during SIV infection. SIGNIFICANCE STATEMENT Even with antiretroviral therapy, neurocognitive deficits, including impairments in attention, memory processing, and retrieval, are still major concerns in people living with HIV. Here, we used the rhesus macaque simian immunodeficiency virus model with and without antiretroviral therapy to study the dynamics of phosphorylation of key amino acid residues of synapsin I, which critically impacts synaptic vesicle function. We found a significant increase in synapsin I phosphorylation at serine 9, which was driven by dysfunction of serine/threonine protein phosphatase 2A in the nerve terminals. Our results suggest that an impaired distribution and lower activity of serine/threonine phosphatases in the context of HIV infection may cause an indirect effect on the phosphorylation levels of essential proteins involved in synaptic transmission., (Copyright © 2019 the authors.)

Despite combination antiretroviral therapies making HIV a chronic rather than terminal condition for many people, the prevalence of HIV-associated neurocognitive disorders (HAND) is increasing. This is especially problematic for children living with HIV. Children diagnosed HAND rarely display the hallmark pathology of HIV encephalitis in adults, namely infected macrophages and multinucleated giant cells in the brain. This finding has also been documented in rhesus macaques infected perinatally with simian immunodeficiency virus (SIV). However, the extent and mechanisms of lack of susceptibility to encephalitis in perinatally HIV-infected children remain unclear. In the current study, we compared brains of macaques infected with pathogenic strains of SIV at different ages to determine neuropathology, correlates of neuroinflammation, and potential underlying mechanisms. Encephalitis was not found in the macaques infected within 24 h of birth despite similar high plasma viral load and high monocyte turnover. Macaques developed encephalitis only when they were infected after 4 months of age. Lower numbers of CCR5-positive cells in the brain, combined with a less leaky blood-brain barrier, may be responsible for the decreased virus infection in the brain and consequently the absence of encephalitis in newborn macaques infected with SIV.

Simian immunodeficiency virus (SIV)-infected macaque is a widely used model to study human immunodeficiency virus. The purpose of the study is to discover the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) changes in SIV-infected macaques. Seven rhesus macaques were involved in the longitudinal MRI scans: (1) baseline (healthy state); (2) SIV infection stage (12 weeks after SIV inoculation). ALFF and fALFF were subsequently computed and compared to ascertain the changes caused by SIV infection. Whole-brain correlation analysis was further used to explore the possible associations between ALFF/fALFF values and immune status parameters (CD4+ T cell counts, CD4/CD8 ratio and virus load). Compared with the baseline, macaques in SIV infection stage displayed strengthened ALFF values in left precuneus, postcentral gyrus, and temporal gyrus, and weakened ALFF values in orbital gyrus and inferior temporal gyrus. Meanwhile, increased fALFF values were found in left superior frontal gyrus, right precentral gyrus, and superior temporal gyrus, while decreased fALFF values existed in left hippocampus, left caudate, and right inferior frontal gyrus. Furthermore, ALFF and fALFF values in several brain regions showed significant relationships with CD4+ T cell counts, CD4/CD8 ratio, and plasma virus load. Our findings could promote the understanding of neuroAIDS caused by HIV infection, which may provide supplementary evidences for the future therapy study in SIV model.

Cognitive impairment in HIV-1 infection is associated with the induction of chronic proinflammatory responses in the brains of infected individuals. The risk of HIV-related cognitive impairment is increased by cigarette smoking, which induces brain inflammation in rodent models. To better understand the role of smoking and the associated immune response on behavioral and motor function in HIV infection, wild-type F344 and HIV-1 transgenic (HIV1Tg) rats were exposed to either smoke from nicotine-containing (regular) cigarettes, smoke from nicotine-free cigarettes, or to nicotine alone. The animals were then tested using the rotarod test (RRT), the novel object recognition test (NORT), and the open field test (OFT). Subsequently, brain frontal cortex from the rats was analyzed for levels of TNF-α, IL-1, and IL-6. On the RRT, impairment was noted for F344 rats exposed to either nicotine-free cigarette smoke or nicotine alone and for F344 and HIV1Tg rats exposed to regular cigarette smoke. Effects from the exposures on the OFT were seen only for HIV1Tg rats, for which function was worse following exposure to regular cigarette smoke as compared to exposure to nicotine alone. Expression levels for all three cytokines were overall higher for HIV1Tg than for F344 rats. For HIV1Tg rats, TNF-α, IL-1, and IL-6 gene expression levels for all exposure groups were higher than for control rats. All F344 rat exposure groups also showed significantly increased TNF-α expression levels. However, for F344 rats, IL-1 expression levels were higher only for rats exposed to nicotine-free and nicotine-containing CS, and no increase in IL-6 gene expression was noted with any of the exposures as compared to controls. These studies, therefore, demonstrate that F344 and HIV1Tg rats show differential behavioral and immune effects from these exposures. These effects may potentially reflect differences in the responsiveness of the various brain regions in the two animal species as well as the result of direct toxicity mediated by the proinflammatory cytokines that are produced by HIV proteins and by other factors that are present in regular cigarette smoke.

We aimed to test the hypothesis that brain large artery diameters relate to distal downstream arteriolar diameters. In a sample of 110 autopsied individuals (69% men, 76% HIV+, mean age 51), we used multilevel models to relate large artery lumen and lumen-to-wall ratio to left frontal lobe arteriolar lumen and lumen-to-wall ratio adjusting for demographics and vascular risk factors. Comparing the large artery characteristics of the whole brain did not disclose significant associations with frontal lobe arteriolar characteristics. However, restricting the comparison to large arteries upstream of the studied arterioles demonstrated an independent association between left-sided frontal lobe arteriolar luminal diameter with large artery luminal diameters (B = 1.82 ± 0.77, P = 0.01) and with large artery lumen-to-wall ratio (B = 0.58 ± 0.29, P = 0.05). In stratified models, the point estimates in the HIV+ subsample were larger than in the HIV- subsample. These finding suggest coupling between higher proximal blood flow represented by large artery diameter and lower distal resistance represented by arteriolar dilatation. The relationship between arteriolar dilatation and brain parenchyma homeostasis should be further studied.

Objective: This study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age., Method: T1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels., Results: Following correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers., Conclusions: Methamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment., (Published by Elsevier Inc.)

We aimed to explore the brain imaging correlates of vocal emotion processing in a group of HIV+ individuals and to compare the vocal emotion processing of HIV+ individuals with a group of healthy adults. We conducted multiple linear regressions to determine the cerebral correlates of a newly designed vocal emotion processing test in a sub-group of HIV+ individuals who completed the cerebral magnetic resonance scan (n = 36). Separately, we test whether the association between our test scores and each cerebral measure persisted regardless of the presence of neurocognitive impairment. We also calculated differences in average test scores between the total HIV+ group (n = 100) and a healthy adult group (n = 46). We found a positive association between the test scores and several brain area volumes: right frontal, temporal and parietal lobes, bilateral thalamus, and left hippocampus. We found a negative association between inflammatory markers in frontal white matter and the test scores. After controlling by neurocognitive impairment, several brain area volumes remained positively associated to the prosody test scores. Moreover, the whole HIV+ sample had significantly poorer test scores than healthy adults, but only in the subset of HIV+ individuals with neurocognitive impairment. For the first time, our results suggest that cerebral dysfunctions in particular brain areas involved in the processing of emotional auditory stimuli may occur in HIV+ individuals. These results highlight the need for broad characterization of the neuropsychological consequence of HIV brain damages.

The molecular mechanisms involved in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain poorly understood. It has been recently reported that HIV-1 Tat transactivation requires menin, suggesting that menin may be involved in HAND pathogenesis. But the role of menin is not clear. Here, we found that protein level of menin was increased in simian-human immunodeficiency chimeric virus (SHIV)-SF162.P4 and simian immunodeficiency virus (SIV) sm543-3-infected rhesus macaques compared with the controls by immunohistochemistry (IHC) and western blot. Menin mainly expressed in the frontal cortex neurons of the brain, more importantly, the number of menin-staining cells was positively correlated with cleaved-caspase-3-positive cells while it was negatively correlated with a neuron-specific nuclear protein NeuN-positive cells, suggesting that expression of menin may induce neuronal apoptosis. Further studies showed that menin level was significantly increased during Tat-induced apoptosis, while downregulation of menin by pll3.7-MEN1-shRNA attenuated the Tat-induced cleavage of caspase-3 and caspase-8 in SY5Y cells and primary neuron cultures. Together, our findings reveal a pro-apoptotic role of menin in the brains of the SIV-infected macaques and the cultured neurons, indicating that targeting menin may be potential to block the HIV-1 Tat induced neuronal damage in HAND.

Human rabies encephalitis is rare in Canada, with only five cases reported in the past 30 years. The first and only patient who contracted rabies encephalitis in British Columbia died in 2003. Here we provide the first detailed clinical and pathological description of that case, which had several unusual features, including preexisting immunosuppression, paralytic presentation, prolonged survival, focal lesions on neuroimaging and severe neuropathology with focal necrosis, intense inflammation, and abundant viral inclusion bodies.

The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) remains puzzling. We interrogated several levels of data (host genetic, histopathology, brain viral load, and neurocognitive) to identify histopathological changes most relevant to HAND. The design of the study is a clinicopathological study employing genetic association analyses. Data and brain tissue from 80 HIV-infected adults were used. Markers in monocyte chemoattractant protein-1 (MCP-1), interleukin 1-alpha (IL1-α), macrophage inflammatory protein 1-alpha (MIP1-α), DRD3, DRD2, and apolipoprotein E (ApoE) were genotyped. Microtubule associated protein 2 (MAP2), synaptophysin (SYP), human leukocyte antigen-DR (HLA-DR), glial fibrillary acidic protein (GFAP), amyloid beta (A-Beta), and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactivity were quantified in the frontal cortex, putamen, and hippocampus. A composite score for each marker (mean of the three brain regions) was used. Neurocognitive functioning and other clinical variables were determined within 1 year of death. Brain HIV RNA viral load was available for a subset of cases. MAP2 and SYP proved most relevant to neurocognitive functioning. Immunoreactivity of these markers, as well as A-Beta and Iba-1, was correlated with brain HIV RNA viral load. Several genetic markers in combination with other factors predicted histopathology: HIV blood viral load, MIP1-α genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-α genotype predicted GFAP immunoreactivity; ApoE genotype and age at death predicted A-Beta immunoreactivity. These data indicate that HIV replication in the brain is the primary driving force leading to neuroinflammation and dysfunctional protein clearance, as reflected by A-Beta and Iba-1. Downstream to these changes are synaptodendritic degeneration, which is the immediate histopathological substrate of the neurocognitive impairment characteristic of HAND. These intermediate histopathological phenotypes are influenced by host genetic polymorphisms in genes encoding cytokines/chemokines, neuronal protein clearance pathways, and dopaminergic factors.

In this autopsy-based study, human herpesvirus-6 (HHV-6) and -7 (HHV-7) genomic sequence frequency, HHV-6 variants, HHV-6 load and the expression of HHV-6 antigens in brain samples from the individuals, with and without unspecified encephalopathy (controls), using nested and real-time polymerase chain reactions, restriction endonuclease, and immunohistochemical analysis were examined. GraphPad Prism 6.0 Mann-Whitney nonparametric and chi-square test and Fisher's exact test were used for statistical analysis. The encephalopathy diagnoses were shown by magnetic resonance imaging made during their lifetime and macro- and microscopically studied autopsy tissue materials. Widespread HHV-6 and/or HHV-7 positivity was detected in the brain tissue of various individuals with encephalopathy, as well as in controls (51/57, 89.4 % and 35/51, 68.6 %, respectively; p = 0.009). Significantly higher detection frequency of single HHV-6 and concurrent HHV-6 + HHV-7 DNA was found in pia mater meninges, frontal lobe, temporal lobe, and olfactory tract DNAs in individuals with encephalopathy compared to the control group. HHV-6 load and higher frequency of the viral load >10 copies/10(6) cells significantly differed in samples from individuals with and without encephalopathy. The expression of HHV-6 antigens was revealed in different neural cell types with strong predominance in the encephalopathy group. In all HHV-6-positive autopsy samples of individuals with and without encephalopathy, HHV-6B was revealed. Significantly higher detection frequency of beta-herpesvirus DNA, more often detected HHV-6 load >10 copies/10(6) cells, as well as the expression of HHV-6 antigens in different brain tissue samples from individuals with encephalopathy in comparison with control group indicate on potential involvement of these viruses in encephalopathy development.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS). Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr, and Glx/Cr) were measured in the basal ganglia, the frontal white matter, and gray matter, and the best predictive models were selected using a bootstrap-enhanced Akaike information criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr, whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease.

Chronic opiate abuse accelerates the development of cognitive deficits in human immunodeficiency virus (HIV)-1 patients. To investigate morphine's effects on viral infection of the central nervous system, we applied chronic morphine treatment to the LP-BM5 murine acquired immunodeficiency syndrome (MAIDS) model. LP-BM5 infection induces proinflammatory cytokine/chemokine production, correlating to increased blood-brain barrier permeability. Morphine treatment significantly increased LP-BM5 viral load in the hippocampus, but not in the frontal lobe. Morphine reduced the chemokine CCL5 to non-infected levels in the frontal lobe, but not in the hippocampus. These data indicate a region-specific mechanism for morphine's effects on virally-induced neurocognitive deficits., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Apathy is a relatively common psychiatric syndrome in HIV infection, but little is known about its neural correlates. In the present study, we examined the associations between apathy and diffusion tensor imaging (DTI) indices in key frontal white matter regions in the thalamocorticostriatal circuit, which has been implicated in the expression of apathy. Nineteen participants with HIV infection and 19 demographically comparable seronegative comparison subjects completed the Apathy subscale of the Frontal Systems Behavioral Scale as a part of a comprehensive neuropsychiatric research evaluation. When compared to the seronegative participants, the HIV+ group had significantly more frontal white matter abnormalities. Within HIV+ persons, and as predicted, higher ratings of apathy were associated with greater white matter alterations in the anterior corona radiata, genu, and orbital medial prefrontal cortex. The associations between white matter alterations and apathy were independent of depression and were stronger among participants with lower current cluster of differentiation 4 (CD4) counts. All told, these findings indicate that apathy is independently associated with white matter abnormalities in anterior, medial brain regions in persons infected with HIV, particularly in the setting of lower current immune functioning, which may have implications for antiretroviral therapy.

Tumors of any type are exceedingly rare in raccoons. High-grade brain tumors, consistently located in the frontal lobes and olfactory tracts, were detected in 10 raccoons during March 2010-May 2012 in California and Oregon, suggesting an emerging, infectious origin. We have identified a candidate etiologic agent, dubbed raccoon polyomavirus, that was present in the tumor tissue of all affected animals but not in tissues from 20 unaffected animals. Southern blot hybridization and rolling circle amplification showed the episomal viral genome in the tumors. The multifunctional nuclear protein large T-antigen was detectable by immunohistochemical analyses in a subset of neoplastic cells. Raccoon polyomavirus may contribute to the development of malignant brain tumors of raccoons.

Background: HIV-associated dementia (HAD) is the most common dementia type in young adults less than 40 years of age. Although the neurotoxins, oxidative/metabolic stress and impaired activity of neurotrophic factors are believed to be underlying reasons for the development of HAD, the genomic basis, which ultimately defines the virus-host interaction and leads to neurologic manifestation of HIV disease is lacking. Therefore, identifying HIV fingerprints on the host gene machinery and its regulation by microRNA holds a great promise and potential for improving our understanding of HAD pathogenesis, its diagnosis and therapy., Results: A parallel profiling of mRNA and miRNA of the frontal cortex autopsies from HIV positive patients with and without dementia was performed using Illumina Human-6 BeadChip and Affymetrix version 1.0 miRNA array, respectively. The gene ontology and pathway analysis of the two data sets showed high concordance between miRNA and mRNAs, revealing significant interference with the host axon guidance and its downstream signalling pathways in HAD brains. Moreover, the differentially expressed (DE) miRNAs identified in this study, in particular miR-137, 153 and 218, based on which most correlations were built cumulatively targeted neurodegeneration related pathways, implying their future potential in diagnosis, prognosis and possible therapies for HIV-mediated and possibly other neurodegenerative diseases. Furthermore, this relationship between DE miRNAs and DE mRNAs was also reflected in correlation analysis using Bayesian networks by splitting-averaging strategy (SA-BNs), which revealed 195 statistically significant correlated miRNA-mRNA pairs according to Pearson's correlation test (P<0.05)., Conclusions: Our study provides the first evidence on unambiguous support for intrinsic functional relationship between mRNA and miRNA in the context of HIV-mediated neurodegeneration, which shows that neurologic manifestation in HIV patients possibly occurs through the interference with the host axon guidance and its downstream signalling pathways. These data provide an excellent avenue for the development of new generation of diagnostic/prognostic biomarkers and therapeutic intervention strategies for HIV-associated neurodegeneration.

Enteroviral CNS infection is common and its clinical course is usually benign. In immunocompromised patients, however, it can cause meningoencephalitis, presenting with altered mentality and seizure. We describe a previously healthy female patient with enteroviral meningoencephalitis who showed rapidly progressive aphasia. Examination of her cerebrospinal fluid (CSF) showed pleocytosis with lymphocyte dominance, elevated protein, and normal glucose, findings compatible with viral encephalitis. Fluid-attenuated inversion recovery (FLAIR) brain MRI showed hyperintensity in the left frontal and parietal cortices. Enterovirus in the CSF was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) of the CSF. Although her neurological deficits had progressed to global aphasia, conservative management resulted in complete improvement within 3 months. This case provides unusual clinical manifestations and imaging findings in enteroviral encephalitis., (Copyright © 2012 Elsevier B.V. All rights reserved.)

HIV infection in the brain and the resultant encephalitis affect approximately one third of individuals infected with HIV, regardless of treatment with antiretroviral drugs. Microglia are the resident phagocytic cell type in the brain, serving as a "first responder" to neuroinvasion by pathogens. The early events of the microglial response to productively infected monocyte/macrophages entering the brain can best be investigated using in vitro techniques. We hypothesized that activation of microglia would be specific to the presence of simian immunodeficiency virus (SIV)-infected macrophages as opposed to responses to macrophages in general. Purified microglia were grown and stimulated with control or SIV-infected macrophages. After 6 h, aliquots of the supernatant were analyzed for 23 cytokines using Millipore nonhuman primate-specific kit. In parallel experiments, morphologic changes and cytokine expression by individual microglia were examined by immunofluorescence. Surprisingly, the presence of macrophages was more important to the microglial response rather than whether the macrophages were infected with SIV. None of the cytokines examined were unique to co-incubation with SIV-infected macrophages compared with control macrophages, or their supernatants. Media from SIV-infected macrophages, however, did induce secretion of higher levels of IL-6 and IL-8 than the other treatments. As resident macrophages in the brain, microglia would be expected to have a strong response to infiltrate innate immune cells such as monocyte/macrophages. This response is triggered by incubation with macrophages, irrespective of whether or not they are infected with SIV, indicating a rapid, generalized immune response when infiltrating macrophages entering the brain.

Background & Aims: Chronic hepatitis C virus (HCV) infection is associated with altered cerebral metabolism and cognitive dysfunction. We aimed to evaluate the effect of pegylated interferon/ribavirin (PIFN/R) and HCV clearance on cerebral metabolism, and neuropsychological performance., Methods: Fifteen non-cirrhotic HCV positive subjects underwent (1)H MR spectroscopy (MRS) before, during, and after treatment with PIFN/R. The metabolites of interest namely, N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), and the control metabolite creatine (Cr), were acquired from 3 different brain regions; left basal ganglia, left frontal cortex, and left dorso-lateral pre-frontal cortex. Coinciding with this, subjects also underwent a battery of neuropsychological tests to evaluate the domains of verbal learning, memory, attention, language, executive functioning, and motor skills. Seven HCV positive controls (not receiving anti-viral therapy) underwent MRS and neuropsychological testing at two time points, 12 weeks apart, to examine for variation in cerebral metabolites over time and the practice effect of repeat neuropsychological testing., Results: Significant reductions in basal ganglia Cho/Cr (p=0.03) and basal ganglia MI/Cr (p=0.03) were observed in sustained virological responders (SVRs, n=8), but not non-responders/relapsers (NR/R, n=6), indicative of reduced cerebral infection and/or immune activation in those who cleared virus. SVRs demonstrated significant improvements in verbal learning, memory, and visuo-spatial memory. A small but significant improvement in neurocognitive function secondary to the practice effect was seen in both HCV controls and HCV subjects during treatment., Conclusions: HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We describe a method for preparing brain infiltrating leukocytes (BILs) from mice. We demonstrate how to infect mice with Theiler's murine encephalomyelitis virus (TMEV) via a rapid intracranial injection technique and how to purify a leukocyte-enriched population of infiltrating cells from whole brain. Briefly, mice are anesthetized with isoflurane in a closed chamber and are free-hand injected with a Hamilton syringe into the frontal cortex. Mice are then killed at various times after infection by isoflurane overdose and whole brains are extracted and homogenized in RPMI with a Tenbroeck tissue grinder. Brain homogenates are centrifuged through a continuous 30% Percoll gradient to remove the myelin and other cell debris. The cell suspension is then strained at 40 μm, washed and centrifuged on a discontinuous Ficoll-Paque Plus gradient to select and purify the leukocytes. The leukocytes are then washed and resuspended in appropriate buffers for immunophenotyping by flow cytometry. Flow cytometry reveals a population of innate immune cells at the early stages of infection in C57BL/6 mice. At 24 hours post infection, multiple subsets of immune cells are present in the BILs, with an enriched population of Gr1(+), CD11b(+) and F4/80(+)cells. Therefore, this method is useful in characterizing the immune response to acute infection in the brain.

Migration of both uninfected and infected monocytes into the brain during acute HIV infection likely initiates metabolic changes that can be observed with magnetic resonance spectroscopy (MRS). Herein, we measured changes in brain metabolism during the first year of HIV infection and examined the relationship of these metabolite levels to CD16+ monocyte populations measured in the blood. MRS was performed on nine HIV+ subjects identified during acute HIV infection and nine seronegative control subjects. HIV+ subjects were examined within 90 days of an indeterminate Western blot, then again 2 and 6 months later, during early infection. Blood samples were collected for plasma viral RNA and monocyte subset quantification. HIV+ subjects were identified with acute viral ailment and did not display severe cognitive deficits such as dementia or minor cognitive motor disorder. Changes in lipid membrane metabolism (choline levels) in the frontal cortex and white matter were observed during the initial year of HIV infection. Greater numbers of CD16+ monocytes were associated with lower N-acetylaspartate levels and higher choline levels in the brain. These results suggest that HIV infection induces metabolic changes in the brain early during infection and that these changes may be related to monocyte dynamics in the periphery.

Background: Autophagy is critical to maintaining cell homeostasis and is implicated in neurodegenerative diseases. This research examined the role of autophagy in human immunodeficiency virus type 1 (HIV-1)-associated encephalitis, the pathologic hallmark of neuroAIDS., Methods: The frontal cortex from 32 HIV-infected persons (12 without evidence HIV-1 encephalitis or clinical signs of central nervous system impairment and 20 with histopathological findings of HIV-1 encephalitis) and 8 persons without HIV infection and any neuropathology were examined postmortem. Green fluorescent protein-labeled (GFP) light chain 3 (LC3)-expressing neuroblastoma SK-N-SH cells treated with gp120 from CXCR4 and CCR5 viruses were also examined. Autophagic markers were assessed by means of Western blot analysis, transmission electron microscopy (TEM), and confocal microscopy., Results: Autophagic proteins Beclin 1, Autophagy-related gene (Atg)-5, Atg-7, and LC3-II were significantly increased in brains with HIV-1 encephalitis (P < .05). These findings were confirmed by TEM and immunostaining of brain tissue. Additionally, levels of autophagic proteins and autophagosomes were increased in neuronal cells treated with both CXCR4- or CCR5-tropic HIV-1 gp120. No increase in the level of autophagy was observed in the brains of HIV-infected persons without HIV-1 encephalitis compared with the level in brains of HIV-uninfected persons., Conclusions: Postmortem brains with HIV-1 encephalitis exhibit increased markers of autophagy compared with brains from HIV-infected persons without HIV-1 encephalitis or HIV-uninfected control brains, which suggests that dysregulation of autophagy may be important in the pathogenesis of neuroAIDS.

In view of the rising prevalence of an overweight body mass among patients living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), clinicians must now be mindful of possible adverse outcomes resulting from the co-occurrence. The present study was designed to examine the additive and interactive effects of HIV/AIDS and an excess body mass, as well as the additional contributions of substance abuse or dependence. The dependent variable was brain function estimated by the measurement of P300 electroencephalographic potentials. P300 potentials were recorded during a task designed to elicit subcomponents with frontal (P300a) and both frontal and non-frontal (P300b) generators. Analyses revealed greater frontal P300a latencies among the 102 HIV-1 seropositive versus the 68 seronegative participants. In addition, frontal P300a latency was further increased by a synergistic interaction of HIV-1 serostatus with a body mass index (BMI)≥25 kg/m². A history of substance abuse/dependence did not alter these changes. However, it did combine with HIV/AIDS to produce a smaller P300a amplitude than was seen in participants with neither disorder. The findings suggest that white matter changes accompanying an excess BMI may exacerbate those that attend HIV/AIDS and thereby slow down frontal brain function. Substance abuse, likewise, interacts with HIV/AIDS but may impair frontal brain function via a different mechanism., (Copyright © 2009 Elsevier Ltd. All rights reserved.)

Cerebral metabolite disturbances occur among human immunodeficiency virus (HIV)-infected people, and are thought to reflect neuropathology, including proinflammatory processes, and neuronal loss. HIV-associated cortical atrophy continues to occur, though its basis is not well understood, and the relationship of cerebral metabolic disturbance to structural brain abnormalities in HIV has not been well delineated. We hypothesized that metabolite disturbances would be associated with reduced cortical and subcortical volumes. Cerebral volumes were measured in 67 HIV-infected people, including 10 people with mild dementia (acquired immunodeficiency syndrome [AIDS] dimentia complex [ADC] stage >1) via automated magnetic resonance imaging (MRI) segmentation. Magnetic resonance spectroscopy (MRS) was used to measure levels of cerebral metabolites N-acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), glutamate/glutamine (Glx), and creatine (Cr) from three brain regions (frontal gray matter, frontal white matter, basal ganglia). Analyses were conducted to examine the associations between MRS and cerebral volumetric measures using both absolute and relative metabolite concentrations. NAA in the mid-frontal gray matter was most consistently associated with cortical (global, frontal, and parietal), ventricular, and caudate volumes based on analysis of absolute metabolite levels, whereas temporal lobe volume was associated with basal ganglia NAA and Glx, and Cho concentrations in the frontal cortex and basal ganglia. Hippocampal volume was associated with frontal white matter NAA, whereas thalamic volume was associated with both frontal white matter NAA and basal ganglia Glx. Analyses of relative metabolite concentrations (referenced to Cr) yielded weaker effects, although more metabolites were retained as significant predictors in the models than the analysis of absolute concentrations. These findings demonstrate that reduced cortical and subcortical volumes, which have been previously found to be linked to HIV status and history, are also strongly associated with the degree of cerebral metabolite disturbance observed via MRS. Reduced cortical and hippocampal volumes were most strongly associated with decreased NAA, though reduced Glx also tended to be associated with reduced cortical and subcortical volumes (caudate and thalamus) as well, suggesting both neuronal and glial disturbances. Interestingly, metabolite-volumetric relationships were not limited to the cortical region from which MRS was measured, possibly reflecting shared pathophysiological processes. The relationships between Cho and volumetric measures suggest a complicated relationship possibly related to the effects of inflammatory processes on brain volume. The findings demonstrate the relationship between MRI-derived measures of cerebral metabolite disturbances and structural brain integrity, which has implication in understanding HIV-associated neuropathological mechanisms.

Encephalitis is a major cause of death worldwide. Although >100 pathogens have been identified as causative agents, the pathogen is not determined for up to 75% of cases. This diagnostic failure impedes effective treatment and underscores the need for better tools and new approaches for detecting novel pathogens or determining new manifestations of known pathogens. Although astroviruses are commonly associated with gastroenteritis, they have not been associated with central nervous system disease. Using unbiased pyrosequencing, we detected an astrovirus as the causative agent for encephalitis in a 15-year-old boy with agammaglobulinemia; several laboratories had failed to identify the agent. Our findings expand the spectrum of causative agents associated with encephalitis and highlight unbiased molecular technology as a valuable tool for differential diagnosis of unexplained disease.

The molecular mechanisms underlying learning and memory impairment in patients with HIV-associated neurological disease have remained unclear. Calcium/calmodulin-dependent kinase II (CaMKII) has key roles in synaptic potentiation and memory storage in neurons and also may have immunomodulatory functions. To determine whether HIV and simian immunodeficiency virus (SIV) induce alterations in CaMKII expression and/or activation (autophosphorylation) in the brain, we measured CaMKII alterations by quantitative immunoblotting in both an in vitro HIV/neuronal culture model and in vivo in an SIV-infected macaque model of HIV-associated neurological damage. Using primary rat hippocampal neuronal cultures treated with culture supernatants harvested from HIV-1-infected human monocyte-derived macrophages (HIV/MDM), we found that CaMKII activation declined after exposure of neurons to HIV/MDM. Consistent with our in vitro measurements, a significant decrease in CaMKII activation was present in both the hippocampus and frontal cortex of SIV-infected macaques compared with uninfected animals. In SIV-infected animals, total CaMKII expression in the hippocampus correlated well with levels of synaptophysin. Furthermore, CaMKII expression in both the hippocampus and frontal cortex was inversely correlated with viral load in the brain. These findings suggest that alterations in CaMKII may compromise synaptic function in the early phases of chronic neurodegenerative processes induced by HIV.

HIV infection disturbs the central nervous system (CNS) through inflammation and glial activation. Evidence suggests roles for microRNA (miRNA) in host defense and neuronal homeostasis, though little is known about miRNAs' role in HIV CNS infection. MiRNAs are non-coding RNAs that regulate gene translation through post-transcriptional mechanisms. Messenger-RNA profiling alone is insufficient to elucidate the dynamic dance of molecular expression of the genome. We sought to clarify RNA alterations in the frontal cortex (FC) of HIV-infected individuals and those concurrently infected and diagnosed with major depressive disorder (MDD). This report is the first published study of large-scale miRNA profiling from human HIV-infected FC. The goals of this study were to: 1. Identify changes in miRNA expression that occurred in the frontal cortex (FC) of HIV individuals, 2. Determine whether miRNA expression profiles of the FC could differentiate HIV from HIV/MDD, and 3. Adapt a method to meaningfully integrate gene expression data and miRNA expression data in clinical samples. We isolated RNA from the FC (n = 3) of three separate groups (uninfected controls, HIV, and HIV/MDD) and then pooled the RNA within each group for use in large-scale miRNA profiling. RNA from HIV and HIV/MDD patients (n = 4 per group) were also used for non-pooled mRNA analysis on Affymetrix U133 Plus 2.0 arrays. We then utilized a method for integrating the two datasets in a Target Bias Analysis. We found miRNAs of three types: A) Those with many dysregulated mRNA targets of less stringent statistical significance, B) Fewer dysregulated target-genes of highly stringent statistical significance, and C) unclear bias. In HIV/MDD, more miRNAs were downregulated than in HIV alone. Specific miRNA families at targeted chromosomal loci were dysregulated. The dysregulated miRNAs clustered on Chromosomes 14, 17, 19, and X. A small subset of dysregulated genes had many 3' untranslated region (3'UTR) target-sites for dysregulated miRNAs. We provide evidence that certain miRNAs serve as key elements in gene regulatory networks in HIV-infected FC and may be implicated in neurobehavioral disorder. Finally, our data indicates that some genes may serve as hubs of miRNA activity.

Infection of the central nervous system with human immunodeficiency virus type 1 (HIV-1) can produce morphological changes in the neocortical synaptodendritic arbor that are correlated with neurocognitive impairment. To determine whether HIV-1 infection influences the protein composition of human synapses, a proteomic study of isolated nerve endings was undertaken. Synaptosomes from frontal neocortex were isolated using isopyknic centrifugation from 19 human brain specimens. Purity and enrichment were assessed by measuring pre- and postsynaptic protein markers. Two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry was used to screen for proteins differentially expressed in HIV/AIDS. The concentrations of 31 candidate protein spots were potentially abnormal in HIV-infected decedents with HIV encephalitis and/or increased expression of immunoproteasome subunits. Immunoblots showed that the concentration of some of them was related to HIV-1 infection of the brain and immunoproteasome (IPS) induction. Synapsin 1b and stathmin were inversely related to brain HIV-1 load; 14-3-3zeta and 14-4-4epsilon proteins were higher in subjects with HIV-1 loads. Perturbed synaptosome proteins were linked with IPS subunit composition, and 14-3-3zeta was histologically colocalized with IPS subunits in stained neocortical neurons. Proteomics illustrates that certain human proteins within the synaptic compartment are involved with changes in the synaptodendritic arbor and neurocognitive impairment in HIV-1-infected people.

Patients infected with human immunodeficiency virus (HIV) have a higher risk of developing major depressive disorder (MDD) than the general population. Immunophilins FKBP51 and FKBP52 are expressed in cortical neurons and regulate the function of the glucocorticoid receptor (GR). Previous reports have shown that genetic variants in the FKBP5 gene encoding FKBP51 are linked to psychiatric disorders. We sought to determine whether immunophilins are upregulated in HIV infection. To determine whether FKBP52 and FKBP51 are associated with MDD and/or HIV, we compared protein and gene expression in autopsy tissues from the frontal cortical gray matter. The study cases were divided into five groups: control, MDD, MDD with psychosis, HIV(+), and HIV(+) with MDD. Gene expression and protein levels were determined by real-time PCR and Western blot analysis of fresh frozen tissues. Genotyping of previously published alleles of the FKBP5 gene was also performed. We found correlation of upregulation of both immunophilins in the HIV-infected groups. In the HIV(+) population with MDD, FKBP4 expression is significantly higher while FKBP5 is more variable. After analyzing the FKBP5 gene for single nucleotide polymorphisms, we found that rs3800373 CC genotype is more frequent in the MDD and MDD/Psychosis groups. We hypothesized that the levels of FKBP51, as modulator of the nuclear translocation of GR, would be lower in MDD. Instead, an increase in FKBP51 at both the transcript (FKBP5) and protein level correlated with MDD. Increased FKBP4 expression of correlated to HIV(+)MDD but not to HIV without MDD.

Neurological complications associated with the acquired immunodeficiency syndrome, in particular, HIV-associated dementia, continue to plague those infected. We report our finding that the concentration of brain Glu is reduced in the frontal white matter region in this condition. In addition, our data appear to absolve highly active retroviral therapy (HAART) from blame, as drug-naïve patients were equally affected. Our findings suggest that Glu neurotransmission is abnormal and may be a key target for early interventions to reduce the later incidence of neurocognitive impairment and dementia among HIV-seropositive patients.

The brains of Alzheimer's disease sufferers are characterized by amyloid plaques and neurofibrillary tangles. However, the cause(s) of these features and those of the disease are unknown, in sporadic cases. We previously showed that herpes simplex virus type 1 is a strong risk factor for Alzheimer's disease when in the brains of possessors of the type 4 allele of the apolipoprotein E gene (APOE-epsilon4), and that beta-amyloid, the main component of plaques, accumulates in herpes simplex virus type 1-infected cell cultures and mouse brain. The present study aimed to elucidate the relationship of the virus to plaques by determining their proximity in human brain sections. We used in situ polymerase chain reaction to detect herpes simplex virus type 1 DNA, and immunohistochemistry or thioflavin S staining to detect amyloid plaques. We discovered a striking localization of herpes simplex virus type 1 DNA within plaques: in Alzheimer's disease brains, 90% of the plaques contained the viral DNA and 72% of the DNA was associated with plaques; in aged normal brains, which contain amyloid plaques at a lower frequency, 80% of plaques contained herpes simplex virus type 1 DNA but only 24% of the viral DNA was plaque-associated (p < 0.001). We suggest that this is because in aged normal individuals, there is a lesser production and/or greater removal of beta-amyloid (Abeta), so that less of the viral DNA is seen to be associated with Abeta in the brain. Our present data, together with our finding of Abeta accumulation in herpes simplex virus type 1-infected cells and mouse brain, suggest that this virus is a major cause of amyloid plaques and hence probably a significant aetiological factor in Alzheimer's disease. They point to the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it.

The human immunodeficiency virus (HIV) damages fronto-striatal regions, and is associated with deficits in executive functioning. We recently developed a semantic event sequencing task based on the Picture Arrangement subtest of the Wechsler Adult Intelligence Scale-III for use with functional magnetic resonance imaging (fMRI) and found recruitment of dorsolateral prefrontal cortex and basal ganglia in healthy participants. To assess the impact of HIV on the functioning of the basal ganglia and prefrontal cortex, we administered this task to 11 HIV+ and 11 Control participants matched for age and education. Neuropsychological evaluation demonstrated that the HIV+ group had mild impairment in memory retrieval and motor functioning, but was not demented. Morphometric measurements suggested no atrophy in basal ganglia regions. The results of the fMRI analysis revealed hypoactivation of the left caudate, left dorsolateral prefrontal cortex, and bilateral ventral prefrontal cortex in the HIV+ group. Functional connectivity analysis demonstrated less functional connectivity between the caudate and prefrontal cortex and basal ganglia regions in the HIV+ group. In contrast, the HIV+ group demonstrated increased activation of right postcentral/supramarginal gyrus, and greater connectivity between the caudate and this same anterior parietal region. The results of this study extend previous investigations by demonstrating compromised function of the caudate and connected prefrontal regions in HIV during cognition. This disruption of fronto-striatal circuitry likely precedes the development of cognitive impairment in HIV.

The authors report a patient with herpes simplex encephalitis who presented with magnetic resonance imaging (MRI) lesions exclusively in the frontal lobes, including the bilateral anterior cingulate gyri. She is making a good recovery after therapy with intravenous acyclovir. A similar presentation with a fatal outcome was previously reported by Rose et al (Neurology 42: 1809-1812, 1992). MRI shows temporal lesions in most patients with herpes simplex encephalitis, whereas occasional patients have normal imaging. A high index of suspicion for the diagnosis of herpes simplex encephalitis should be maintained when a patient presents with fever and brain lesions involving extratemporal limbic system structures.

Human immunodeficiency virus type 1 (HIV-1) enters the central nervous system shortly after the infection and becomes localized in different regions of the brain, leading to various neurological abnormalities including motor disorders and neurocognitive deficits. Although HIV-1-associated functional abnormalities of the central nervous system (CNS) can be evaluated during life by using various test batteries, HIV-1 virus concentration in different brain regions can be measured only after death. The tissues obtained at autopsy provide a valuable source for determining the role of various factors, including that of HIV-1 viral load in the CNS, that may contribute to the regional CNS neuropathogenesis. For this study, we obtained from the National Institutes of Health-sponsored National NeuroAIDS Tissue Consortium (NNTC) the tissues from different brain regions collected at autopsy of HIV-1-positive (N = 38) and HIV-negative (N = 11) individuals, with postmortem intervals of 2 to 29 h, and measured HIV-1 RNA concentration in the frontal cortex, frontal cortex area 4, frontal cortex area 6, basal ganglia, caudate nucleus, putamen, globus pallidus, substantia nigra, and cerebrospinal fluid. Because HIV-1+ individuals were infected with the virus for up to 21 years and the majority of them had used highly active antiretroviral therapy (HAART), we used highly sensitive real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay in order to detect a wide dynamic range of HIV-1 RNA with lower detection limit of a single copy. The primers and probes were from the long terminal repeat (LTR) region of HIV genome for achieving higher specificity and sensitivity of detection and amplification. Our results demonstrate a wide variation in the concentration of HIV-1 RNA in different brain regions (5.51 and 8,144,073; log(10) 0.74 and 6.91 copies/g tissue), and despite the high specificity and sensitivity of this method, viral RNA was not detected in 50% of all the samples, and in 30% to 64% of samples of each region of HIV-1+ individuals. However, the highest concentration of viral RNA was found in the caudate nucleus and the lowest concentration in the frontal cortex and cerebrospinal fluid. The viral RNA was undetectable in all samples of HIV-negative individuals.

Isolated cases of human herpesvirus 6 encephalopathy have recently been reported, although the pathophysiology remains largely unknown. To elucidate the changes specific to human herpesvirus 6 encephalopathy on diagnostic images, this study investigated magnetic resonance imaging findings in 10 patients with a diagnosis of human herpesvirus 6 encephalopathy including diffusion-weighted imaging in 6 of 10, and findings of cerebral blood flow imaging by single-photon emission computed tomography in 9 of 10 patients. No abnormalities were evident on T(1)-weighted, T(2)-weighted, or fluid-attenuated inversion-recovery magnetic resonance imaging during acute phases; however, diffusion-weighted imaging indicated abnormal hyperintensity in the subcortical white matter of the frontal lobes in all six patients during the acute phase. Cerebral blood flow single-photon emission computed tomography revealed decreased perfusion, predominantly in the frontal region of all nine patients during their clinical course. Disturbances predominantly affecting the frontal lobes (region) on magnetic resonance imaging and cerebral blood flow single-photon emission computed tomography were common in all patients, suggesting that the findings may be characteristic of human herpesvirus 6 encephalopathy.

This report describes a previously 28-year-old healthy woman, identified as an asymptomatic human T-lymphotropic virus type I (HTLV-I) carrier, who developed both progressive multifocal leukoencephalopathy (PML) and Pneumocystis jiroveci pneumonia. For diagnostic confirmation of PML, stereotactic brain biopsy demonstrated multiple demyelinating lesions with the presence of JC viral antigen. Intramuscular alpha-interferon therapy for 2 weeks brought considerable neurologic improvement. Three years later, the patient developed lymphoma-type of adult T-cell leukemia, suggesting that HTLV-I carrier might be one of the underlying diseases of PML.

Background: With the introduction of antibiotics, neurosyphilis is now considered uncommon, and accurate diagnosis sometimes is problematic as the symptoms and signs are not pathognomonic., Review Summary: We present a 51-year-old man who had a 4-month history of general malaise and subtle cognitive impairment, combined with a normal brain image study, who ultimately developed an episode of status epilepticus as the main manifestation of unrecognized neurosyphilis., Conclusion: Because a clinical diagnosis of neurosyphilis is rarely encountered today in the developed world, a high index of suspicion and clinician awareness is very important in early diagnosis.

Several studies have demonstrated that antiretroviral therapy diminishes the adverse effects of HIV/AIDS on brain function. Yet, few studies have examined the role of comorbid psychiatric disorders in limiting the magnitude of recovery. The present study examined the effects of the presence versus absence of one such disorder--antisocial personality disorder (ASPD)--on brain function in an HIV-1 seronegative control group (n=68) and in HIV-1 seropositive patients receiving (n=26), versus not receiving (n=71), antiretroviral treatment. The primary dependent measures of brain function were the amplitude, latency, and topography of the P300 event-related potential. ANCOVA revealed a significant main effect of ASPD as well as an interaction between ASPD and HIV-1/treatment status. Participants with ASPD exhibited a significant decrement in frontal P300 amplitude in comparison to the ASPD-negative groups. More importantly, further analyses showed that ASPD blunted the decrement in P300 accompanying untreated HIV/AIDS as well as the improvement in P300 accompanying antiretroviral treatment. The results suggest that P300 is minimally improved by antiretroviral therapy among HIV-1 seropositive patients with comorbid ASPD. The lack of antiretroviral efficacy is not easily explained by poor medication compliance. The diminished response to treatment is more likely related to a pre-existing neurophysiological decrement localized to the same brain regions where HIV/AIDS and antiretroviral treatment exert their maximal effect., (Copyright (c) 2006 S. Karger AG, Basel.)

The neurodegenerative process in HIV encephalitis (HIVE) is associated with extensive damage to the dendritic and synaptic structure that often leads to cognitive impairment. Several mechanisms might be at play, including release of neurotoxins, oxidative stress and decreased activity of neurotrophic factors. Furthermore, HIV-mediated dysregulation of genes involved in neuronal maintenance might play an important role. For this purpose, cRNA was prepared from the brains of 17 AIDS patients for analysis with the Affymetrix Human U95Av2 GeneChip and analyzed with the GeneSpring Expression Analysis Software. Out of 12,625 genes analyzed, 74 were downregulated and 59 were upregulated compared to controls. Initial alternative analysis of RNA was performed by ribonuclease protection assay (RPA). In cases with HIVE, downregulated genes included neuronal molecules involved in synaptic plasticity and transmission (ion channels, synaptogyrin, synapsin II), cell cycle (p35, p39, CDC-L2, CDC42, PAK1) and signaling molecules (PI3K, Ras-Raf-MEK1), transcription factors and cytoskeletal components (MAP-1B, MAP-2, tubulin, adducin-2). Upregulated genes included those involved in neuroimmune (IgG, MHC, beta2microglobulin) and anti-viral responses (interferon-inducible molecules), transcription (STAT1, OLIG2, Pax-6) and signaling modulation (MEK3, EphB1) of the cytoskeleton (myosin, aduccin-3, radixin, dystrobrevin). Taken together, this study suggests that HIV proteins released from infected macrophages might not only induce a neuroinflammatory response, but also may promote neurodegeneration by interfering with neuronal transcription of genes involved in regulating signaling and cytoskeletal molecules important in maintaining synapto-dendritic functioning and integrity.