Search Results (8)

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: HIV-associated neurocognitive impairment (NCI) remains a prevalent issue among people with HIV (PWH) despite advancements in antiretroviral therapy (ART). The pathogenesis of HIV-associated NCI is linked to chronic neuroinflammation caused by HIV, even in those with successful viral suppression. Growth Differentiation Factor 15 (GDF15), a protein involved in inflammatory and metabolic stress responses, has emerged as a key player and potential biomarker for various neurological conditions. This study investigates the relationship between GDF15 expression and HIV-associated NCI. Methods: PWH from the California NeuroAIDS Tissue Network (CNTN) underwent comprehensive neuropsychological exams within 12 months before death and were categorized based on cognitive performance. We examined GDF15 levels in their CSF (Cerebrospinal Fluid) and brain tissues using immunoblotting, immunohistochemistry, double immunolabeling, and ELISA. Results: The cohort was of a similar age across HIV-associated NCI statuses (mean = 40.5), with a predominance of males (77%). The mean plasma viral load was 3.56 log₁₀ copies/mL for Neurocognitively Unimpaired (NUI) PWH and 5.38 log10 copies/mL for people with HIV-associated NCI. GDF15 protein levels were significantly elevated in the frontal cortices of PWH with NCI compared to NUI PWH. Conclusions: The findings indicate that GDF15 may play a role in the pathogenesis of HIV-associated NCI, possibly through neuroinflammatory mechanisms. The strong association between GDF15 levels and cognitive impairment severity suggests its potential as a biomarker for the early detection and monitoring of NCI in PWH. Full article

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2^R47H mutant mice were used to study HIV’s impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH (n = 42) and people without HIV (PWoH; n = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2^R47H mice, with increased IBA1 protein in TREM2^R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies. Full article

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (FTH1), ferritin light-chain (FTL), and urinary F₂-isoprostanes (uF₂-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ-4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCIs were evaluated by multivariable regression; correlations with uF₂-isoPs were also assessed. Higher FTL and FTH1 levels were associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% confidence interval (95% CI) 0.36–0.79 and 0.66, 95% CI 0.45–0.97, respectively). In women, higher FTL and FTH1 were also associated with better NPZ-4 (FTL adjusted beta (β) = 0.15, 95% CI 0.02–0.29; FTL-by-sex β_interaction = 0.32, p = 0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF₂-isoPs in women (FTL: rho = −0.47, p < 0.001). Circulating FTL and FTH1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate the underlying mechanisms. Full article

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

Neurocognitive impairment (NCI) associated with HIV infection of the brain impacts a large proportion of people with HIV (PWH) regardless of antiretroviral therapy (ART). While the number of PWH and severe NCI has dropped considerably with the introduction of ART, the sole use of ART is not sufficient to prevent or arrest NCI in many PWH. As the HIV field continues to investigate cure strategies, adjunctive therapies are greatly needed. HIV imaging, cerebrospinal fluid, and pathological studies point to the presence of continual inflammation, and the presence of HIV RNA, DNA, and proteins in the brain despite ART. Clinical trials exploring potential adjunctive therapeutics for the treatment of HIV NCI over the last few decades have had limited success. Ideally, future research and development of novel compounds need to address both the HIV replication and neuroinflammation associated with HIV infection in the brain. Brain mononuclear phagocytes (MPs) are the primary instigators of inflammation and HIV protein expression; therefore, adjunctive treatments that act on MPs, such as immunomodulating agents, look promising. In this review, we will highlight recent developments of innovative therapies and discuss future approaches for HIV NCI treatment. Full article

The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle—a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical scaffolds from the National Cancer Institute (NCI) Diversity Set V that inhibited HIV-1 RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183, which has no known association with previously reported drug resistance. This finding supports the possibility of a novel druggable site on p51 for a new class of non-nucleoside RT inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally to only be in the micromolar range, the scaffolds serve as a proof-of-concept of targeting the HIV RT p51 subunit, with the possibility of medical chemistry methods being applied to improve inhibitory activity towards more effective drugs. Full article

The aims of the present study were to evaluate the prevalence of undiagnosed mental health conditions (UMHC) in people living with HIV (PLWHIV) on antiretroviral treatment and with long-term suppressed HIV viremia, and its association with neurocognitive impairment (NCI). A cross-sectional observational study on HIV subjects, ≥18 years old, on stable antiretroviral treatment and with HIV viral load <50 copies/mL was carried out. Patients with known comorbidities, substances abuse, anxiety or depression were excluded. UMHC were evaluated by the Millon Clinical Multiaxial Inventory-III and NCI by Frascati criteria. The association between NCI and sociodemographic, clinical HIV variables and mental health conditions was analyzed. Further, the relationship between mental health conditions scores and NCI diagnosis was evaluated. Eighty patients were included, 37.5% had at least one undiagnosed mental health condition, and 26.3% had NCI. The most frequent mental health conditions were: anxiety (21.3%); bipolar disorder (11.3%); and substance dependence (8.8%). Only longer time since HIV diagnosis (p = 0.030) and at least one mental health condition diagnosis (p = 0.002) showed an association with NCI. Participants with NCI presented higher scores in anxiety, alcohol dependence and post-traumatic stress. Undiagnosed mental health conditions are frequent in PLWHIV. These disorders cannot be identified by HIV clinicians or basic screening questionnaires, and they are not usually self-reported by patients. UMHC could act as confounders in the evaluation of NCI. Full article