Cannabis Use and Cannabidiol Modulate HIV-Induced Alterations in TREM2 Expression: Implications for Age-Related Neuropathogenesis.

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.

Sera from people with HIV and depression induce commensurate metabolic alterations in astrocytes: toward precision diagnoses and therapies.

Objectives: People with HIV (PWH) have high rates of depression and neurocognitive impairment (NCI) despite viral suppression on antiretroviral therapy (ART). Mounting evidence suggests that immunometabolic disruptions may contribute to these conditions in some PWH. We hypothesized that metabolic dysfunction in astrocytes is associated with depressive symptoms and cognitive function in PWH.

Mitochondrial DNA and Electron Transport Chain Protein Levels Are Altered in Peripheral Nerve Tissues from Donors with HIV Sensory Neuropathy: A Pilot Study.

Distal sensory polyneuropathy (DSP) and distal neuropathic pain (DNP) remain significant challenges for older people with HIV (PWH), necessitating enhanced clinical attention. HIV and certain antiretroviral therapies (ARTs) can compromise mitochondrial function and impact mitochondrial DNA (mtDNA) replication, which is linked to DSP in ART-treated PWH. This study investigated mtDNA, mitochondrial fission and fusion proteins, and mitochondrial electron transport chain protein changes in the dorsal root ganglions (DRGs) and sural nerves (SuNs) of 11 autopsied PWH.

Elevated Biomarkers of Inflammation and Vascular Dysfunction Are Associated with Distal Sensory Polyneuropathy in People with HIV.

Distal sensory polyneuropathy (DSP) is a disabling, chronic condition in people with HIV (PWH), even those with viral suppression of antiretroviral therapy (ART), and with a wide range of complications, such as reduced quality of life. Previous studies demonstrated that DSP is associated with inflammatory cytokines in PWH. Adhesion molecules, essential for normal vascular function, are perturbed in HIV and other conditions linked to DSP, but the link between adhesion molecules and DSP in PWH is unknown.

Nicotine, THC, and Dolutegravir Modulate E-Cigarette-Induced Changes in Addiction- and Inflammation-Associated Genes in Rat Brains and Astrocytes.

E-cigarette use has been marketed as a safer alternative to traditional cigarettes, as a means of smoking cessation, and are used at a higher rate than the general population in people with HIV (PWH). Early growth receptor 2 (EGR2) and Activity-Regulated Cytoskeleton-Associated Protein (ARC) have a role in addiction, synaptic plasticity, inflammation, and neurodegeneration. This study showed that 10 days of exposure to e-cigarette vapor altered gene expression in the brains of 6-month-old, male, Sprague Dawley rats.

Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management.

People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system.

GP120 and tenofovir alafenamide alter cannabinoid receptor 1 expression in hippocampus of mice.

Central nervous system (CNS) dysfunction remains prevalent in people with HIV (PWH) despite effective antiretroviral therapy (ART). There is evidence that low-level HIV infection and ART drugs may contribute to CNS damage in the brain of PWH with suppressed viral loads. As cannabis is used at a higher rate in PWH compared to the general population, there is interest in understanding how HIV proteins and ART drugs interact with the endocannabinoid system (ECS) and inflammation in the CNS.

Differential expression of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in Alzheimer's disease and HIV-1 associated neurocognitive disorders.

The United Nations projects that one in every six people will be over the age of 65 by the year 2050. With a rapidly aging population, the risk of Alzheimer's disease (AD) becomes a major concern. AD is a multifactorial disease that involves neurodegeneration in the brain with mild dementia and deficits in memory and other cognitive domains.

Complement component 3 and complement factor H protein levels are altered in brain tissues from people with human immunodeficiency virus: A pilot study.

People with HIV (PWH) continue to suffer from dysfunction of the central nervous system, as evidenced by HIV-associated neurocognitive disorder (HAND), despite antiretroviral therapy and suppressed viral loads. As PWH live longer they may also be at risk of age-related neurodegenerative diseases such Alzheimer's disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). The complement system is associated with deposition of AD-related proteins such as beta amyloid (Aβ), neuroinflammation, and neurological dysfunction in PWH.

Caloric Restriction Mimetic 2-Deoxyglucose Reduces Inflammatory Signaling in Human Astrocytes: Implications for Therapeutic Strategies Targeting Neurodegenerative Diseases.

Therapeutic interventions are greatly needed for age-related neurodegenerative diseases. Astrocytes regulate many aspects of neuronal function including bioenergetics and synaptic transmission. Reactive astrocytes are implicated in neurodegenerative diseases due to their pro-inflammatory phenotype close association with damaged neurons.

Higher buccal mitochondrial DNA and mitochondrial common deletion number are associated with markers of neurodegeneration and inflammation in cerebrospinal fluid.

Human immunodeficiency virus (HIV) infection is potentially associated with premature aging, but demonstrating this is difficult due to a lack of reliable biomarkers. The mitochondrial (mt) DNA "common deletion" mutation (mtCDM) is a 4977-bp deletion associated with aging and neurodegenerative diseases. We examined how mtDNA and mtCDM correlate with markers of neurodegeneration and inflammation in people with and without HIV (PWH and PWOH).

Alterations in Brain Cannabinoid Receptor Levels Are Associated with HIV-Associated Neurocognitive Disorders in the ART Era: Implications for Therapeutic Strategies Targeting the Endocannabinoid System.

HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB and CB) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties.

Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine.

HIV-associated distal sensory polyneuropathy (HIV-DSP) affects about one third of people with HIV and is characterized by distal degeneration of axons. The pathogenesis of HIV-DSP is not known and there is currently no FDA-approved treatment. HIV trans-activator of transcription (TAT) is associated with mitochondrial dysfunction and neurotoxicity in the brain and may play a role in the pathogenesis of HIV-DSP.

The Cannabinoid Receptor Agonist, WIN-55212-2, Suppresses the Activation of Proinflammatory Genes Induced by Interleukin 1 Beta in Human Astrocytes.

Alterations of astrocyte function play a crucial role in neuroinflammatory diseases due to either the loss of their neuroprotective role or the gain of their toxic inflammatory properties. Accumulating evidence highlights that cannabinoids and cannabinoid receptor agonists, such as WIN55,212-2 (WIN), reduce inflammation in cellular and animal models. Thus, the endocannabinoid system has become an attractive target to attenuate chronic inflammation in neurodegenerative diseases.

Effects of innate immune receptor stimulation on extracellular α-synuclein uptake and degradation by brain resident cells.

Synucleinopathies are age-related neurological disorders characterized by the progressive deposition of α-synuclein (α-syn) aggregates and include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Although cell-to-cell α-syn transmission is thought to play a key role in the spread of α-syn pathology, the detailed mechanism is still unknown. Neuroinflammation is another key pathological feature of synucleinopathies.

Nucleic acid oxidation is associated with biomarkers of neurodegeneration in CSF in people with HIV.

Objective: To determine whether oxidative stress in virologically suppressed people with HIV (PWH) may contribute to or result from neurodegeneration, we measured 7,8-dihydro-8-oxoguanine (8-oxo-dG), a marker of DNA damage due to oxidative stress, and markers of age-related neurodegeneration, specifically, reduced levels of CSF Aβ-42, and elevated CSF total tau and neurofilament light (NFL).

Methods: This cross-sectional study prospectively enrolled participants at 6 US centers in the CNS HIV Antiretroviral Effects Research study. Inclusion criteria included HIV+ with a plasma level of HIV RNA ≤50 copies/mL.

Methamphetamine and Cannabis: A Tale of Two Drugs and their Effects on HIV, Brain, and Behavior.

HIV infection and drug use intersect epidemiologically, and their combination can result in complex effects on brain and behavior. The extent to which drugs affect the health of persons with HIV (PWH) depends on many factors including drug characteristics, use patterns, stage of HIV disease and its treatment, comorbid factors, and age. To consider the range of drug effects, we have selected two that are in common use by PWH: methamphetamine and cannabis.

Antiretroviral drug concentrations in brain tissue of adult decedents.

Objective: Determine concentrations of antiretroviral therapy (ART) drugs in the human brain.

Design: Cohort study of persons with HIV who consented to antemortem assessment and postmortem autopsy.

Methods: Eleven persons with HIV who were taking ART at the time of death and had detectable concentrations of at least one ART drug in intracardiac aspirate at autopsy were evaluated.

Predictors of worsening neuropathy and neuropathic pain after 12 years in people with HIV.

Objective: Distal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact.

Methods: Ambulatory, community-dwelling HIV seropositive individuals were recruited at six research centers.

Lipocalin-2 mediates HIV-1 induced neuronal injury and behavioral deficits by overriding CCR5-dependent protection.

People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex.

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorder.

Background: HIV-associated neurocognitive disorders (HAND) persist in the era of combined antiretroviral therapy (ART) despite reductions in viral load (VL) and overall disease severity. The mechanisms underlying HAND in the ART era are not well understood but are likely multifactorial, involving alterations in common pathways such as inflammation, autophagy, neurogenesis, and mitochondrial function. Newly developed omics approaches hold potential to identify mechanisms driving neuropathogenesis of HIV in the ART era.