Search Results (141)

HIV-associated neurocognitive disorders (HAND) arise from HIV infection of the central nervous system, resulting in chronic neuroinflammation and progressive neuronal damage that impair cognitive, motor, and behavioral functions. Clinically, HAND encompasses a spectrum of neurological impairments ranging from asymptomatic neurocognitive impairment to severe HIV-associated dementia. Despite the widespread use of combination antiretroviral therapy (cART) and significant improvements in the life expectancy of people living with HIV, HAND remains prevalent and continues to pose a major clinical challenge. One of the primary limitations of cART is the limited penetration of many antiretroviral drugs across the blood–brain barrier (BBB), thereby allowing the persistence of viral reservoirs within the CNS and contributing to sustained neuroinflammation and neuronal damage. To address these challenges, novel nanotherapeutic strategies have been developed to enhance the delivery of antiretroviral agents to the brain. These approaches include targeted delivery systems and the co-delivery of therapeutics across the BBB through mechanisms such as receptor-mediated transcytosis and other transport pathways. In this review, we discuss the pathophysiological challenges associated with HAND and recent advances in nanotherapeutic approaches designed to improve treatment efficacy. We also discuss the current state of the art in vitro and in vivo models used to test the efficacy of these advanced therapeutics. Finally, we outline the remaining challenges and future prospects for the development of nanotherapeutics to improve the treatment of HAND. Full article

Although neurons are not productively infected by HIV-1, the envelope glycoprotein gp120, detectable in cerebrospinal fluid independently of active viral replication, gains intraneuronal access via lipid raft-mediated endocytosis, macropinocytosis, and retrograde axonal transport, contributing to persistent neurobiological dysfunction within the central nervous system. Once internalized, gp120 is associated with neuronal dysfunction involving convergent pathways, including excitotoxic calcium dysregulation, mitochondrial and metabolic failure, and inflammatory and senescence-associated amplification. These pathways converge on suppression of CREB and BDNF signaling, dismantling the transcriptional and neurotrophic programs required for synaptic maintenance and cognitive resilience. Extracellular vesicle-mediated dissemination and microRNA reprogramming extend gp120-associated neurobiological effects beyond sites of receptor engagement, while gut-derived metabolites, particularly quinolinic acid, lower the excitotoxic threshold through synergistic activation of NMDA receptors. Together, these mechanisms define HAND as a network disorder in which gp120 contributes to persistent neurocognitive dysfunction beyond active viral replication, identifying convergent therapeutic nodes where combination strategies targeting excitotoxicity, mitochondrial dysfunction, and neuroinflammation offer the most promising path toward durable neuroprotection. Full article

Microglia, the resident macrophages of the central nervous system (CNS), serve as the primary reservoir of HIV-1 in the brain and play a crucial role in the development of HIV-1-associated neurocognitive disorders (HAND). While long non-coding RNAs (lncRNAs) have emerged as essential regulators of HIV-1 replication in T cells and macrophages, their role in microglia remains poorly understood. Here, we performed RNA sequencing of polyadenylated transcripts from a human microglial cell line exposed to HIV-1 infection or TNF-α stimulation to investigate transcriptional responses and identify lncRNAs with potential regulatory functions. Gene set enrichment analysis revealed broad overlap between viral and inflammatory responses, reflecting convergence on common molecular pathways. Among differentially expressed lncRNAs, we focused on TALAM1, which was specifically induced by HIV-1, and LINC00702, which responded to both HIV-1 and TNF-α. Validation by RT-qPCR confirmed the upregulation of TALAM1 and LINC00702 at 24 h post-infection. Furthermore, knockdown of either lncRNA affected viral genomic RNA levels, while only LINC00702 knockdown affected p55 production. Given that subcellular localization informs lncRNA function, we assessed the distribution of TALAM1 and LINC00702. TALAM1 was predominantly cytoplasmic under basal conditions but shifted toward nuclear enrichment upon HIV-1 infection, whereas LINC00702 remained primarily nuclear regardless of infection status. Consistent with their genomic context, protein interaction predictions, and pathway enrichment analyses suggested that TALAM1 may influence RNA processing and splicing, whereas LINC00702 may contribute to translational regulation and is associated with proteins involved in immune responses. Together, these findings provide an initial characterization of lncRNA responses to HIV-1 infection in a human microglial cell line and identify TALAM1 and LINC00702 as candidates for future functional studies in the context of viral infection and neuroinflammation. Full article

HIV-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART) and can be exacerbated by repeated cocaine (COC) exposure. Because COC, HAND, and cART independently disrupt medial prefrontal cortex (mPFC) function, their combined neurotoxic impact is a critical clinical concern. Using patch-clamp electrophysiology in HIV-1 transgenic (Tg) and non-Tg rats, we examined mPFC pyramidal neuron activity following repeated exposure to COC and/or cART. In non-Tg rats, COC and cART independently increased neuronal firing, trending toward an additive hyperactive effect when combined. Conversely, HIV-1 Tg rat neurons exhibited plateaued excitability, with no further firing elevations induced by COC or cART. Under intense depolarizing stimuli, treated neurons displayed overactivation-induced firing declines. These findings indicate that while COC and cART additively disrupt mPFC function in non-Tg rats, excitability mechanisms appear saturated in the HIV-1 Tg model. This restricted experimental context highlights the overlapping neurobiological impacts of cART and stimulant use, providing foundational insights into the comorbidity of COC use disorder and HAND. Full article

HIV infection remains a major global health challenge due to its complex pathogenesis and lifelong persistence in people living with HIV (PLWH). A central barrier to eradication is the virus’s ability to establish long-lived latent reservoirs in different tissues, including the central nervous system (CNS), where it evades immune clearance and antiretroviral therapy (ART). These reservoirs, seeded early during infection, fuel viral rebound if ART is interrupted, requiring lifelong treatment. In the CNS, HIV persists despite systemic viral suppression because of limited ART penetration across the blood–brain barrier (BBB), and infection of long-lived cells such as microglia and perivascular macrophages. Although modern ART regimens significantly reduce viral burden and HIV-related morbidity, they do not eliminate neurocognitive complications. Suboptimal CNS drug penetration and certain ART-associated toxicities contribute to CNS dysfunction, persistent neuroinflammation, and accelerated aging of the brain. As PLWH now experience increased life expectancy, prolonged exposure to ART and persistent low-level viral activity exacerbate chronic inflammation, immune activation, and metabolic dysregulation, collectively accelerating neurobiological aging. These pathological processes contribute to the development of HIV-associated neurocognitive disorders (HAND), which affect nearly half of virally suppressed PLWH. This review examines HIV-associated inflammation, neurotoxic pathways, and accelerated aging in PLWH in the modern ART era. Full article

Background/Objectives. Oxidative stress is a key contributor to HIV-associated neurocognitive disorders (HANDs), yet the regional organization and functional engagement of the NRF2 antioxidant pathway in the human brain remain incompletely defined. This study aimed to characterize NRF2 pathway architecture, baseline brain expression, and disease-associated transcriptional and coexpression remodeling across HAND stages. Methods. The NRF2 signaling network was reconstructed using curated pathway data and protein–protein interaction analysis to identify central hub genes. Baseline expression in the normal human cortex was assessed using the Human Protein Atlas. Transcriptomic profiling of postmortem brain samples from individuals with HAND (GSE35864) was performed using differential expression, hierarchical clustering, and region-specific coexpression analyses across white matter, frontal cortex, and basal ganglia. Results. Low-to-medium baseline expression of NRF2-related genes was observed in the normal cortex. Bulk differential expression revealed minimal NRF2 pathway modulation in the frontal cortex and basal ganglia. On the other hand, white matter exhibited robust NRF2 transcriptional activation specifically in HIV encephalitis (HIVE). Coexpression analysis performed specifically within HAND samples revealed a highly coordinated transcriptional organization of the NRF2 signaling network across all analyzed brain regions. Conclusions. NRF2 signaling in HAND is preserved as a coordinated transcriptional network but is selectively activated in white matter during encephalitic disease, highlighting region- and cell-type-targeted therapeutic opportunities. Full article

HIV infection is accompanied by production of pro-inflammatory cytokines, which are regarded as critical in neuronal damage, leading to brain dysfunction. To develop diagnostic tools and therapeutic interventions, we need to measure CNS response to immune activation, hence the need to identify specific cytokine biomarkers that are associated with brain damage in HIV infection. This cross-sectional retrospective study applied Magnetic Resonance Imaging (MRI) for brain volumetric measurements and high-throughput Luminex-based immunoassays to quantify plasma cytokine and chemokine concentrations. We then used generalized linear models and Partial Least Square Regression models to evaluate the association between brain volume and plasma cytokines in predominantly treatment-naïve participants with HIV. After adjusting for clinical and demographic variables, we observed that higher MCP-1 (p = 0.013) and RANTES (p = 0.002) remained significantly associated with lower cortical white matter volume, whereas the anti-inflammatory cytokine IL-9 (p = 0.025) and the growth factors PDGFBB (p = 0.012) and VEGF (p = 0.001) were associated with higher cortical white matter volume. Only IL-6 (p = 0.010) was significantly associated with lower subcortical grey matter volume. Higher concentrations of five pro-inflammatory cytokines, IL-6 (p = 0.0001), IL-8 (p = 0.018), GCSF (p = 0.004), MCP-1 (p = 0.004), and RANTES (p = 0.015), were associated with lower total grey matter volume. Associations of pro-inflammatory cytokines with lower brain volume could imply a link to mechanisms of HIV-associated brain damage, which may lead to neurocognitive impairment. Therefore, the use of highly sensitive neuroimaging and high-throughput immunoassays in HIV-associated brain disorders has potential applications in clinical assessments and therapeutic monitoring. Full article

p17, the human immunodeficiency virus type 1 (HIV-1) matrix protein traditionally associated with viral assembly, has been recently investigated for its extracellular functions linked to vascular damage. This review examines the molecular and pathogenic signatures by which p17 and its variants (vp17s) contribute to endothelial activation, aberrant angiogenesis, and vascular inflammation, highlighting their relevance even under effective antiretroviral therapy (ART). Specifically, p17 exerts chemokine-like activities by binding to chemokine (C-X-C motif) receptor-1 and 2 (CXCR-1/2) on endothelial cells (ECs). This interaction triggers key signaling cascades, including the protein kinase B (Akt)-dependent extracellular signal-regulated kinase (ERK) pathway and endothelin-1/endothelin receptor B axis, driving EC motility, capillary formation, and lymphangiogenesis. Variants such as S75X demonstrate enhanced lymphangiogenic potency, associating them with tumorigenic processes involved in non-Hodgkin lymphoma (NHL) pathogenesis. Importantly, p17 promotes endothelial von Willebrand factor (vWF) storage and secretion, implicating a pro-coagulant state that may trigger the increased thromboembolic risks observed in HIV-positive patients. Furthermore, p17 crosses the blood–brain barrier (BBB) via CXCR-2-mediated pathways, contributing to neuroinflammation by activating microglia and astrocytes and amplifying monocyte chemoattractant protein-1 (MCP-1) levels, therefore playing a critical role in the development of HIV-associated neurocognitive disorders. Hence, the elaboration of potential therapeutic strategies finalized at inhibiting p17/vp17s’ interaction with their receptors could complement ART by addressing HIV-related neurovascular morbidity. Full article

Although antiviral therapy has improved quality of life, around 50% of people with HIV (PWH) experience neurodegeneration and cognitive decline. This is prompted in part by the migration of HIV-infected monocyte-derived macrophages (MDMs) to the brain, leading to neuronal death. Previous studies in our lab have shown that HIV-infected MDMs secrete cathepsin B (CATB), which is a pro-inflammatory neurotoxic enzyme that is reduced by the addition of cannabinoid receptor-2 (CB2R) agonist JWH-133 to cell cultures. In this study, we aimed to identify the proteins secreted (secretome) by HIV-infected macrophages exposed to JWH-133 and quantify them using tandem mass tag (TMT) mass spectrometry. Frozen 13-day MDM supernatants from (1) an MDM negative control; (2) HIV+MDM, and (3) HIV+MDM-JWH-133 were compared in triplicate by mass spectrometry (LC/MS/MS) and analyzed for protein identification. Subsequently, the same samples were labeled by TMT labeling and quantified by LC/MS/MS. After a database search, 528 proteins were identified from all groups. Thereafter, proteins with more than three unique peptides and more than 10% coverage were selected for protein identification. Venn diagrams revealed one unique protein secreted by MDM-HIV, 10 unique proteins in HIV+MDM-JWH-133, and 15 common proteins in the three groups. CATB was unique to HIV+MDM. HIV+MDM exposed to JWH-133 showed proteins related to metabolism, cell organization, antiviral activity, and stress response. TMT analysis revealed 1454 proteins with abundance for statistical analysis based on FC ≥ |1.5| and p-value ≤ 0.05, of which Ruvb-like 1 and Hornerin decreased significantly with JWH-133 treatment. Both proteins stimulate HIV replication. In addition, HIV infection upregulated proteins associated with pathways of viral latency that were inhibited by JWH-133. In conclusion, JWH-133 treatment in HIV-infected macrophages leads to the secretion of antiviral host factors and decreases the secretion of proviral, inflammatory, and neurotoxic host factors. Full article

Background: Despite effective antiretroviral therapy, HIV-associated neurocognitive disorders (HANDs) remain prevalent, highlighting the need for sensitive biomarkers of early brain alterations. Trace-weighted diffusion spectroscopic imaging offers a non-invasive means to assess microstructural changes in brain metabolites in a single shot by measuring apparent diffusion coefficients (ADCs) of total N-acetylaspartate (tNAA), total creatine (tCr), total choline (tCho), and water. Methods: In this study, we used trace-weighted single-shot diffusion-weighted radial echo-planar spectroscopic imaging (DW-RESPI) to investigate metabolite diffusion and relative concentrations in the brains of people living with HIV (PLWH). Using a 3T MRI scanner, we studied 16 PLWH and 15 healthy controls (HCs), and we collected two sets of data with low and high b-values from which metabolite ADCs were computed. Metabolite ratios were derived from the low b-value spectra. A brief neuropsychological assessment evaluated attention, executive function, and memory in a subset of subjects. Cognitive and affective performance was quantified using domain-specific deficit scores, as well as depression and anxiety assessments, offering a comprehensive evaluation of neurobehavioral function. In the male subgroup (N = 15) of PLWH, we calculated the correlations between ADC values and neuropsychological domain scores. Results: tNAA, tCr, tCho, and water ADC values were significantly elevated in multiple gray and white matter regions in PLWH compared to HC, with the most pronounced differences observed in the superior precuneus, anterior cingulate cortex, and corona radiata. Notably, regional ADC values and metabolite ratios showed significant correlations with neuropsychological domain scores. Conclusions: These findings indicate the potential of metabolite and water diffusion metrics as biomarkers for HIV-associated microstructural brain alterations and cognitive impairment. However, the small sample size and preliminary nature of this data warrant further investigation to validate these findings. Full article

Chronic neuroinflammation and impaired protein clearance are hallmarks of neurodegenerative diseases such as Alzheimer’s disease (AD) and HIV-associated neurocognitive disorders (HAND). Central to these processes are microglia, the brain’s resident immune cells, which normally maintain brain homeostasis by clearing amyloid-beta (Aβ) and other misfolded proteins through phagocytosis and receptor-mediated degradation. However, in both AD and HAND, microglial dysfunction promotes ongoing inflammation, impaired Aβ clearance, and progressive neuronal damage. This review synthesizes evidence from human and animal studies showing how key microglial pattern recognition receptors, including the Triggering receptor expressed on myeloid cells 2 (TREM2), Toll-like receptors (TLRs), and scavenger receptors (SR-AI/II, CD36, SR-BI, CD163), coordinate Aβ sensing, uptake, and inflammatory responses. We describe how HIV infection and viral proteins such as the trans-activator of transcription (Tat) and glycoprotein 120 (gp120) disrupt these pathways by altering receptor expression, lysosomal function, and microglial metabolism, creating a cycle of neurotoxicity and amyloid buildup. We further highlight current scientific gaps in elucidating how HIV affects microglial function and implications for HAND. Full article

Although antiretroviral regimens achieve durable suppression of human immunodeficiency virus (HIV) replication, individuals living with HIV remain at an increased risk of developing chronic comorbidities, such as HIV-associated neurocognitive disorder (HAND). In the absence of definitive biomarkers or curative treatments, HAND impacts the survival and quality of life in up to 50% of individuals with HIV. Therefore, novel strategies are highly warranted to improve the diagnosis, monitoring, and treatment of individuals with HAND and a deeper characterization of the still poorly understood pathogenesis of HAND is fundamental to this aim. The pathogenesis, progression, and clinical outcomes of HAND are influenced by different factors, including viral proteins like negative factor (Nef). Among HIV proteins, Nef emerges as a potential key contributor to HAND pathogenesis. Nef could drive specific histopathological alterations in the brain and could be involved in HAND through different interconnected pathogenetic mechanisms. These include: immune dysregulation, oxidative stress, mitochondrial dysfunction, disruption of autophagy, myelin damage and oligodendrocytes dysfunction, blood–brain barrier disruption, alterations of cholesterol homeostasis, and certain potential converging mechanisms with Alzheimer’s disease. Both extracellular and intracellular Nef can contribute to the development of HAND. Interestingly, it has been proposed that Nef may participate in HAND through its incorporation into extracellular vesicles. This review explores the multifaceted role of Nef in HAND, highlighting the histopathological alterations and the pathogenetic mechanisms potentially involved and the potential emerging relevance of Nef as a diagnostic and therapeutic target in HAND. Full article

Background: In people living with HIV (PLHIV), ongoing neuronal injury has shown a correlation with elevated levels of soluble markers of immune activation, such as sCD163. Additionally, various risk factors, such as injection drug use (IDU), can independently affect immune and cognitive functions, leading to neurocognitive impairment (NCI). However, the potential sCD163-IDU-NCI axis in ART-experienced PLHIV is not clear. This study aims to determine NCI prevalence and investigate the interplay between risk factors and sCD163 in Pakistani PLHIV. Methods: For this cross-sectional study, 150 PLHIV and 30 HIV-negative people who inject drugs (PWID) were recruited using a convenience sampling strategy. NCI screening was performed using the International HIV Dementia Scale (IHDS) tool. Blood samples from PLHIV were used to perform HIV recency testing using the Asante Rapid Recency Assay, and to evaluate sCD163 levels using ELISA. Sociodemographic and clinical data were collected from medical records. Subsequently, descriptive statistics were used to summarize data variables, while comparisons (two and multiple groups) between participants with and without NCI were conducted, respectively, using the Mann–Whitney test or Kruskal–Wallis test for continuous variables, and Fisher’s exact test for categorial variables. Receiver Operating Characteristic (ROC) curve analysis was performed to assess the discriminative ability of sCD163. Logistic regression was used to identify predictors of neurocognitive impairment. Results: The majority of PLHIV had IDU as a high-risk behavior. In PLHIV, the median age was 34.5 years (IQR: 30–41), ART duration was 35 months (IQR: 17–54), and median CD4 count was 326.5 cells/µL (IQR: 116–545.5). Long-term infections (>6 months post-seroconversion; median ART duration: 35 months; median CD4 counts: 326.5 cells/μL) were noted in 83.3% of PLHIV. IHDS-based screening showed that 83.33% (all PLHIV) and 50% (PLHIV with no IDU history) scored ≤ 9 on the IHDS, suggestive of NCI. IHDS-component analysis showed the memory recall to be significantly affected in PLHIV compared to controls (median score 3.2 versus 3.7, respectively, p < 0.001). Regression analysis showed only long-term infection (OR: 2.99, p = 0.03) to be significantly associated with neurocognitive impairment. sCD163 levels were significantly lower in PLHIV with NCI (mean = 7.48 ng/mL, SD = 7.05) compared to those without NCI (mean = 14.82 ng/mL, SD = 8.23; p < 0.0001), with an AUC of 0.803 (95% CI: 0.72–0.88). However, after adjusting for IDU history, the regression analysis showed an odds ratio for sCD163 of 0.998 (95% CI: 0.934, 1.067, p = 0.957), indicating no association between sCD163 levels and NCI. Conclusion: This study reports a high prevalence of NCI in Pakistani PLHIV, and no association between sCD163 and neurocognitive impairment in PLHIV after adjustment for a history of IDU. Long-term infection and IDU were significantly linked to NCI, while only IDU was associated with lower sCD163 levels, regardless of NCI. Full article

Background: HIV-associated neurocognitive disorders (HANDs) continue to be a significant concern, despite the advancements in prognosis achieved through Combination Antiretroviral Therapy (cART). Neuropsychological assessment, recommended by international guidelines for HANDs diagnosis, can be resource-intensive. Brief screening tools, like the International HIV Dementia Scale (IHDS) and the Montreal Cognitive Assessment (MoCA), are crucial in facilitating initial evaluations. This study aims to assess the Italian IHDS (IHDS-IT) and evaluate its sensitivity and specificity in detecting cognitive impairment in HIV patients. Methods: This cross-sectional study involved 294 patients aged ≥30 years, evaluated at the Immunology Unit of the University of Cagliari. Cognitive function was assessed using the MoCA and IHDS. Laboratory parameters, such as CD4 nadir, current CD4 count, and HIV-RNA levels, were also collected. Statistical analyses included Spearman’s correlation, Receiver Operating Characteristic analysis, and the Youden J statistic to identify the optimal IHDS-IT cut-off for cognitive impairment detection. Results: The IHDS and MoCA scores showed a moderate positive correlation (Spearman’s rho = 0.411, p < 0.0001). ROC analysis identified an IHDS-IT cut-off of ≤9, yielding an Area Under the Curve (AUC) of 0.76, sensitivity of 71.7%, and specificity of 67.2%. At this threshold, 73.1% of patients with MoCA scores below 23 also presented abnormal IHDS scores, highlighting the complementary utility of both cognitive assessment instruments. Conclusions: The IHDS-IT exhibited fair diagnostic accuracy for intercepting cognitive impairment, with a lower optimal cut-off than previously reported. The observed differences may reflect this study cohort’s demographic and clinical characteristics, including advanced age and long-lasting HIV infection. Further, longitudinal studies are necessary to validate these findings and to confirm the proposed IHDS cut-off over extended periods. Full article

Treatment for HIV infection has become more manageable due to advances in combination antiretroviral therapy (cART). However, HIV still significantly affects the central nervous system (CNS) in infected individuals, even with effective plasma viral suppression, due to persistent viral reservoirs and chronic neuroinflammation. This ongoing inflammation contributes to the development of HIV-associated neurocognitive disorders (HANDs), including dementia and Alzheimer’s disease-like pathology. These complications are particularly prevalent among the aging population with HIV. This review aims to provide a comprehensive overview of HAND, with a focus on the contribution of oxidative stress induced by HIV-mediated reactive oxygen species (ROS) production through viral proteins such as gp120, Tat, Nef, Vpr, and reverse transcriptase. In addition, we discuss current and emerging therapeutic interventions targeting HAND, including antioxidant strategies and poly (ADP-ribose) polymerase (PARP) inhibitors. These are potential adjunctive approaches to mitigate neuroinflammation and oxidative damage in the CNS. Full article