RESUMO
Human immunodeficiency virus type-1 (HIV-1) is responsible for significant mortality and morbidity worldwide. Despite complete control of viral replication with antiretrovirals, cells with integrated HIV-1 provirus can produce viral transcripts. In a cross-sectional study of 84 HIV+ individuals of whom 43 were followed longitudinally, we found that HIV-1 RNAs are present in extracellular vesicles (EVs) derived from cerebrospinal fluid and serum of all individuals. We used seven digital droplet polymerase chain reaction assays to evaluate the transcriptional status of the latent reservoir. EV-associated viral RNA was more abundant in the CSF and correlated with neurocognitive dysfunction in both, the cross-sectional and longitudinal studies. Sequencing studies suggested compartmentalization of defective viral transcripts in the serum and CSF. These findings suggest previous studies have underestimated the viral burden and there is a significant relationship between latent viral transcription and CNS complications of long-term disease despite the adequate use of antiretrovirals.
Assuntos
Vesículas Extracelulares , Infecções por HIV , HIV-1 , RNA Viral , Humanos , Vesículas Extracelulares/metabolismo , HIV-1/genética , HIV-1/fisiologia , RNA Viral/genética , Masculino , Estudos Transversais , Infecções por HIV/virologia , Infecções por HIV/sangue , Feminino , Adulto , Pessoa de Meia-Idade , Estudos Longitudinais , Carga Viral , Latência Viral/genética , Transtornos Neurocognitivos/virologia , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/etiologiaRESUMO
During the antiretroviral era, individuals living with HIV continue to experience milder forms of HIV-associated neurocognitive disorder (HAND). Viral proteins, including Tat, play a pivotal role in the observed alterations within the central nervous system (CNS), with mitochondrial dysfunction emerging as a prominent hallmark. As a result, our objective was to examine the expression of genes associated with mitophagy and mitochondrial biogenesis in the brain exposed to the HIV-1 Tat protein. We achieved this by performing bilateral stereotaxic injections of 100 ng of HIV-1 Tat into the hippocampus of Sprague-Dawley rats, followed by immunoneuromagnetic cell isolation. Subsequently, we assessed the gene expression of Ppargc1a, Pink1, and Sirt1-3 in neurons using RT-qPCR. Additionally, to understand the role of Tert in telomeric dysfunction, we quantified the activity and expression of Tert. Our results revealed that only Ppargc1a, Pink1, and mitochondrial Sirt3 were downregulated in response to the presence of HIV-1 Tat in hippocampal neurons. Interestingly, we observed a reduction in the activity of Tert in the experimental group, while mRNA levels remained relatively stable. These findings support the compelling evidence of dysregulation in both mitophagy and mitochondrial biogenesis in neurons exposed to HIV-1 Tat, which in turn induces telomeric dysfunction.
Assuntos
Infecções por HIV , HIV-1 , Transtornos Neurocognitivos , Sirtuína 3 , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Animais , Ratos , Produtos do Gene tat/metabolismo , Infecções por HIV/metabolismo , HIV-1/metabolismo , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/virologia , Neurônios/metabolismo , Biogênese de Organelas , Proteínas Quinases/metabolismo , Ratos Sprague-Dawley , Sirtuína 3/genética , Sirtuína 3/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de PeroxissomoRESUMO
We evaluated whether biomarkers of age-related neuronal injury and amyloid metabolism are associated with neurocognitive impairment (NCI) in people with and without HIV (PWH, PWoH). This was a cross-sectional study of virally suppressed PWH and PWoH. NCI was assessed using a validated test battery; global deficit scores (GDS) quantified overall performance. Biomarkers in cerebrospinal fluid (CSF) were quantified by immunoassay: neurofilament light (NFL), total Tau (tTau), phosphorylated Tau 181 (pTau181), amyloid beta (Aß)42, and Aß40. Factor analysis was used to reduce biomarker dimensionality. Participants were 256 virally suppressed PWH and 42 PWoH, 20.2% female, 17.1% Black, 7.1% Hispanic, 60.2% non-Hispanic White, and 15.6% other race/ethnicities, mean (SD) age 56.7 (6.45) years. Among PWH, the best regression model for CSF showed that higher tTau (ß = 0.723, p = 3.79e-5) together with lower pTau181 (ß = -0.510, p = 0.0236) best-predicted poor neurocognitive performance. In univariable analysis, only higher tTau was significantly correlated with poor neurocognitive performance (tTau r = 0.214, p = 0.0006; pTau181 r = 0.00248, p = 0.969). Among PWoH, no CSF biomarkers were significantly associated with worse NCI. Predicted residual error sum of squares (PRESS) analysis showed no evidence of overfitting. Poorer neurocognitive performance in aging PWH was associated with higher CSF tTau, a marker of age-related neuronal injury, but not with biomarkers of amyloid metabolism. The findings suggest that HIV might interact with age-related neurodegeneration to contribute to cognitive decline in PWH.
Assuntos
Infecções por HIV , Transtornos Neurocognitivos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Neurocognitivos/líquido cefalorraquidiano , Transtornos Neurocognitivos/virologia , Proteínas tau/líquido cefalorraquidianoRESUMO
Abstract: COVID-19 has affected many people all around the world for more than two years now have suffered many long-term consequences which is commonly referred to as long-haulers. Despite multiorgan complaints in long haulers, symptoms related to cognitive functions commonly referred as brain fog are seen in the high risk covid patients with age more than 50, women more than men, obesity, asthma and those who experienced more than five symptoms during the first week of covid illness. Long term isolation has certainly contributed to high level of anxiety and stress calling for an empathetic response to this group of covid patients as there is no specific test to detect long haulers and no specific cognitive rehabilitation techniques available as of today.
Assuntos
COVID-19/psicologia , COVID-19/reabilitação , Transtornos Neurocognitivos/reabilitação , Transtornos Neurocognitivos/virologia , Reabilitação Neurológica , HumanosRESUMO
HIV enters the CNS early after peripheral infection, establishing reservoirs in perivascular macrophages that contribute to development of HIV-associated neurocognitive disorders (HAND) in 15-40% of people with HIV (PWH) despite effective antiretroviral therapy (ART). Opioid use may contribute to dysregulated macrophage functions resulting in more severe neurocognitive symptoms in PWH taking opioids. Macroautophagy helps maintain quality control in long-lived cell types, such as macrophages, and has been shown to regulate, in part, some macrophage functions in the CNS that contribute to HAND. Using Western blotting and confocal immunofluorescence in primary human macrophages, we demonstrated that morphine and a commonly prescribed ART regimen induce bulk autophagy. Morphine and ART also inhibited completion of autophagy. HIV infection increased these inhibitory effects. We also examined two types of selective autophagy that degrade aggregated proteins (aggrephagy) and dysfunctional mitochondria (mitophagy). Morphine and ART inhibited selective autophagy mediated by p62 regardless of HIV infection, and morphine inhibited mitophagic flux in HIV-infected cells demonstrating potential mitotoxicity. These results indicate that inhibition of autophagy, both in bulk and selective, in CNS macrophages may mediate neurocognitive dysfunction in PWH using opioids. Increasing autophagic activity in the context of HIV may represent a novel therapeutic strategy for reducing HAND in these individuals.
Assuntos
Antirretrovirais/farmacologia , Autofagia/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Morfina/farmacologia , Transtornos Neurocognitivos/tratamento farmacológico , Células Cultivadas , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Mitofagia/efeitos dos fármacos , Transtornos Neurocognitivos/virologiaRESUMO
BACKGROUND: Mannose-binding lectin 2 (MBL2) gene has a significant role in the essential protective mechanism of the body. Variations reported in the genetic makeup of this gene influence the circulating MBL levels that could lead to the vulnerability to various viral infections including HIV. Hence, we assessed the MBL2 coding region (52A/D, 54A/B, and 57A/C) variations in HIV-associated neurocognitive disorders (HAND). METHOD: In this proposed study, 208 HIV seropositive individuals were included, 104 were on ART undergone for IHDS evaluation (44 HAND+60 without HAND), and 104 HIV seropositive individuals naïve to ART, and 130 unrelated HIV uninfected individuals. PCR-RFLP was used to genotype the MBL2 coding region polymorphism (52A/D, 54A/B and 57A/C). RESULTS: MBL-2 57AC genotype was associated with risk of HAND severity (ORâ¯=â¯4.69, Pâ¯=â¯0.0009). MBL-2 57AC and 57C alleles were associated with susceptibility to HAND (ORâ¯=â¯3.14, Pâ¯=â¯0.003). Furthermore, the MBL-2 57AC genotype and 57C allele were found to be significantly linked with the susceptibility to HIV disease severity. (ORâ¯=â¯6.34, Pâ¯=â¯0.001; 16.82% vs. 3.46%, ORâ¯=â¯5.64, Pâ¯=â¯0.001). Haplotype ACA was significantly linked with susceptibility to HAND and its severity (ORâ¯=â¯3.23, Pâ¯=â¯0.004, 26.1%-8.1%, ORâ¯=â¯4.70, Pâ¯=â¯0.0024), similarly, haplotype ACA was linked with the acquisition of HIV-1 (ORâ¯=â¯4.26, Pâ¯=â¯0.005). MBL-2 57AC genotype in presence of tobacco showed a significantly higher risk for HIV disease severity (48.0% vs. 12.5%, ORâ¯=â¯7.00, Pâ¯=â¯0.035). Alcohol-taking HIV seropositive individuals on ART showed a greater MBL-2 57AC genotype than with alcohol-taking naïve to ART (32.3% vs. 15.4%, ORâ¯=â¯2.75, Pâ¯=â¯0.40). CONCLUSION: MBL-2 57AC genotype and haplotype ACA were associated with the modulation of HAND. Individuals with haplotype ACA were at higher risk of HIV-1 acquisition.
Assuntos
Infecções por HIV , Lectina de Ligação a Manose , Transtornos Neurocognitivos/virologia , Predisposição Genética para Doença , Genótipo , Infecções por HIV/genética , HIV-1 , Humanos , Lectina de Ligação a Manose/genéticaRESUMO
The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to (1) evaluate the HIV-1 mRNA distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat, and (2) validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 h of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results that are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments and synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway and/or neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.
Assuntos
Reservatórios de Doenças/virologia , HIV-1/genética , Microglia/virologia , Transtornos Neurocognitivos/virologia , Doenças Neuroinflamatórias/virologia , RNA Viral/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , HIV-1/patogenicidade , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos TransgênicosRESUMO
With the introduction of antiretroviral therapy, the worldwide AIDS-related deaths have decreased, and life expectancy has increased, including the prevalence of AIDS-related neurological disorders or neuroAIDS. HIV-associated neurocognitive disorders such as mild neurocognitive disorder and asymptomatic neurocognitive impairment have largely remained stable or increased among the HIV-infected individuals in the combination antiretroviral therapy era. The emerging evidence that antiretrovirals with high CNS penetration effectiveness score contribute to the neurotoxicity and HIV-associated neurocognitive disorders has ushered the search for natural, nontoxic bioactive constituents having pre-established neuroprotective, anti-inflammatory, and restorative neurocognitive activity. In this review, we have highlighted the probable mechanism of neuroAIDS infection, the problem with the existing antiretroviral therapy, along with various bioactive constituents with in vivo, in vitro, or ex vivo evidence of their neuroprotective activity that can be used as an adjuvant with the current combination antiretroviral therapy regimen or can even serve as an alternate to the antiretrovirals for treatment of HIV associated neurocognitive disorder.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Antirretrovirais/farmacologia , Produtos Biológicos/farmacologia , Transtornos Neurocognitivos/tratamento farmacológico , Neurônios/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/patologia , Síndrome da Imunodeficiência Adquirida/virologia , Antirretrovirais/química , Antirretrovirais/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Humanos , Transtornos Neurocognitivos/patologia , Transtornos Neurocognitivos/virologia , Neurônios/patologia , Neurônios/virologiaRESUMO
HIV-related neurocognitive impairment (NCI) may increase the risk of death. However, a survival disadvantage for patients with NCI has not been well studied in the post-combination antiretroviral therapy (cART) era. Specifically, limited research has been conducted considering the reversible nature and variable progression of the impairment and this area demands further evaluation. We performed multivariable Cox proportional hazards modeling to assess the association between baseline NCI (global T scores) and mortality. A joint modeling approach was then used to model the trajectory of global neurocognitive functioning over time and the association between neurocognitive trajectory and mortality. Among the National NeuroAIDS Tissue Consortium's (NNTC) HIV-infected participants, we found a strong negative association between NCI and mortality in the older age groups (e.g., at age = 55, HR = 0.79; 95% CI 0.64-0.99). Three neurocognitive sub-domains (abstraction and executive functioning, speed of information processing, and motor) had the strongest negative association with mortality. Joint modelling indicated a 33% lower hazard for every 10-unit increase in global T scores (HR = 0.67; 95% CI 0.56-0.80). The study identified older HIV-infected individuals with NCI as a group needing special attention for the longevity of life. The study has considerable prognostic utility by not only predicting mortality hazard, but also future cognitive status.
Assuntos
Disfunção Cognitiva/mortalidade , Disfunção Cognitiva/fisiopatologia , Infecções por HIV/mortalidade , Adulto , Antirretrovirais/uso terapêutico , Cognição/fisiologia , Disfunção Cognitiva/virologia , Estudos de Coortes , Bases de Dados Factuais , Função Executiva/fisiologia , Feminino , HIV/metabolismo , HIV/patogenicidade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Neurocognitivos/mortalidade , Transtornos Neurocognitivos/fisiopatologia , Transtornos Neurocognitivos/virologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
PURPOSE OF REVIEW: The COVID-19 infection results in various viral-related physical and mental health problems, joined with the long-term psychological impact of the pandemic in general. However, the accompanying neurocognitive changes remain poorly understood. RECENT FINDINGS: We synthetize the current knowledge of viral (SARS-CoV-2) induced inflammation, mechanisms to viral entry into the central nervous system and altered neurotransmitter systems to provide an informed neurobiological explanation for the rise of neurocognitive disorders (defined as per the DSM-5 criteria). SUMMARY: The mild and major neurocognitive disorder symptoms due to the COVID-19 pandemic provide a unique opportunity to address the early changes underlying neurocognitive impairment at both clinical and molecular level. We discuss the utilization of the available evidence for their management and future novel therapeutic opportunities.
Assuntos
COVID-19/complicações , Transtornos Neurocognitivos/virologia , Humanos , PandemiasRESUMO
The development of effective combined anti-retroviral therapy (cART) led to a significant reduction in the death rate associated with human immunodeficiency virus type 1 (HIV-1) infection. However, recent studies indicate that considerably more than 50% of all HIV-1 infected patients develop HIV-1-associated neurocognitive disorder (HAND). Microglia are the foremost cells infected by HIV-1 in the central nervous system (CNS), and so, are also likely to contribute to the neurotoxicity observed in HAND. The activation of microglia induces the release of pro-inflammatory markers and altered secretion of cytokines, chemokines, secondary messengers, and reactive oxygen species (ROS) which activate signalling pathways that initiate neuroinflammation. In turn, ROS and inflammation also play critical roles in HAND. However, more efforts are required to understand the physiology of microglia and the processes involved in their activation in order to better understand the how HIV-1-infected microglia are involved in the development of HAND. In this review, we summarize the current state of knowledge about the involvement of oxidative stress mechanisms and role of HIV-induced ROS in the development of HAND. We also examine the academic literature regarding crucial HIV-1 pathogenicity factors implicated in neurotoxicity and inflammation in order to identify molecular pathways that could serve as potential therapeutic targets for treatment of this disease. KEY MESSAGES Neuroinflammation and excitotoxicity mechanisms are crucial in the pathogenesis of HAND. CNS infiltration by HIV-1 and immune cells through the blood brain barrier is a key process involved in the pathogenicity of HAND. Factors including calcium dysregulation and autophagy are the main challenges involved in HAND.
Assuntos
Sistema Nervoso Central/virologia , Infecções por HIV/psicologia , HIV-1 , Microglia/virologia , Transtornos Neurocognitivos/virologia , Animais , Infecções por HIV/virologia , Humanos , Inflamação Neurogênica , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de SinaisRESUMO
Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 is responsible for a new coronavirus disease known as coronavirus disease-19 (COVID-19). SARS-CoV-2 reports neurotropic properties and may have neurological implications, and this creates another health burden for people living with HIV. As yet, the impact of COVID-19 on (neuro)inflammation and the development of HIV-associated neurocognitive disorders (HAND) is not fully known. Here, we reviewed preliminary evidence that provides clues that COVID-19 may exacerbate inflammatory mechanisms related to the development of HAND.
Assuntos
Nefropatia Associada a AIDS/complicações , COVID-19/complicações , Inflamação/complicações , Transtornos Neurocognitivos/complicações , Nefropatia Associada a AIDS/virologia , COVID-19/virologia , Humanos , Inflamação/virologia , Transtornos Neurocognitivos/virologia , SARS-CoV-2/patogenicidadeRESUMO
BACKGROUND: We identified host single-nucleotide variants (SNVs) associated with neurocognitive impairment (NCI) in perinatally HIV-infected (PHIV) children. METHODS: Whole-exome sequencing (WES) was performed on 217 PHIV with cognitive score for age (CSA)â <â 70 and 247 CSAâ ≥â 70 (discovery cohort [DC]). SNVs identified in DC were evaluated in 2 validation cohorts (VC). Logistic regression was used to estimate adjusted odds ratios (ORs) for NCI. A human microglia NLRP3 inflammasome assay characterized the role of identified genes. RESULTS: Twenty-nine SNVs in 24 genes reaching Pâ ≤â .002 and OR ≥ 1.5 comparing CSAâ <â 70 to CSA ≥ 70 were identified in the DC, of which 3 SNVs were identified in VCs for further study. Combining the 3 cohorts, SNV in CCRL2 (rs3204849) was associated with decreased odds of NCI (Pâ <â .0001); RETREG1/FAM134B (rs61733811) and YWHAH (rs73884247) were associated with increased risk of NCI (Pâ <â .0001 and Pâ <â .001, respectively). Knockdown of CCRL2 led to decreased microglial release of IL-1ß following exposure to ssRNA40 while knockdown of RETREG1 and YWHAH resulted in increased IL-1ß release. CONCLUSIONS: Using WES and 2 VCs, and gene silencing of microglia we identified 3 genetic variants associated with NCI and inflammation in HIV-infected children.
Assuntos
Infecções por HIV/complicações , HIV-1 , Transmissão Vertical de Doenças Infecciosas , Inflamação/genética , Transtornos Neurocognitivos/genética , Proteínas 14-3-3 , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Genômica , Infecções por HIV/psicologia , Infecções por HIV/transmissão , Humanos , Lactente , Inflamassomos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana , Microglia , Transtornos Neurocognitivos/diagnóstico , Transtornos Neurocognitivos/virologia , Receptores CCRRESUMO
OBJECTIVES: The aim was to investigate the correlation between biomarkers of brain injury and long-term neurocognitive outcome, and the interplay with intrathecal inflammation and neuronal autoimmunity, in patients with herpes simplex encephalitis (HSE). METHODS: A total of 53 adult/adolescent HSE patients were included from a prospective cohort in a randomized placebo-controlled trial investigating the effect of a 3-month follow-up treatment with valaciclovir. Study subjects underwent repeated serum/cerebrospinal fluid (CSF) sampling and brain magnetic resonance imaging in the first 3 months along with cognitive assessment using the Mattis Dementia Rating Scale (MDRS) at 24 months. CSF samples were analysed for biomarkers of brain injury, inflammation and synaptic autoimmunity. The predefined primary analysis was the correlation between peak CSF neurofilament protein (NFL), a biomarker of neuronal damage, and MDRS at 24 months. RESULTS: Impaired cognitive performance significantly correlated with NFL levels (rho = -0.36, p = 0.020). Development of IgG anti-N-methyl-D-aspartate receptor (NDMAR) antibodies was associated with a broad and prolonged proinflammatory CSF response. In a linear regression model, lower MDRS at 24 months was associated with previous development of IgG anti-N-methyl-D-aspartate receptor (NMDAR) (beta = -0.6249, p = 0.024) and age (z-score beta = -0.2784, p = 0.024), but not CSF NFL, which however significantly correlated with subsequent NMDAR autoimmunization (p = 0.006). DISCUSSION: Our findings show that NFL levels are predictive of long-term neurocognitive outcome in HSE, and suggest a causative chain of events where brain tissue damage increases the risk of NMDAR autoimmunisation and subsequent prolongation of CSF inflammation. The data provides guidance for a future intervention study of immunosuppressive therapy administered in the recovery phase of HSE.
Assuntos
Autoimunidade , Lesões Encefálicas/líquido cefalorraquidiano , Encefalite por Herpes Simples , Inflamação/líquido cefalorraquidiano , Transtornos Neurocognitivos/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Lesões Encefálicas/virologia , Encefalite por Herpes Simples/líquido cefalorraquidiano , Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/tratamento farmacológico , Feminino , Humanos , Imunoglobulina G , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de N-Metil-D-Aspartato/imunologia , Adulto JovemRESUMO
Increased life expectancy of patients diagnosed with HIV in the current era of antiretroviral therapy is unfortunately accompanied with the prevalence of HIV-associated neurocognitive disorders (HANDs) and risk of comorbidities such as Alzheimer-like pathology. HIV-1 transactivator of transcription (Tat) protein has been shown to induce the production of toxic neuronal amyloid protein and also enhance neurotoxicity. The contribution of astrocytes in Tat-mediated amyloidosis remains an enigma. We report here, in simian immunodeficiency virus (SIV)+ rhesus macaques and patients diagnosed with HIV, brain region-specific up-regulation of amyloid precursor protein (APP) and Aß (40 and 42) in astrocytes. In addition, we find increased expression of ß-site cleaving enzyme (BACE1), APP, and Aß in human primary astrocytes (HPAs) exposed to Tat. Mechanisms involved up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the long noncoding RNA (lncRNA) BACE1-antisense transcript (BACE1-AS), resulting, in turn, in the formation of the BACE1-AS/BACE1 RNA complex, subsequently leading to increased BACE1 protein, and activity and generation of Aß-42. Gene silencing approaches confirmed the regulatory role of HIF-1α in BACE1-AS/BACE1 in Tat-mediated amyloidosis. This is the first report implicating the role of the HIF-1α/lncRNABACE1-AS/BACE1 axis in Tat-mediated induction of astrocytic amyloidosis, which could be targeted as adjunctive therapies for HAND-associated Alzheimer-like comorbidity.
Assuntos
Amiloidose/virologia , Astrócitos/metabolismo , Infecções por HIV/complicações , Transtornos Neurocognitivos/virologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Animais , Encéfalo/metabolismo , Células Cultivadas , Infecções por HIV/metabolismo , HIV-1 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macaca mulatta , Pessoa de Meia-Idade , Transtornos Neurocognitivos/metabolismo , Fragmentos de Peptídeos/metabolismo , RNA Longo não Codificante/metabolismo , Regulação para CimaRESUMO
AIMS: To explore the role of chemokine CC motif ligand 2 (CCL2) in spatial memory and cognition impairment, and the underlying mechanisms focused on inflammatory, glutamate metabolistic and apoptotic- associated mRNA expression. MATERIALS AND METHODS: Stereotaxic surgery was performed here to establish a rat model by bilateral intra-hippocampal injection of CCL2. Morris water maze (MWM) and Novel object recognition test (NORT) were used to assess the learning, memory and cognitive ability respectively. RT-PCR was used to detect the relative mRNA expression of inflammatory, glutamate metabolistic and apoptotic- associated indexes. Nissl and TUNEL staining were performed to observe the morphological changes of hippocampal CA1 zone and quantified the apoptosis of hippocampal neurons of CA1 zones respectively. KEY FINDINGS: We found CCL2 injured cognitive function in rats. Six days after CCL2 injection, we revealed the following obvious mRNA expression changes: (1) increasing of the neuroinflammatory cytokines IL-1ß, CXCL-10, IL-6; (2) decreasing of the glutamate transporters GLT-1 and GLAST and increasing of PAG; (3) increasing of the apoptotic genes caspase-8, caspase-3 and Bax, while decreasing the anti-apoptotic gene Bcl-2. Further, Nissl staining and TUNEL confirmed the injury of the structure of hippocampal CA1 zones and the apoptosis of hippocampal neurons. SIGNIFICANCE: Our results indicated that CCL2 impaired spatial memory and cognition, the involving mechanisms may link to the up-regulation of mRNA expression of the three major pathological events: inflammation, excitotoxicity and neuronal apoptosis, which were involved in HIV-associated neurocognitive disorder (HAND). Taken together, these findings suggest a potential therapeutic strategy against CCL2.
Assuntos
Quimiocina CCL2/metabolismo , Infecções por HIV/complicações , Inflamação/patologia , Transtornos da Memória/fisiopatologia , Transtornos Neurocognitivos/fisiopatologia , Animais , Apoptose/fisiologia , Quimiocina CCL2/administração & dosagem , Cognição/fisiologia , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos Neurocognitivos/virologia , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Memória Espacial/fisiologiaRESUMO
Despite antiretroviral therapy human immunodeficiency virus type-1 (HIV-1) infection results in neuroinflammation of the central nervous system that can cause HIV-associated neurocognitive disorders (HAND). The molecular mechanisms involved in the development of HAND are unclear, however, they are likely due to both direct and indirect consequences of HIV-1 infection and inflammation of the central nervous system. Additionally, opioid abuse in infected individuals has the potential to exacerbate HIV-comorbidities, such as HAND. Although restricted for productive HIV replication, astrocytes (comprising 40-70% of all brain cells) likely play a significant role in neuropathogenesis in infected individuals due to the production and response of viral proteins. The HIV-1 protein Tat is critical for viral transcription, causes neuroinflammation, and can be secreted from infected cells to affect uninfected bystander cells. The Wnt/ß-catenin signaling cascade plays an integral role in restricting HIV-1 infection in part by negatively regulating HIV-1 Tat function. Conversely, Tat can overcome this negative regulation and inhibit ß-catenin signaling by sequestering the critical transcription factor TCF-4 from binding to ß-catenin. Here, we aimed to explore how opiate exposure affects Tat-mediated suppression of ß-catenin in astrocytes and the downstream modulation of neuroinflammatory genes. We observed that morphine can potentiate Tat suppression of ß-catenin activity in human astrocytes. In contrast, Tat mutants deficient in secretion, and lacking neurotoxic effects, do not affect ß-catenin activity in the presence or absence of morphine. Finally, morphine treatment of astrocytes was sufficient to reduce the expression of genes involved in neuroinflammation. Examining the molecular mechanisms of how HIV-1 infection and opiate exposure exacerbate neuroinflammation may help us inform or predict disease progression prior to HAND development.
Assuntos
Analgésicos Opioides/efeitos adversos , Infecções por HIV/complicações , HIV-1/efeitos dos fármacos , Morfina/efeitos adversos , Transtornos Neurocognitivos/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Produtos do Gene tat do Vírus da Imunodeficiência Humana/imunologia , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Astrócitos/virologia , Linhagem Celular , Células Cultivadas , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Transtornos Neurocognitivos/imunologia , Transtornos Neurocognitivos/virologia , Transtornos Relacionados ao Uso de Substâncias/imunologia , beta Catenina/imunologiaRESUMO
AIMS: The prognosis and the clinical manifestations of HIV infection have changed with the introduction of the potent combination antiretroviral therapy (cART); however, up to 50% of patients meet research criteria for "HIV-associated neurocognitive disorders" (HAND) according with current nosology. The majority of patients affected by HAND, especially in cohorts with suppressed plasma viremia, showed an Asymptomatic Neurocognitive Impairment (ANI), without any functional impairment. After more than 10 years from the introduction of the current so-called "Frascati criteria", this mini-review aimed to address the emerging limitations in current diagnosis procedures. METHODS: We discussed the most relevant literature on HAND prevalence, etiology, and diagnosis. RESULTS: We addressed three main emerging issues: (1) the unclear clinical relevance of ANI entity; (2) the evidences that Frascati criteria could produce a significant overestimation of HAND; (3) the need to better identify patients with a higher risk to develop HAND requiring routine neuropsychological examinations. CONCLUSIONS: Frascati criteria should be updated to better respond to the present characteristics of HIV + cohorts and to help clinicians in their cognitive and global management.
Assuntos
Infecções por HIV/complicações , Transtornos Neurocognitivos , Humanos , Transtornos Neurocognitivos/diagnóstico , Transtornos Neurocognitivos/epidemiologia , Transtornos Neurocognitivos/virologiaRESUMO
OBJECTIVE: Gene-environment interactions contribute to the development of HIV-associated neurocognitive disorders. We examined whether childhood trauma, apolipoprotein E isoforms and viral protein R (Vpr) variants were associated with change in cognitive performance. Seventy-three seropositive women completed neuropsychological assessments at baseline and 1-year follow-up. We conducted genetic analyses using DNA obtained from blood and calculated risk scores based on Vpr amino acid 37, 41 and 55 variants that were previously associated with cognitive performance. RESULTS: Global cognitive scores declined significantly over the 1-year study period (p = 0.029). A reduction in global cognitive scores was associated with childhood trauma experience (p = 0.039).
Assuntos
Experiências Adversas da Infância , Apolipoproteínas E/genética , Infecções por HIV/psicologia , Transtornos Neurocognitivos/etiologia , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/sangue , Adulto , Apolipoproteínas E/sangue , Criança , Cognição/fisiologia , Estudos de Coortes , Demografia , Feminino , Seguimentos , Genótipo , Infecções por HIV/complicações , Humanos , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/psicologia , Transtornos Neurocognitivos/virologia , Testes Neuropsicológicos , África do Sul , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Neurocognitive dysfunction remains prevalent among people living with HIV (PLWH), even after viral suppression on combination antiretroviral therapy (cART). We investigated associations between neuropsychological performance (NP) and patterns of circulating exosomal microRNA (exo-miRNA) expression in PLWH on cART. SETTING: A cross-sectional examination of plasma exo-miRNA among PLWH on cART with systemic viral suppression and volunteers without HIV infection. METHODS: Thirty-one PLWH who started cART during early infection (n = 19) or chronic infection (n = 12) participated in phlebotomy and an 11-test neuropsychological battery after >1 year on treatment. NP higher- or lower-performing participants were categorized based on normalized neuropsychological scores. Total RNA was extracted from purified exosomes of 31 PLWH and 5 volunteers without HIV and subject to small RNA sequencing. Differential expression of exo-miRNAs was examined and biological functions were predicted. RESULTS: Eleven exo-miRNAs were up-regulated in NP lower-performing (n = 18) relative to higher-performing PLWH (n = 13). A high proportion of the differentiating exo-miRNA target the axon guidance KEGG pathway and neurotrophin tyrosine receptor kinase signaling Gene Ontology pathway. Differential expression analysis of exo-miRNAs between NP lower- (n = 7) and higher-performing (n = 12) PLWH within the early infection group alone confirmed largely consistent findings. CONCLUSIONS: Plasma exo-miRNA content differed between NP higher- and lower-performing PLWH. Several differentially expressed exo-miRNAs were predicted to be involved in inflammation and neurodegeneration pathways. Exo-miRNA in plasma may indicate cross-talk between the circulation and central nervous system and thus may be clinically relevant for neurocognitive dysfunction in PLWH.