Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Abstract For people with HIV (PWH), substance use disorders (SUDs) are a prominent neurological risk factor, and the impacts of both on dopaminergic pathways potential point deleterious convergence. Here, we profile, at single nucleus resolution, substantia nigra (SN) transcriptomes 90 postmortem donors in context chronic opioid/cocaine SUD, including 67 prospectively characterized PWH. We report altered microglial expression for hundreds pro- anti-inflammatory regulators attributable to HIV, separately, SUD. Stepwise, progressive dysregulation, coupled SN GABAergic signaling, was associated SUD/HIV dual diagnosis further lack viral suppression blood. In virologically suppressed donors, SUD comorbidity transcriptional changes permissive infection. HIV-related downregulation monoamine reuptake transporters specifically neurons regardless status or load, additional signatures consistent selective vulnerability dopamine neurons.

Язык: Английский

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Multi-omic Characterization of HIV Effects at Single Cell Level across Human Brain Regions

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 8, 2025

Abstract HIV infection exerts profound and long-lasting neurodegenerative effects on the central nervous system (CNS) that can persist despite antiretroviral therapy (ART). Here, we used single-nucleus multiome sequencing to map transcriptomic epigenetic landscapes of postmortem human brains from 13 healthy individuals 20 with who have a history treatment ART. Our study spanned three distinct regions—the prefrontal cortex, insular ventral striatum—enabling comprehensive exploration region-specific cross-regional perturbations. We found widespread persistent HIV-associated transcriptional alterations across multiple cell types. Detailed analyses microglia revealed state changes marked by immune activation metabolic dysregulation, while integrative multiomic profiling astrocytes identified subpopulations, including reactive subpopulation unique HIV-infected brains. These findings suggest cells people exhibit molecular shifts may underlie ongoing neuroinflammation CNS dysfunction. Furthermore, cell–cell communication uncovered dysregulated pro-inflammatory interactions among glial populations, underscoring multifaceted enduring impact brain milieu. Collectively, our atlas reveals states signatures signaling providing framework for developing targeted therapies neurological

Язык: Английский

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Neuroinflammation: An Oligodendrocentric View

Glia, Год журнала: 2025, Номер unknown

Опубликована: Март 10, 2025

Chronic neuroinflammation, driven by central nervous system (CNS)-resident astrocytes and microglia, as well infiltration of the peripheral immune system, is an important pathologic mechanism across a range neurologic diseases. For decades, research focused almost exclusively on how neuroinflammation impacted neuronal function; however, there accumulating evidence that injury to oligodendrocyte lineage component for both clinical outcomes. While oligodendrocytes are able undergo endogenous repair process known remyelination, this becomes inefficient usually fails in presence sustained inflammation. The present review focuses our current knowledge regarding activation innate adaptive systems chronic demyelinating disease, multiple sclerosis, provides other conditions, such perinatal white matter injury, traumatic brain viral infections, converges injury. Lastly, therapeutic potential targeting impact inflammation these diseases discussed.

Язык: Английский

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Nef is a key player in neuroinflammation and myelin impairment associated with neuroHIV

Frontiers in Neurology, Год журнала: 2025, Номер 16

Опубликована: Март 12, 2025

Anti-retroviral treatment (ART) has transformed HIV infection into a manageable chronic disease.It restores immune functionality and eliminates or reduces many AIDS-defining co-morbidities. In particular, the severity of HIV-associated neurocognitive disorders (HAND) been greatly reduced, significantly decreasing prevalence dementia [1]. However, overall milder forms HAND remains comparable to pre-ART era [2; 3; 4].Neurocognitive impairment affects nearly 50% people living with (PLWH), yet HIVspecific factors responsible for this co-morbidity remain poorly understood. A role viral proteins such as gp120, Tat, Nef suggested [5; 6; 7; 8; 9]. Two recent articles have provided evidence that is key protein neuroinflammation, myelin impairment, neuronal injury.Both studies underscore detrimental effects on CNS, particularly in context HIV-1 infection. The first study [10] demonstrates Nef's neuroinflammation damage mouse brain EcoHIV, hybrid virus carrying core envelope murine leukemia [11]. This model consistent ART-suppressed people, EcoHIV establishes latent [12].Considering inflammation, expression inflammatory cytokines mice infected Nefdeficient was between levels observed mock-infected Nef-positive differed from both [10], indicating other besides contributed neuroinflammation. conclusion line proposed Tat [8; Interestingly, (presumably Tat) appear additive, suggesting they may work throw different mechanisms. Indeed, disrupt BBB activate NF-kB monocytes microglia, promoting migration activated cells production [13; 14], whereas induces inflammation myeloid by affecting cholesterol homeostasis lipid rafts [15].While appears cooperate promote injury were attributed exclusively Nef, no defects detected Nef-deficient [10]. be influenced relatively short post-infection observation period (2-3 weeks), expected contribute over time.Consequently, potential contribution proteins, neurotoxicity via induction overlooked. These findings also argue against direct acute cytotoxicity previous [16]. discrepancy arise because concentrations required induce vitro (approximately 400 nM [17]) are likely not achieved model, although directly measured context. Notably, cerebrospinal fluid (CSF) ART-treated PLWH range 0.5 6.5 ng/mL (36-465 pM) [18], which lower than neurotoxic used studies. Collectively, these results suggest primary driver HAND. Further needed explore long-term contributions neuropathogenesis model.The second [19] provides more in-depth analysis Nef-mediated introduces concept Nef-containing EVs mediators oligodendrocyte injury. Instead injecting directly, injected EVs, strategy informed growing EVs' roles neurological diseases [20]. efficiently incorporated vesicles blood undetectable loads [21]. Since can routinely cross bloodbrain barrier [22], serve vehicle reach affect central nervous system. Furthermore, identified brains [23] SIVinfected monkeys [24], it taken up neighboring cells, including neurons, leading [25]. mechanism significant offers novel explanation how propagate throughout without requiring every affected cell. Importantly, even when replication suppressed ART, continue produced [26] capable exerting effects.This demonstrated disrupted sheaths inflicted upon glial particular oligodendrocytes, within CNS. oligodendrocytes partially prevented agents blocked inhibition activity cellular transporter, ABCA1, myelination mediated alterations homeostasis, known feature [15]. addition, promoted responses increasing number microglial at sites injection.Both similar pro-inflammatory impairment. study, unclear whether driven solely combination EV-mediated toxicity. scenario mechanisms contribute, microglia triggering while demyelination. supported low EV falling below limit detection.When related HAND, two support following model: Under ART treatment, persists brain-resident astrocytes, produce EVs. Additionally, originating peripheral sources enter bloodstream. HIV-infected adopt phenotype, releasing cytokines, further exacerbate integrity. Together, impaired synaptic communication, ultimately cognitive deficits.The reviewed here several limitations. They did specifically assess neurotoxicity, though prior research suggests caspase activation free radical [27]. death defining mild most prevalent [28]. Beyond its blood-brain [29], potentially exacerbating pathogenic discussed review. Nefdriven could amplified stimulation CCL5 [30], creating feedback loop sustains neuroinflammatory damage. aspects, along unexamined. Clarifying pathogenesis only deepens our understanding disease but identifies promising therapeutic targets preventing decline PLWH.The relevance incompletely limitation absence implicated neuropathogenesis, restricts investigations pathological impact.Additionally, unlike HIV-1, enters CD4/CCR5 CD4/CXCR4, utilizes mCAT-1, receptor broadly expressed across various tissues, brain. Despite difference, primarily infects CD4+ T monocytes/macrophages periphery [11], brain, predominantly resides [31; 32].Notably, EcoHIV-infected develop (NCI) resembling seen individuals [32; 33]. mice, play NCI pathogenesis, mirroring humans [34]. Specifically, hippocampusand amygdala-dependent deficits memory consolidation recall [32] closely parallel impairments [35]. selective loss dopaminergic neurons-without nondopaminergic neurons-in substantia nigra subventricular zones [36] mirrors aspects [37]. Crucially, depends persistent continues despite [32], persistence [38]. While differences exist human resulting share striking similarities.Given parallels, reasonable infer underlying neuropathology infections related.Neuroinflammation hallmark widely recognized [39; 40; 41; 42]. [15; 43; 44], presence post-mortem tissues [24] highlight driving neuroinflammation.Beyond shown exert proinflammatory [45; 46]. systemic leakage bacterial products through gut due incomplete restoration mucosa ("leaky gut") contributing factor [47]. relative require investigation.Less about disruption consistently [28; 48] SIV-infected [49; 50]. regions critical cognition motor function, where demyelination evident [48]. Together demonstrating [51] attenuation Nef-attenuated SIV [52], reinforce significance Nef-dependent research. damaging impact characterize HAND.The strategies mitigating improving management targeting smallmolecule inhibitors [53], blocking interference efflux presents approach protecting preserving inducers main effector efflux, LXR agonists [54], interaction calnexin, thereby ABCA1 maturation [55]. help reduce Nef-driven [5].Furthermore, discovery exposed [56] opens possibility entities using monoclonal antibodies. Monoclonal antibody therapies revolutionized providing precise effective interventions. Examples include autoimmune rheumatoid arthritis, treated anti-TNF antibodies [57]; infectious like COVID-19, managed SARS-CoV-2 spike protein-targeting [58]; cancers anti-PD-1 [59]. To apply neutralizing will essential identify high-affinity conserved region ensuring broad efficacy all variants.The current body supporting Its involvement damage, highlights target identification extracellular reinforces intervention. insight effect offering Future should focus delineating molecular pathways exerts effects, well exploring block prevent reverse CNS priority distinguishing respective fully elucidated. Advancing areas crucial accelerating development treatments neurotoxicity. Given challenges managing targeted interventions neutralize provide much-needed improve outcomes HIV.

Язык: Английский

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Microglia Exhibit a Unique Intact HIV Reservoir in Human Postmortem Brain Tissue

Viruses, Год журнала: 2025, Номер 17(4), С. 467 - 467

Опубликована: Март 25, 2025

A proviral reservoir persists within the central nervous system (CNS) of people with HIV, but its characteristics remain poorly understood. Research has primarily focused on cerebrospinal fluid (CSF), as acquiring brain tissue is challenging. We examined size, cellular tropism, and infection-dynamics viral in post-mortem from five individuals off antiretroviral therapy (ART) across three regions. Microglia-enriched fractions (CD11b+) were isolated levels intact DNA quantified (IPDA). Full-length envelope reporter viruses generated characterized CD4+ T cells monocyte-derived microglia. HIV was observed microglia-enriched all individuals, proviruses identified only one ART-treated individual, representing 15% total proviruses. Phenotypic analyses clones this individual showed that 80% replicated efficiently microglia cells, while remaining cells. No region-specific effects observed. These results indicate a distinct for although detected one. Given unique immune environment CNS, microglia, challenges associated targeting these CNS should be considered cure strategies.

Язык: Английский

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Eliminating the persistent HIV reservoir based on biomarker expression – how do we get there?

Virology, Год журнала: 2024, Номер 603, С. 110368 - 110368

Опубликована: Дек. 20, 2024

Язык: Английский

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