ABSTRACT
The aim of the study was to evaluate the incidence of brain opportunistic pathologies and survival in patients living with HIV from a Romanian tertiary center. A 15-year prospective observational study of brain opportunistic infections diagnosed in HIV-infected patients was performed at Victor Babes Hospital, Bucharest, between January 2006 and December 2021. Characteristics and survival were compared related to modes of HIV acquisition and type of opportunistic infection. A total of 320 patients were diagnosed with 342 brain opportunistic infections (incidence 9.79 per 1000 person-years), 60.2% males with median age at diagnosis of 31 years (IQR 25, 40). Median CD4 cell count and VL were 36/µL (IQR 14, 96) and 5.1 log10 copies/mL (IQR 4, 5.7) respectively. The routes of HIV acquisition were heterosexual (52.6%), parenteral route in early childhood (31.6%), injecting drug use (12.9%), men having sex with men (1.8%), and vertical (1.2%). The most common brain infections were progressive multifocal leukoencephalopathy (31.3%), cerebral toxoplasmosis (26.9%), tuberculous meningitis (19.3%), and cryptococcal meningitis (16.7%). Patients infected by parenteral mode in early childhood were younger at diagnosis of both opportunistic infection and HIV (p < 0.001 and p < 0.001, respectively), developed more frequently PML (p < 0.001), and had the lowest early (p = 0.002) and late (p = 0.019) mortality rates. Risk factors for shorter survival were age > 30 years (p = 0.001), injecting drug use (p = 0.003), CD4 + < 100/µL (p = 0.007), and VL > 5 log10 copies/mL at diagnosis (p < 0.001). The incidence and mortality rate of brain opportunistic infections were high and did not decrease significantly during the study period, due to late presentation or non-adherence to ART.
Subject(s)
AIDS-Related Opportunistic Infections , HIV Infections , Neoplasms , Male , Humans , Child, Preschool , Adult , Female , AIDS-Related Opportunistic Infections/drug therapy , AIDS-Related Opportunistic Infections/epidemiology , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Neoplasms/epidemiology , CD4 Lymphocyte Count , Brain/pathologyABSTRACT
Given the co-occurrence of memory impairment in HIV-associated neurocognitive disorders (HAND) and amnestic mild cognitive impairment/Alzheimer's disease (aMCI/AD), biomarkers are needed that can disentangle these conditions among people with HIV (PWH). We assessed whether cerebrospinal fluid (CSF) markers of AD could help in this effort by determining their relationship to learning and memory deficits versus cognitive deficits more characteristic of HAND than aMCI/AD (processing speed and complex visual/motor coordination) among 31 older PWH. CSF amyloid-ß42 phosphorylated-tau, amyloid-ß40/amyloid-ß42 and phosphorylated-tau/amyloid-ß42 ratio related to learning/memory performance but not HAND-related deficits, suggesting that these biomarkers may have utility in disentangling aMCI/AD from HAND.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , HIV Infections , Aged , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Cognitive Dysfunction/psychology , HIV Infections/complications , Humans , Memory Disorders , Neuropsychological Tests , Peptide Fragments/cerebrospinal fluid , Pilot Projects , tau Proteins/cerebrospinal fluidABSTRACT
The neuropathogenesis of HIV associated neurocognitive disorders (HAND) involves disruption of mitochondrial homeostasis and increased neuroinflammation. However, it is unknown if alterations in mitochondrial biogenesis in the brain underlie the neuropathogenesis of HAND. In this study, neuropathological and molecular analyses of mitochondrial biogenesis and inflammatory pathways were performed in brain specimens from a well-characterized cohort of HIV+ cases that were on antiretroviral regimens. In vitro investigations using primary human astroglia and neurons were used to probe the underlying mechanisms of mitochondrial alterations. In frontal cortices from HAND brains compared to cognitive normal brains, total levels of transcription factors that regulate mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and transcription factor A, mitochondrial (TFAM) were decreased. Immunohistochemical analyses revealed that TFAM was decreased in neurons and increased in astroglia. These changes were accompanied by decreased total mitochondrial DNA per cell and increased levels of messenger RNA for the proinflammatory cytokine interleukin (IL)-1ß. To determine how IL-1ß affects astroglial bioenergetic processes and mitochondrial activity, human astroglial cultures were exposed to recombinant IL-1ß. IL-1ß induced mitochondrial activity within 30â¯min of treatment, altered mitochondrial related gene expression, altered mitochondrial morphology, enhanced adenoside triphosphate (ATP) utilization and increased the expression of inflammatory cytokines. WIN55,212-2 (WIN), an aminoalkylindole derivative and cannabinoid receptor agonist, blocked IL-1ß-induced bioenergetic fluctuations and inflammatory gene expression in astroglia independent of cannabinoid receptor (CB)1 and peroxisome proliferator-activated receptor (PPAR) γ. A PPARα antagonist reversed the anti-inflammatory effects of WIN in human astroglia. These results show that mitochondrial biogenesis is differentially regulated in neurons and astroglia in HAND brains and that targeting astroglial bioenergetic processes may be a strategy to modulate neuroinflammation.
Subject(s)
Anti-HIV Agents/therapeutic use , Astrocytes/metabolism , Brain/metabolism , HIV Seropositivity/metabolism , Mitochondria/metabolism , Organelle Biogenesis , Anti-HIV Agents/pharmacology , Astrocytes/drug effects , Astrocytes/pathology , Brain/drug effects , Brain/pathology , Cells, Cultured , DNA-Binding Proteins/metabolism , HIV Seropositivity/drug therapy , HIV Seropositivity/pathology , Humans , Inflammation/metabolism , Inflammation/pathology , Interleukin-1beta/pharmacology , Mitochondria/drug effects , Mitochondria/pathology , Mitochondrial Proteins/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Transcription Factors/metabolismABSTRACT
People over the age of 50 are the fastest growing segment of the HIV-infected population in the USA. Although antiretroviral therapy has remarkable success controlling the systemic HIV infection, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group, and cognitive deficits appear more severe in aged patients with HIV. The mechanisms of HAND in the aged population are not completely understood; a leading hypothesis is that aged individuals with HIV might be at higher risk of developing Alzheimer's disease (AD) or one of the AD-related dementias (ADRD). There are a number of mechanisms through which chronic HIV disease alone or in combination with antiretroviral therapy and other comorbidities (e.g., drug use, hepatitis C virus (HCV)) might be contributing to HAND in individuals over the age of 50 years, including (1) overlapping pathogenic mechanisms between HIV and aging (e.g., decreased proteostasis, DNA damage, chronic inflammation, epigenetics, vascular), which could lead to accelerated cellular aging and neurodegeneration and/or (2) by promoting pathways involved in AD/ADRD neuropathogenesis (e.g., triggering amyloid ß, Tau, or α-synuclein accumulation). In this manuscript, we will review some of the potential common mechanisms involved and evidence in favor and against a role of AD/ADRD in HAND.
Subject(s)
AIDS Dementia Complex/etiology , AIDS Dementia Complex/epidemiology , AIDS Dementia Complex/pathology , Age of Onset , Aged , Aged, 80 and over , Amyloidogenic Proteins/metabolism , Anti-HIV Agents/therapeutic use , Autophagy , Brain/metabolism , Brain/pathology , Brain/virology , Comorbidity , Epigenesis, Genetic , Female , HIV/isolation & purification , HIV/physiology , Humans , Macrophages/virology , Male , Microglia/virology , Middle Aged , Neural Stem Cells/pathology , Neurocognitive Disorders/epidemiology , Protein Aggregation, Pathological , Proteostasis , Viral Tropism , White Matter/pathologyABSTRACT
Neuroinflammation is a common pathological correlate of HIV-associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)-ß, surveys for damaged neurons, and orchestrates microglial differentiation. TREM2 has not been studied in HIV+ brain tissues. In this retrospective study, we investigated TREM2 expression levels and localization to microglia, Aß protein levels, and tumor necrosis factor (TNF)-α transcript levels in the frontal cortices of 52 HIV+ decedents. All donors had been on ART; 14 were cognitively normal (CN), 17 had an asymptomatic neurocognitive impairment (ANI), and 21 had a minor neurocognitive disorder (MND). Total TREM2 protein levels were increased in the soluble and decreased in the membrane-enriched fractions of MND brain tissues compared to CN; however, brains from MND Hispanics showed the most robust alterations in TREM2 as well as significantly increased TNF-α mRNA and Aß levels when compared to CN Hispanics. Significant alterations in the expression of total TREM2 protein and transcripts for TNF-α were not observed in non-Hispanics, despite higher levels of Aß in the non-Hispanic CN group compared to the non-Hispanic MND groups. These findings show that decreased and increased TREM2 in membrane-bound fractions and in soluble-enriched fractions, respectively, is associated with increased Aß and neuroinflammation in this cohort of HIV+ brains, particularly those identifying as Hispanics. These findings suggest a role for TREM2 in the brain of HIV+ individuals may deserve more investigation as a biomarker for HAND and as a possible therapeutic target. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
Subject(s)
AIDS Dementia Complex/metabolism , AIDS Dementia Complex/psychology , Amyloid beta-Peptides/metabolism , Antiretroviral Therapy, Highly Active , Brain Chemistry , Cognition Disorders/metabolism , Cognition Disorders/psychology , Membrane Glycoproteins/metabolism , Receptors, Immunologic/metabolism , AIDS Dementia Complex/drug therapy , Adult , Amyloid beta-Peptides/analysis , Biomarkers , Ethnicity , Female , HIV Seropositivity , Hispanic or Latino , Humans , Male , Membrane Glycoproteins/analysis , Microglia/metabolism , Middle Aged , Neuropsychological Tests , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Receptors, Immunologic/analysis , Retrospective Studies , Tumor Necrosis Factor-alpha/metabolismABSTRACT
OBJECTIVE: Peripheral inflammation has been associated with adverse effects on cognition and brain structure in late life, a process called 'inflammaging.' Identifying biomarkers of preclinical cognitive decline is critical in the development of preventative therapies, and peripheral inflammation may be able to serve as an indicator of cognitive decline. However, little is known regarding the relationship between peripheral inflammation and brain structure and function among older adults. METHODS: Twenty-four older adults (mean age = 78) underwent a functional magnetic resonance imaging (fMRI) resting state functional connectivity scan, and a subset (n = 14) completed the n-Back working memory task in the scanner. All participants completed a blood draw, and inflammation was measured with interleukin 6 (IL-6) and C-Reactive Protein (CRP). RESULTS: Surprisingly, age was unrelated to measures of inflammation (IL-6, CRP) or brain function (default mode network (DMN) connectivity; working memory performance; blood oxygenation level dependent (BOLD) activation with higher working memory load). However, lower functional connectivity between the left parietal seed and all other DMN regions was associated with higher levels of IL-6 and CRP. Additionally, greater plasma concentration of IL-6 was associated with lower BOLD activation in the left middle frontal gyrus in response to increased working memory load. CONCLUSIONS: These preliminary findings support the importance of IL-6 and CRP in brain function among older adults. Frontal and parietal regions may be particularly sensitive to the effects of inflammation. Additionally, these findings provide preliminary evidence of inflammatory contributions to level of neural activity, even after accounting for vascular risk factors.
Subject(s)
Brain Mapping , Cognitive Dysfunction , Inflammation , Magnetic Resonance Imaging , Parietal Lobe , Aged , C-Reactive Protein/analysis , Cognition , Female , Frontal Lobe , Humans , Interleukin-6/blood , Male , Memory, Short-Term/physiology , Parietal Lobe/diagnostic imaging , Parietal Lobe/physiopathology , RestABSTRACT
This study aimed to investigate the influence of antiretroviral therapy on methylation markers, in a group of HIV infected, heavily treated patients. Immune and molecular methods were used to investigate potential changes in methylation profile in DNA isolated from peripheral blood mononuclear cells collected from antiretroviral-experienced HIV infected patients and healthy controls. The percentage of 5-methylcytosine was inversely correlated with proviral DNA and active replication while DNMT1 (p = 0.01) and DNMT3A (p = 0.004) independently correlated with active viral replication. DNMT3A expression increased with total treatment duration (p = 0.03), number of antiretroviral drugs ever used (p = 0.003), and cumulative exposure to protease inhibitors (p = 0.02) even in currently HIV undetectable patients.
Subject(s)
Anti-HIV Agents/therapeutic use , DNA Methylation/immunology , HIV Infections/drug therapy , HIV Infections/pathology , Immunoassay/methods , Leukocytes, Mononuclear/metabolism , Adult , Antiretroviral Therapy, Highly Active , Female , HIV Infections/metabolism , Humans , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology , Male , Young AdultABSTRACT
BACKGROUND: HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson's disease, Alzheimer's disease, and Huntington's disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity. METHODS: GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy. RESULTS: We found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field. CONCLUSIONS: Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations.
Subject(s)
HIV Envelope Protein gp120/toxicity , Immunosuppressive Agents/therapeutic use , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/etiology , Tacrolimus/therapeutic use , Analysis of Variance , Animals , Calcium/metabolism , Calcium-Binding Proteins/metabolism , Disease Models, Animal , Encephalitis/drug therapy , Interleukin-6/metabolism , Mice , Microfilament Proteins/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Nerve Degeneration/drug therapy , Nerve Degeneration/etiology , Nerve Tissue Proteins/metabolism , Neurotoxicity Syndromes/complications , Tacrolimus Binding Proteins/metabolism , Treatment OutcomeABSTRACT
MicroRNAs (miRNAs) are small, non-coding RNA species essential for the post-translational regulation of gene expression. Several miRNA have been proposed to contribute to Human immunodeficiency virus-1 (HIV-1) infection establishment, progression and latency. Among them, miR-29a seems to be of particular interest. The aim of this study was to investigate the association between miR-29a expression and immunologic and virologic markers of HIV infection progression in long-term antiretroviral-treated individuals. In a homogenous group of 165 young adults, with chronic HIV infection, parenterally acquired during childhood, the expression level of miR-29a was found to be inversely correlated with HIV viral load and the degree of immunosuppression, expressed by both CD4 cell count and the CD4/CD8 ratio. There was a significant difference in miR-29a expression according to the patient's response to treatment, with the lowest levels expressed by patients with treatment failure, defined as detectable viremia and CD4 < 350 cells/mm3 . No significant correlation was found between miRNA level and the nadir CD4 count or zenith HIV viral load. This study establishes the association between miR-29a expression and markers of HIV infection in long-term survivors, treatment-experienced patients, suggesting its potential use as an indicator for the on-treatment disease evolution. J. Med. Virol. 88:2132-2137, 2016. © 2016 Wiley Periodicals, Inc.
Subject(s)
HIV Infections/physiopathology , MicroRNAs/blood , Viral Load , Adult , Antiretroviral Therapy, Highly Active , Biomarkers/blood , CD4 Lymphocyte Count , CD4-CD8 Ratio , Disease Progression , Female , HIV Infections/drug therapy , HIV Infections/genetics , HIV Infections/immunology , HIV-1/genetics , Humans , Male , MicroRNAs/genetics , RNA, Viral/blood , Treatment Failure , Treatment Outcome , Young AdultABSTRACT
Methamphetamine (Meth) use is common among HIV-infected persons. It remains unclear whether Meth dependence is associated with long-lasting degenerative changes in the brain parenchyma and microvasculature of HIV-infected individuals. We examined the postmortem brains of 78 HIV-infected adults, twenty of whom were diagnosed with lifetime Meth dependence (18 past and two current at the final follow-up visit). Using logistic regression models, we analyzed associations of Meth with cerebral gliosis (immunohistochemistry for ionized calcium-binding adapter molecule-1 (Iba1) and glial fibrillary acidic protein (GFAP) in frontal, temporo-parietal, and putamen-internal capsule regions), synaptodendritic loss (confocal microscopy for synaptophysin (SYP) and microtubule-associated protein-2 (MAP2) in frontal cortex), ß-amyloid plaque deposition (immunohistochemistry in frontal and temporo-parietal cortex and putamen), and arteriolosclerosis (histopathology in forebrain white matter). We found that Meth was associated with marked Iba1 gliosis in the temporo-parietal region (odds ratio, 4.42 (95 % confidence interval, 1.36, 14.39), p = 0.014, n = 62), which remained statistically significant after adjusting for HIV encephalitis, white matter lesions, and opportunistic diseases (n = 61); hepatitis C virus seropositivity (n = 54); and lifetime dependence on alcohol, opiates, and cannabis (n = 62). There was no significant association of Meth with GFAP gliosis, SYP or MAP2 loss, ß-amyloid plaque deposition, or arteriolosclerosis. In conclusion, we found lifetime Meth dependence to be associated with focal cerebral microgliosis among HIV-infected adults, but not with other brain degenerative changes examined. Some of the changes in select brain regions might be reversible following extended Meth abstinence or, alternatively, might have not been induced by Meth initially.
Subject(s)
Alcoholism/physiopathology , Amphetamine-Related Disorders/physiopathology , Gliosis/physiopathology , HIV Infections/physiopathology , Opioid-Related Disorders/physiopathology , Adult , Aged , Alcoholism/complications , Alcoholism/genetics , Alcoholism/pathology , Amphetamine-Related Disorders/complications , Amphetamine-Related Disorders/genetics , Amphetamine-Related Disorders/pathology , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Autopsy , Calcium-Binding Proteins , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Frontal Lobe/metabolism , Frontal Lobe/pathology , Frontal Lobe/physiopathology , Gene Expression , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , Gliosis/complications , Gliosis/genetics , Gliosis/pathology , HIV Infections/complications , HIV Infections/genetics , HIV Infections/pathology , Humans , Male , Microfilament Proteins , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Middle Aged , Opioid-Related Disorders/complications , Opioid-Related Disorders/genetics , Opioid-Related Disorders/pathology , Parietal Lobe/metabolism , Parietal Lobe/pathology , Parietal Lobe/physiopathology , Prosencephalon/metabolism , Prosencephalon/pathology , Prosencephalon/physiopathology , Putamen/metabolism , Putamen/pathology , Putamen/physiopathology , Synaptophysin/genetics , Synaptophysin/metabolism , Temporal Lobe/metabolism , Temporal Lobe/pathology , Temporal Lobe/physiopathologyABSTRACT
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.
Subject(s)
AIDS Dementia Complex/pathology , Microtubule-Associated Proteins/genetics , Multilevel Analysis , Synaptophysin/genetics , Virus Replication , AIDS Dementia Complex/genetics , AIDS Dementia Complex/immunology , AIDS Dementia Complex/virology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/immunology , Adult , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/immunology , Biomarkers/metabolism , Calcium-Binding Proteins , Chemokine CCL2/genetics , Chemokine CCL2/immunology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/immunology , Female , Frontal Lobe/immunology , Frontal Lobe/pathology , Frontal Lobe/virology , Gene Expression , Hippocampus/immunology , Hippocampus/pathology , Hippocampus/virology , Humans , Interleukin-1alpha/genetics , Interleukin-1alpha/immunology , Male , Microfilament Proteins , Microtubule-Associated Proteins/immunology , Middle Aged , Putamen/immunology , Putamen/pathology , Putamen/virology , Receptors, Dopamine/genetics , Receptors, Dopamine/immunology , Severity of Illness Index , Synaptophysin/immunology , Viral LoadABSTRACT
HIV infection leads to age-related conditions in relatively young persons. HIV-associated neurocognitive disorders (HAND) are considered among the most prevalent of these conditions. To study the mechanisms underlying this disorder, researchers need an accurate method for measuring biological aging. Here, we apply a recently developed measure of biological aging, based on DNA methylation, to the study of biological aging in HIV+ brains. Retrospective analysis of tissue bank specimens and pre-mortem data was carried out. Fifty-eight HIV+ adults underwent a medical and neurocognitive evaluation within 1 year of death. DNA was obtained from occipital cortex and analyzed with the Illumina Infinium Human Methylation 450K platform. Biological age determined via the epigenetic clock was contrasted with chronological age to obtain a measure of age acceleration, which was then compared between those with HAND and neurocognitively normal individuals. The HAND and neurocognitively normal groups did not differ with regard to demographic, histologic, neuropathologic, or virologic variables. HAND was associated with accelerated aging relative to neurocognitively normal individuals, with average relative acceleration of 3.5 years. Age acceleration did not correlate with pre-mortem neurocognitive functioning or HAND severity. This is the first study to demonstrate that the epigenetic age of occipital cortex samples is associated with HAND status in HIV+ individuals pre-mortem. While these results suggest that the increased risk of a neurocognitive disorder due to HIV might be mediated by an epigenetic aging mechanism, future studies will be needed to validate the findings and dissect causal relationships and downstream effects.
Subject(s)
Acceleration , Aging/genetics , Cognitive Dysfunction/genetics , Epigenesis, Genetic , HIV Infections/genetics , Occipital Lobe/metabolism , Adult , Aging/pathology , Autopsy , Cognitive Dysfunction/complications , Cognitive Dysfunction/virology , DNA Methylation , Female , HIV Infections/complications , HIV Infections/virology , Humans , Male , Middle Aged , Occipital Lobe/virology , Retrospective StudiesABSTRACT
The Romanian cohort can provide valuable information about the effect of chronic HIV-infection and exposure to combined antiretroviral therapy (cART) on the developing brain, based on its unique characteristics: young adults infected parenterally with HIV clade F in the late 1980s and exposed to cART for a decade. We conducted a prospective study using a neuropsychological test battery validated in other international HIV cohorts, in order to evaluate the rate and severity of neurocognitive impairment in a group of young Romanian adults. The 49 HIV-infected (HIV+) participants and the 20 HIV negative (HIV-) controls were similar for age and gender, although the HIV- group tended to be more educated. We found higher cognitive impairment prevalence in the HIV+ group (59.1 %) versus the HIV- group (10 %), and the impairment rate remained significantly higher even when the groups were matched based on the educational level (38.7 % for the HIV+ group vs. 10.0 % for the HIV- controls; p = 0.025). The nadir CD4 count was <200 in 71.4 % of patients, but at the time of neurocognitive assessment, 89.5 % of patients had normal immunological status and 81.8 % undetectable HIV load. Among the HIV-impaired group, 26 % of the participants had syndromic impairment while the other 74 % had asymptomatic neurocognitive impairment. We found a high prevalence of neurocognitive dysfunction in the Romanian young adults growing-up with HIV. The greatest HIV-related cognitive deficits were in the domains of executive and motor functioning, consistent with a frontosubcortical pattern.
Subject(s)
Cognition Disorders/epidemiology , Cognition Disorders/virology , HIV Infections/complications , Adolescent , Cohort Studies , Female , Humans , Male , Neuropsychological Tests , Prevalence , Romania/epidemiology , Young AdultABSTRACT
BACKGROUND: Integrase inhibitors are a promising class of antiretroviral drugs to treat chronic human immunodeficiency virus (HIV) infection. During HIV infection, macrophages can extravasate from the blood to the brain, while producing chemotaxic proteins and cytokines, which have detrimental effects on central nervous system cells. The main goal of this study was to understand the effects of raltegravir (RAL) on human brain macrophage production of immune-mediators when infected with HIV, but did not compare with other antiretroviral agents. METHODS: Pro-inflammatory cytokines, IFN-γ, IL-10, IL-12-p70, IL-1, IL-8, TNF-α, and IL-6 were measured simultaneously in tissue culture supernatants from primary brain derived macrophages, microglia. We tested the effects of RAL on markers of astrocytosis and neurite integrity in primary human neuroglial cultures. RESULTS: RAL administered at 20 nM effectively suppressed HIV infection in microglia over 9 days. Only IL-8, IL-10, and TNF-α were above the detection limit in the majority of samples and RAL significantly suppressed the rate of cytokine production in HIV-infected microglia. During RAL-alone, the rate of IL-8 secretion was higher. CONCLUSIONS: RAL did not affect neurite area but inhibited astrocyte growth in the neuroglial cultures. Exploring the effects of RAL on pro-inflammatory molecule production in brain macrophages may contribute to designing ARV neuroprotective strategies in chronic HIV infection.
Subject(s)
HIV Infections/virology , Macrophages/drug effects , Macrophages/virology , Microglia/drug effects , Microglia/virology , Pyrrolidinones/therapeutic use , Brain/embryology , Brain/virology , Cytokines/metabolism , Humans , Interleukin-10/metabolism , Interleukin-12/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Microglia/metabolism , Raltegravir Potassium , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Elevated serum pro-inflammatory molecules have been reported in early psychosis. What is not known is whether peripheral inflammatory biomarkers are associated with CNS biomarkers. In the brain, release of pro-inflammatory molecules by microglial hyperactivity may lead to neuronal apoptosis seen in neurodegenerative disorders and account for loss of brain tissue observed in psychotic disorders. Neurochemical changes, including elevated glutamate levels, are also associated with neuroinflammation, present in early psychosis and change with antipsychotic treatment. METHODS: Antipsychotic naïve patients with first episode psychosis (FEP) were studied as part of a collaborative project of neuroinflammation. In Study 1 we explored associations between plasma inflammatory molecules and neurometabolites in the dorsal caudate using magnetic resonance spectroscopy (1H-MRS) in N = 13 FEP participants. Study 2 examined the relationship between inflammatory molecules in the Plasma and CSF in N = 20 FEP participants. RESULTS: In Study 1, the proinflammatory chemokine MDC/CCL22 and IL10 were significantly positively correlated with Glutamate and Glx (glutamate + glutamine) levels in the dorsal caudate. In Study 2, plasma inflammatory molecules (MIP1ß/CCL4, MCP1/CCL2, Eotaxin-1/CCL11 and TNFα) were significantly correlated with CSF MIP1ß/CCL4, IL10, MCP1/CCL2 and Fractalkine/CX3CL1 and symptoms ratings. DISCUSSION: Plasma inflammatory biomarkers are elevated in early psychosis, associated with neurochemical markers as well as CSF inflammatory molecules found in neurodegenerative disorders. Future studies are needed that combine both peripheral and central biomarkers in both FEP and HC to better understand a potential neuroinflammatory subtype of psychosis likely to respond to targeted interventions.
Subject(s)
Antipsychotic Agents , Neurodegenerative Diseases , Psychotic Disorders , Humans , Antipsychotic Agents/therapeutic use , Neuroinflammatory Diseases , Pilot Projects , Interleukin-10/therapeutic use , Glutamic Acid , Biomarkers , Neurodegenerative Diseases/chemically induced , Neurodegenerative Diseases/drug therapyABSTRACT
Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aß42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.
Subject(s)
Alzheimer Disease , Amyloidosis , HIV Infections , Aged , Humans , Middle Aged , Alzheimer Disease/pathology , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Brain/pathology , Brain/metabolism , Brain/diagnostic imaging , Cohort Studies , HIV Infections/complications , HIV Infections/drug therapy , Prospective Studies , tau Proteins/cerebrospinal fluid , tau Proteins/metabolismABSTRACT
The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (â¼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.
Subject(s)
Chromatin , HIV Infections , Microglia , Microglia/metabolism , Microglia/virology , Humans , HIV Infections/virology , HIV Infections/drug therapy , HIV Infections/genetics , HIV Infections/metabolism , Chromatin/metabolism , Chromatin/genetics , Male , HIV-1/genetics , HIV-1/physiology , Virus Latency/genetics , RNA, Viral/genetics , RNA, Viral/metabolism , Brain/metabolism , Brain/virology , Brain/pathology , Female , Adult , Middle Aged , Gene Expression/genetics , Viral LoadABSTRACT
Human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause significant neurologic disease. Central nervous system (CNS) involvement of HIV has been extensively studied, with well-documented invasion of HIV into the brain in the initial stage of infection, while the acute effects of SARS-CoV-2 in the brain are unclear. Neuropathologic features of active HIV infection in the brain are well characterized whereas neuropathologic findings in acute COVID-19 are largely non-specific. On the other hand, neuropathologic substrates of chronic dysfunction in both infections, as HIV-associated neurocognitive disorders (HAND) and post-COVID conditions (PCC)/long COVID are unknown. Thus far, neuropathologic studies on patients with HAND in the era of combined antiretroviral therapy have been inconclusive, and autopsy studies on patients diagnosed with PCC have yet to be published. Further longitudinal, multidisciplinary studies on patients with HAND and PCC and neuropathologic studies in comparison to controls are warranted to help elucidate the mechanisms of CNS dysfunction in both conditions.
ABSTRACT
In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the "Global NeuroAIDS Roundtable" in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the "Global NeuroAIDS Roundtable", presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective.
Subject(s)
AIDS Dementia Complex/epidemiology , Global Health/standards , AIDS Dementia Complex/diagnosis , AIDS Dementia Complex/microbiology , Health Services Needs and Demand , Humans , Neuropsychological Tests/standardsABSTRACT
OBJECTIVES: We hypothesized that microRNA (miR) expression may be involved in memory function because it controls local protein translation at synapses and dendritic spines. DESIGN: Case-control animal study. METHODS: We assessed the miR repertoire in the hippocampus of young, 6-month-old (N = 18) mice compared with aged, 26-month-old (N = 23) mice and compared miR quantity to memory scores as determined by the novel object recognition task. We performed a histological brain regional analysis of miR-138, acyl protein thioesterase 1 (APT1) mRNA, and APT1 protein. RESULTS: We found that higher miR-138 expression in the mouse hippocampus is correlated with better memory performance. We also found that APT1 (a depalmytoylation enzyme expressed at dendritic spines whose translation is controlled by miR-138) mRNA is increased in the mouse hippocampal CA1 and dentate gyrus in aged mice compared with young mice, but not in mice with memory impairment. We found APT1 protein distribution to be lower in cells with high miR-138 expression. CONCLUSIONS: These results suggest that increased miR-138 is associated with better memory and increased APT1 gene transcription occurs with aging. The role of miR-138 and APT1 protein function in memory and aging warrants further investigation.