Search Results (134)

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

Introduction: Human immunodeficiency virus (HIV)-associated neurocognitive impairment (NCI) remains a concern despite combination antiretroviral therapy (cART), with cognitive problems often persisting even after viral suppression. The mechanisms underlying neurocognitive deterioration in people living with HIV (PLWH) and the role of plasma biomarkers remain unclear. This study aims to evaluate neurocognitive trajectories and biomarker changes in a real-world cohort of newly diagnosed PLWH initiating cART in Greece. Methods: This prospective, single-center study assessed neuropsychological performance and plasma biomarkers in treatment-naïve PLWH at baseline and 18 months after cART initiation. HIV-associated neurocognitive disorder (HAND) was classified using the Frascati criteria, and plasma biomarkers of inflammation and monocyte activation were measured. Correlations between biomarkers and cognitive performance were analyzed. Results: A total of 39 treatment-naïve PLWH were enrolled in this study. At baseline, 45.7% of participants met criteria for HAND, predominantly, asymptomatic neurocognitive impairment (ANI). Over 18 months, neurocognitive function improved, particularly in speed of information processing, executive function, and visuospatial ability, while verbal fluency, fine motor dexterity, and attention/working memory remained unchanged. Biomarkers of inflammation and monocyte activation decreased following cART, except for neopterin, which increased (10.6 vs. 13 ng/mL, p = 0.002), and plasma NFL (7.5 vs. 7.2 pg/mL, p = 0.54), which remained stable. A negative correlation between monocyte activation markers and cognitive performance was observed only at follow-up, suggesting that systemic inflammation may mask these associations in untreated PLWH. Conclusions: Early cART initiation supports neurocognitive recovery and reduces immune activation in PLWH. The observed correlation between cognitive performance and monocyte activation markers after viral suppression highlights the potential utility of plasma biomarkers in predicting cognitive impairment. Full article

Background/Objectives: This study aims to investigate the influence of demographic, behavioral, anthropometric, and comorbid factors on brain atrophy in people living with HIV (PLWH). Methods: We conducted a cross-sectional study involving 121 HIV-positive patients, stratified into two groups, those with and without brain atrophy (BA). For each participant, we recorded demographic data, smoking status, physical activity levels, disease and treatment duration, and comorbidities. BA was quantitatively assessed using MRI-derived volumetric measurements of 47 cerebral substructures. Results: Patients with BA exhibited significantly reduced gray matter (GM) and white matter (WM) volumes alongside increased cerebrospinal fluid volumes, both in absolute and percentage measurements. WM atrophy was most pronounced in the frontal, parietal, and temporal lobes, with relative sparing of the occipital lobe. GM atrophy predominantly affected the basal ganglia (notably, the thalamus and putamen) and cortical regions, including the hippocampus, frontal, and parietal lobes. Significant positive correlations were observed between BA and both smoking status (pack–years) and disease duration, while physical activity demonstrated an inverse relationship (higher atrophy risk in those with less than 30 min of daily continuous walking). Non-adherence to antiretroviral therapy (ART) was also associated with BA. Among comorbidities, type 2 diabetes and HIV-associated neurocognitive disorders (HAND) showed the strongest associations with BA. Conclusions: Brain atrophy in PWH is correlated with smoking, physical inactivity, and the duration of HIV infection. Comorbid conditions, such as type II diabetes and HAND, amplify the risk for BA. We consider that early lifestyle interventions and optimized ART may mitigate the neurodegeneration process. Full article

HIV-associated neurocognitive disorders (HANDs) refer to a range of cognitive deficits that afflict people living with the Human Immunodeficiency Virus (HIV). The fundamental processes of HAND include persistent inflammation, immunological activation, and direct viral impact on the central nervous system. Emerging research shows that nutritional status, especially food consumption and body weight, is critical in determining the course and severity of HAND. Malnutrition exacerbates neurocognitive impairment by increasing inflammation and oxidative stress, while obesity may contribute to HAND through the promotion of metabolic disruption, gut microbiota alterations, and systemic inflammation. Additionally, the introduction of antiretroviral treatment (ART) has substantially enhanced the prognosis of people living with HIV by lowering viral load and improving immune function. However, depending on the regimen, ART can cause changes in body weight, which may influence the progression of HAND. This emphasizes the intricate interplay between HIV, nutrition, body weight, and neurocognitive health. As a result, various dietary approaches are currently being investigated to improve the quality of life of individuals with HIV and possibly help prevent neurocognitive decline in this population. This review aims to elucidate the relationship between nutrition and neurocognitive function in individuals living with HIV, shedding light on aspects of HANDs related to diet, body weight fluctuations, and metabolic syndrome. It explores the shift from current pharmacological treatments to innovative non-pharmacological interventions, including specific dietary strategies, to support overall health and cognitive well being in HIV-positive people. Full article

HIV, primarily targeting CD4 cells, infiltrates the CNS through various mechanisms, including chemokine-mediated signaling and blood–brain barrier disruption, leading to neuroinflammation and neuronal dysfunction. Viral proteins such as gp120, Tat, and Vpr directly induce neurotoxicity, oxidative stress, and mitochondrial dysfunction, exacerbating cognitive deficits and motor impairments observed in HIV-associated neurocognitive disorders (HANDs). Host genetic factors, including CCR5 mutations and HLA alleles, influence susceptibility to HIV-related neurologic complications, shaping disease progression and treatment responses. Advanced molecular and bioinformatics techniques, from genome sequencing to structural modeling and network analysis, provide insights into viral pathogenesis and identify potential therapeutic targets. These findings underscore the future potential of precision medicine approaches tailored to individual genetic profiles to mitigate neurologic complications and improve outcomes in HIV-infected populations. This comprehensive review explores the intricate interplay between HIV infection and neurogenetics, focusing on how the virus impacts the central nervous system (CNS) and contributes to neurocognitive disorders. This report delves into how the virus influences genetic expression, neuroinflammation, and neurodegeneration, offering insights into molecular mechanisms behind HAND. Full article

Background: The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite antiretroviral treatment (ART). Changes in gut microbiota and persistent immune activation have been suggested as possible causes, while the role of probiotic supplementation remains controversial. Methods: We included subjects with mild HAND and successful ART. They were randomized to receive either 6 months of high-dose probiotic supplementation or to continue with only ART. Immune activation markers and neuropsychological testing were performed at baseline and the end of follow-up. Neuropsychological testing assessed learning, episodic memory, attention/concentration, executive functions, language, information processing speed, and motor skills. Z- and T-scores were calculated for all domains but motor skills, allowing the measurement of the global deficit score (GDS). The trajectories of neuropsychological performances and immune activation markers were compared between groups. Results: From September 2020 to July 2021, 31 PWHs were included (median age 62, 73% men, CD4 744 cc/mm³), and 28 completed the 6-month follow-up. The characteristics of the subjects and their neuropsychological performance at baseline in the two groups were similar. At the end of follow-up, probiotics did not have any impact on immune activation markers, while they were associated with better improvement in GDS (T-score 0.0 in controls vs. −0.3 in probiotics, p = 0.048) and the attention/concentration test (Z-score 0.4 in controls vs. 1.2 in probiotics, p = 0.035). Conclusions: Oral supplementation with high-dose probiotics for 6 months did not affect systemic immune activation but was associated with improved neurocognitive performance, suggesting benefits from probiotic supplementation for mild HAND. Full article

HIV-1 infection in microglia induces HIV-associated neurocognitive disorder (HAND). Recent evidence suggests that microglia can be infected with HIV-1 in the active, persistent, or latent replication stages. The molecular mechanisms governing these stages of infection are still the subject of continuous study. In this study, we analyzed the relationship between HIV-1 infection and two lncRNAs, NEAT1 and ZBTB11-AS1, on different days post-infection. We found that on days 1 and 4 post-infection, HIV-1 was actively replicating; meanwhile, by day 21, HIV-1 had entered a persistent stage. We also noted that the expression levels of NEAT1 and ZBTB11-AS1 varied during these different stages of HIV-1 infection in microglia, as did their subcellular localization. We performed an interaction network analysis and identified DDX3X and ZC3HAV1 as hypothetically related to NEAT1 and ZBTB11-AS1 in the C20 human microglial cell line. Additionally, we determined that IL-6, a cytokine regulated by DDX3X and ZC3HAV1, exhibits changes in protein expression levels during both active and persistent HIV-1 infection. Full article