Innate immune memory in chronic HIV and HIV-associated neurocognitive disorders (HAND): potential mechanisms and clinical implications DOI Creative Commons

Zachary Capriotti,

Zachary Klase

Journal of NeuroVirology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 28, 2024

Abstract Although antiretroviral therapy (ART) has dramatically improved the outlook of HIV/AIDS pandemic, people living with HIV (PLWH) on suppressive are still at higher risk for a range comorbidities including cardiovascular disease (CVD) and HIV-associated neurocognitive disorders (HAND), among others. Chronic inflammation immune activation thought to be an underlying cause these comorbidities. Many factors drive chronic in overlap known induce trained immunity. Trained immunity is form innate memory that metabolically epigenetically reprograms cells mount enhanced inflammatory responses upon secondary encounter unrelated stimuli. While this phenotype been characterized variety states animals humans, very little about its potential contribution pathogenesis. In review, broad overview periphery central nervous system (CNS) provided evidence context considered. PLWH ART, could contribute associated complicate cure strategies due persistence after eradication virus. Further research into state may open door new therapeutics aimed treating like HAND.

Язык: Английский

Mapping the intersection of HIV and Alzheimer’s disease: a bibliometric analysis of emerging research trends DOI Creative Commons
Hao Zhang,

S. C. Yuan,

H. -R. Bao

и другие.

Frontiers in Neurology, Год журнала: 2025, Номер 16

Опубликована: Апрель 29, 2025

HIV and Alzheimer's disease (AD) are significant global health challenges with overlapping neuroinflammatory protein aggregation mechanisms. Understanding their intersection is critical for advancing therapeutic strategies, particularly in aging populations. This study aims to provide a comprehensive bibliometric analysis of research trends at the AD, identify emerging themes, highlight key contributors this interdisciplinary field. Using Web Science Core Collection, we retrieved 4,856 articles reviews published between 1994 2025. Bibliometric was conducted VOSviewer, CiteSpace, R software examine publication trends, international collaboration, institutional contributions, journal dynamics, author networks, thematic evolution. The reveals 14.18% annual growth rate publications, U.S. leading productivity, followed by China, Germany, Japan. Key institutions include NIH University California System, while journals such as Journal Biological Chemistry PLOS ONE show growth. Prominent authors Masliah, Eliezer, Heaton, RK. Research highlights overlap HIV-associated neurocognitive disorders (HAND) emphasizing shared mechanisms like neuroinflammation, aggregation, blood-brain barrier disruption. Recent advances focus on cerebrospinal fluid biomarkers, oxidative stress, impact antiretroviral therapy (ART) neurological outcomes. Studies increasingly explore role advanced methodologies, including machine learning, elucidating endoplasmic reticulum misfolding. underscores dynamic rapidly evolving landscape driven collaborative efforts technological advancements. Future should prioritize longitudinal studies, mechanistic insights, translational applications address unanswered questions

Язык: Английский

Процитировано

1
Multimodal Approach to Neurocognitive Function in People Living with HIV in the cART Era: A Comprehensive Review DOI Creative Commons
Charalampos D. Moschopoulos, Evangelia Stanitsa, Konstantinos Protopapas

и другие.

Life, Год журнала: 2024, Номер 14(4), С. 508 - 508

Опубликована: Апрель 15, 2024

Combination antiretroviral treatment (cART) has revolutionized the management of human immunodeficiency virus (HIV) and markedly improved disease burden life expectancy people living with HIV. HIV enters central nervous system (CNS) early in course infection, establishes latency, produces a pro-inflammatory milieu that may affect cognitive functions, even cART era. Whereas severe forms neurocognitive impairment (NCI) such as HIV-associated dementia have declined over last decades, milder become more prevalent, are commonly multifactorial, associated comorbidity burdens, mental health, neurotoxicity, ageing. Since 2007, Frascati criteria been used to characterize classify disorders (HAND) into three stages, namely asymptomatic (ANI), mild disorder (MND), (HAD). These based on comprehensive neuropsychological assessment presupposes availability validated, demographically adjusted, normative population data. Novel neuroimaging modalities biomarkers proposed order complement NCI assessments, elucidate neuropathogenic mechanisms, support diagnosis, monitoring, prognosis. By integrating assessments holistic care approach, clinicians can enhance diagnostic accuracy, prognosis, patient outcomes. This review interrogates value these modes proposes unified approach diagnosis.

Язык: Английский

Процитировано

3
Bridging brain and blood: a prospective view on neuroimaging-exosome correlations in HIV-associated neurocognitive disorders DOI Creative Commons
Haixia Luo,

J M Chen,

Jiaojiao Liu

и другие.

Frontiers in Neurology, Год журнала: 2025, Номер 15

Опубликована: Янв. 7, 2025

HIV-associated neurocognitive disorder (HAND) is a complex neurological complication resulting from human immunodeficiency virus (HIV) infection, affecting about 50% of individuals with HIV and significantly diminishing their quality life. HAND includes variety cognitive, motor, behavioral disorders, severely impacting patients' life social functioning. Although combination antiretroviral therapy (cART) has greatly improved the prognosis for patients, incidence remains high, underscoring urgent need to better understand its pathological mechanisms develop early diagnostic methods. This review highlights latest advancements in neuroimaging exosome biomarkers research. Neuroimaging, particularly magnetic resonance imaging (MRI), offers non-invasive repeatable method monitor subtle changes brain structure function, potentially detecting signs HAND. Meanwhile, exosomes are nano-sized vesicles secreted by cells that serve as key mediators intercellular communication, playing crucial role neuropathology acting critical bridge between peripheral blood central nervous system lesions. Thus, combining plasma indicators derived scans may enhance diagnosis summarizes evidence supporting reliable detection management Furthermore, we emphasize correlation explore potential combined use. discusses technical challenges methodological limitations integrating these two types proposes future research directions. multidisciplinary integrative approach not only promises improve health patients but also offer valuable insights into other neurodegenerative diseases.

Язык: Английский

Процитировано

0
Nef is a key player in neuroinflammation and myelin impairment associated with neuroHIV DOI Creative Commons
Michael Bukrinsky

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

Процитировано

0
HIV-1 Nef activates proviral DNA transcription by recruiting Src kinase to phosphorylate host protein Nef-associated factor 1 to compromise its viral restrictive function DOI Creative Commons

Tian-Jiao Fan,

Chengzuo Xie, Lisha Li

и другие.

Journal of Virology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 24, 2025

ABSTRACT HIV-1 accessory protein Nef is a multifunctional pathogenic factor that mediates immune evasion, enhances virion infectivity, antagonizes host restrictive factors, and promotes viral dissemination. However, the modulation of on proviral DNA transcription latently infected viruses not well understood. In this study, we found activated by recruiting Src Family Kinases (SFKs) member to stimulate downstream PI3K/AKT/mTOCR1/CDK9 cellular pathway, Naf1 (Nef-associated 1), known suppress transcription, was required for function Nef. This seemingly contradictory interplay between investigated. repressor but in presence Nef, phosphorylated at Tyrosine-552 Nef-recruited Src, consequently converting its normal role coordinate with activate transcription. These findings reveal mechanism which activates discover dual regulating HIV infection, depending phosphorylation status. study reports new interaction mode factors proteins replication. IMPORTANCE factor; however, virus demonstrates Nef's activating uncovers underlying mechanism. recruits kinase phosphorylate Naf1, converts stimulating pathway. also report

Язык: Английский

Процитировано

0
Macrophage-intrinsic MDA5-IRF5 axis drives HIV-1 icRNA-induced inflammatory responses DOI Creative Commons
Sita Ramaswamy, Hisashi Akiyama,

Jacob Berrigan

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 6, 2024

Abstract Despite effective antiretroviral therapy (ART), transcriptionally competent HIV-1 reservoirs persist and contribute to persistent immune activation in people living with HIV (PWH). HIV-1-infected macrophages are important mediators of chronic innate activation, though mechanisms remain unclear. We previously reported that nuclear export cytoplasmic expression intron-containing RNA (icRNA) activates mitochondrial antiviral signaling protein (MAVS)-mediated type I interferon (IFN) responses macrophages. In this study, we demonstrate an essential role melanoma differentiation-associated 5 (MDA5) sensing icRNA promoting MAVS-dependent IRF5 Suppression MDA5, but not RIG-I nor disruption endosomal TLR pathway, abrogated icRNA-induced IFN IP-10 Furthermore, induction upon by MDA5 was uniquely dependent on IRF5. Additionally, monocytes MDMs from older (>50 years) individuals exhibit constitutively higher levels compared younger (<35 individuals, induced significantly enhanced macrophages, which attenuated ablation suggesting functions as a major mediator pro-inflammatory response downstream MDA5-dependent sensing, dysregulation might inflammation PWH.

Язык: Английский

Процитировано

2
Adult human brain tissue cultures to study neuroHIV DOI Open Access
Rachel Van Duyne,

Elena Irollo,

Angel Lin

и другие.

Опубликована: Апрель 19, 2024

HIV-associated neurocognitive disorders (HAND) persist under antiretroviral therapy as a complex pathology that has been difficult to study in cellular and animal models. Therefore, we generated an ex vivo human brain slice model of HIV-1 infection from surgically resected adult tissue. Brain cultures processed for flow cytometry showed &gt;90% viability dissoci-ated cells within the first three weeks vitro, with parallel detection astrocyte, myeloid, neuronal populations. Neurons slices stable dendritic spine density mature morphologies culture, they detectable activity multi-electrode arrays. We infected cultured using patient-matched CD4+ T-cells or monocyte-derived macrophages (MDMs) were exposed GFP-expressing R5-tropic vitro. Infected expressed viral RNA developed spreading up 9-days post-infection, which significantly decreased by antiretrovirals. also detected myeloid astrocytes observed minimal effect on via-bility over time. Overall, this human-centered offers promising resource cel-lular mechanisms contributing HAND (including toxicity, substance use, aging), resident cells, new neuroprotective therapeutics.

Язык: Английский

Процитировано

1
Adult Human Brain Tissue Cultures to Study NeuroHIV DOI Creative Commons
Rachel Van Duyne,

Elena Irollo,

Angel Lin

и другие.

Cells, Год журнала: 2024, Номер 13(13), С. 1127 - 1127

Опубликована: Июнь 29, 2024

HIV-associated neurocognitive disorders (HAND) persist under antiretroviral therapy as a complex pathology that has been difficult to study in cellular and animal models. Therefore, we generated an ex vivo human brain slice model of HIV-1 infection from surgically resected adult tissue. Brain cultures processed for flow cytometry showed >90% viability dissociated cells within the first three weeks vitro, with parallel detection astrocyte, myeloid, neuronal populations. Neurons slices stable dendritic spine density mature morphologies culture, they detectable activity multi-electrode arrays. We infected cultured using patient-matched CD4+ T-cells or monocyte-derived macrophages (MDMs) were exposed GFP-expressing R5-tropic vitro. Infected expressed viral RNA developed spreading up 9 days post-infection, which significantly decreased by antiretrovirals. also detected myeloid astrocytes observed minimal effect on over time. Overall, this human-centered offers promising resource mechanisms contributing HAND (including toxicity, substance use, aging), resident cells, new neuroprotective therapeutics.

Язык: Английский

Процитировано

1
Role of Monocyte/Macrophages in the Pathogenesis of NeuroHIV DOI
David Ajasin, Eliseo A. Eugenín

Results and problems in cell differentiation, Год журнала: 2024, Номер unknown, С. 365 - 385

Опубликована: Янв. 1, 2024

Язык: Английский

Процитировано

0
Innate immune memory in chronic HIV and HIV-associated neurocognitive disorders (HAND): potential mechanisms and clinical implications DOI Creative Commons

Zachary Capriotti,

Zachary Klase

Journal of NeuroVirology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 28, 2024

Abstract Although antiretroviral therapy (ART) has dramatically improved the outlook of HIV/AIDS pandemic, people living with HIV (PLWH) on suppressive are still at higher risk for a range comorbidities including cardiovascular disease (CVD) and HIV-associated neurocognitive disorders (HAND), among others. Chronic inflammation immune activation thought to be an underlying cause these comorbidities. Many factors drive chronic in overlap known induce trained immunity. Trained immunity is form innate memory that metabolically epigenetically reprograms cells mount enhanced inflammatory responses upon secondary encounter unrelated stimuli. While this phenotype been characterized variety states animals humans, very little about its potential contribution pathogenesis. In review, broad overview periphery central nervous system (CNS) provided evidence context considered. PLWH ART, could contribute associated complicate cure strategies due persistence after eradication virus. Further research into state may open door new therapeutics aimed treating like HAND.

Язык: Английский

Процитировано

0