HIV-1 gp120 Interactions with Nicotine Modulate Mitochondrial Network Properties and Amyloid Release in Microglia

Neurochemical Research, Journal Year: 2025, Volume and Issue: 50(2)

Published: Feb. 24, 2025

Abstract Human immunodeficiency virus (HIV) infections remain a significant public health burden globally with infected individuals at high risk for cognitive decline and memory loss even on combination antiretroviral therapy. Almost half of HIV smoke, which drives poorer outcomes including higher dementia rate. Microglia are the brain’s immune cells that serve as persistent reservoir contributing to neuroinflammatory signaling. We examined interactions between envelope glycoprotein gp120 nicotine within human microglia (HMC3) endogenously express chemokine receptor 5 (CCR5) nicotinic acetylcholine receptors (nAChRs). Liquid chromatography coupled electrospray ionization mass spectrometry (LC-ESI/MS) shows alters mitochondria proteins HMC3 cells. In presence nicotine, increased expression mitochondrial prohibitin 2 (PHB2), cytochrome c (cyt c), mitofusin (MFN2) but decreased fission 1 (FIS1) levels. An analysis mito-YFP confirms interaction increases size branching networks. Interaction is also surprisingly found promote release amyloid precursor protein (APP) peptides from microglia. This was accompanied by visualization containing vesicles colocalized autophagy LC3B-II in cell. Taken together, our findings show impact manner regulates network properties impacts management These mechanisms may contribute understanding signaling smokers HIV.

Language: Английский

---

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

Frontiers in Neurology, Journal Year: 2025, Volume and Issue: 16

Published: March 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.

Language: Английский

---

Neuroinflammation, Blood–Brain Barrier, and HIV Reservoirs in the CNS: An In-Depth Exploration of Latency Mechanisms and Emerging Therapeutic Strategies

Viruses, Journal Year: 2025, Volume and Issue: 17(4), P. 572 - 572

Published: April 16, 2025

Despite the success of antiretroviral therapy (ART) in suppressing viral replication blood, HIV persists central nervous system (CNS) and causes chronic neurocognitive impairment, a hallmark HIV-associated disorders (HAND). This review looks at complex interactions among HIV, blood–brain barrier (BBB), neuroinflammation, roles proteins, immune cell trafficking, pro-inflammatory mediators establishing maintaining latent reservoirs CNS, particularly microglia astrocytes. Key findings show disruption BBB, monocyte infiltration, activation CNS-resident cells by proteins like Tat gp120, contributing to neuroinflammatory environment neuronal damage. Advances epigenetic regulation latency have identified targets histone modifications DNA methylation, new therapeutic strategies latency-reversing agents (LRAs), gene editing (CRISPR/Cas9), nanoparticle-based drug delivery also offer hope. While we made significant progress understanding molecular basis persistence overcoming challenges BBB penetration neuroinflammation is key developing effective therapies. Further research into combination therapies novel systems will help improve outcomes for HAND patients bring us closer functional cure HIV.

Language: Английский

---

Population analysis and immunologic landscape of melanoma in people living with HIV

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Abstract People living with HIV (PLWH) diagnosed melanoma have consistently exhibited worse clinical outcomes than HIV-negative individuals (PLw/oH) the same cancer, even in era of antiretroviral therapy (ART). To investigate underlying factors contributing to these disparities, we analyzed electronic health records from 922 PLWH and 334,972 PLw/oH melanoma. were at a younger age had higher representation Hispanic Black individuals. Notably, markedly increased risk brain metastases. Additionally, despite similar treatment durations, experienced significant delays initiating immune checkpoint (ICI) survival both five- ten-years post-treatment ICI. explore potential biological determinants conducted spatial transcriptomics on tumors (n=11). This analysis revealed more immunosuppressive tumor landscape PLWH, characterized by upregulated checkpoints (e.g., PD1, LAG3, CTLA4) diminished antigen presentation HLA-DRB, B2M ), distinct distributions versus microenvironments. Downstream validation via multiplex immunofluorescence (n=15 n=14 PLw/oH) confirmed an exhausted CD8 + T cell compartment, marked enrichment PD1 int LAG3 - subpopulations, along accumulation myeloid-derived suppressor cells (CD11b HLA-DR CD33 ) PLWH. These profiles suggest chronic infection fosters permissive microenvironment that might undermine effective responses contribute poor for Targeting actionable pathways identified this study could inform tailored therapeutic strategies mitigate disparities.

Language: Английский

---

Neuroinflammation—the role of heteroreceptor complexes

Exploration of Neuroprotective Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: May 12, 2025

Neuroinflammation is a hallmark of various neurodegenerative and neuropsychiatric disorders, driven by complex interactions between neurotransmitter receptors immune signaling pathways. Among these, heteroreceptor complexes—functional assemblies formed the physical interaction different G protein-coupled or ionotropic receptor subtypes within same membrane microdomain—play crucial role in modulating synaptic activity, neuroimmune responses, inflammatory cascades. For example, A2A-D2 modulates dopaminergic striatum has been implicated Parkinson’s disease pathology. These receptor-receptor influence key pathways involving dopamine, serotonin, glutamate, adenosine, cannabinoid systems, thereby contributing to pathophysiology Alzheimer’s disease, multiple sclerosis, schizophrenia, depression. Dysregulation complexes disrupts neuronal homeostasis, exacerbates neuroinflammatory influences microglial astrocytic activation. Understanding molecular mechanisms governing these interactions, including allosteric modulation biased agonism, offers novel therapeutic avenues for targeting neuroinflammation. Pharmacological strategies, such as selective modulators, agonists, receptor-specific ligands, aim restore function mitigate damage. Emerging clinical trials—such those evaluating A2A antagonists like istradefylline 5-HT2A schizophrenia—have shown promising neuroprotective anti-inflammatory effects, although larger-scale, long-term studies are needed confirm efficacy. This review highlights pivotal neuroinflammation, discusses their potential, underscores need further research into functional dynamics develop effective interventions diseases.

Language: Английский

---