HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology.

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood-brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND.

Neuropathogenic role of astrocyte-derived extracellular vesicles in HIV-associated neurocognitive disorders.

Our previous findings demonstrated that astrocytic HIF-1α plays a major role in HIV-1 Tat-mediated amyloidosis which can lead to Alzheimer's-like pathology-a comorbidity of HIV-Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV-1 Tat stimulated astrocyte-derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF-1α could likely mitigate HIV-1 Tat-ADEV-mediated neuronal injury. Rat hippocampal neurons when exposed to HIV-1 Tat-ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF-1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV-1 Tat-ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV-1 Tat-ADEVs, exhibited behavioural changes, and Alzheimer's 's-like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF-1α silenced ADEVs. This is the first report demonstrating the role of amyloid-carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF-1α.

Comprehensive analyses identify potential biomarkers for encephalitis in HIV infection.

Human immunodeficiency virus encephalitis (HIVE) is a severe neurological complication after HIV infection. Evidence shows that genetic factors play an important role in HIVE. The aim of the present study was to identify new potential therapeutic targets for HIVE. Differentially expressed gene (DEG), functional annotation and pathway, and protein-protein interaction analyses were performed to identify the hub genes associated with HIVE. Gene co-expression analysis was carried out to confirm the association between the hub genes and HIVE. Finally, the role of the hub genes in HIVE therapy was evaluated by conducting drug-gene interaction analysis. A total of 20 overlapping DEGs closely related to HIVE were identified. Functional annotation and pathway enrichment analysis indicated that the markedly enriched DEG terms included ion transport, type II interferon signaling, and synaptic signaling. Moreover, protein-protein interaction analysis revealed that 10 key HIVE-related genes were hub genes, including SCN8A, CDK5R2, GRM5, SCN2B, IFI44L, STAT1, SLC17A7, ISG15, FGF12, and FGF13. Furthermore, six hub genes were co-expressed with HIVE-associated host genes in human brain tissue. Finally, three hub genes (STAT1, ISG15, and SCN2B) interacted with several inflammation-associated drugs. These findings suggested that SCN8A, CDK5R2, GRM5, SCN2B, IFI44L, STAT1, SLC17A7, ISG15, FGF12, and FGF13 may be new targets for diagnosis and therapy of HIVE.

HIV-associated neurotoxicity and cognitive decline: Therapeutic implications.

As our understanding of changes to the neurological system has improved, it has become clear that patients who have contracted human immunodeficiency virus type 1 (HIV-1) can potentially suffer from a cascade of neurological issues, including neuropathy, dementia, and declining cognitive function. The progression from mild to severe symptoms tends to affect motor function, followed by cognitive changes. Central nervous system deficits that are observed as the disease progresses have been reported as most severe in later-stage HIV infection. Examining the full spectrum of neuronal damage, generalized cortical atrophy is a common hallmark, resulting in the death of multiple classes of neurons. With antiretroviral therapy (ART), we can partially control disease progression, slowing the onset of the most severe symptoms such as, reducing viral load in the brain, and developing HIV-associated dementia (HAD). HAD is a severe and debilitating outcome from HIV-related neuropathologies. HIV neurotoxicity can be direct (action directly on the neuron) or indirect (actions off-site that affect normal neuronal function). There are two critical HIV-associated proteins, Tat and gp120, which bear responsibility for many of the neuropathologies associated with HAD and HIV-associated neurocognitive disorder (HAND). A cascade of systems is involved in HIV-related neurotoxicity, and determining a critical point where therapeutic strategies can be employed is of the utmost importance. This review will provide an overview of the existing hypotheses on HIV-neurotoxicity and the potential for the development of therapeutics to aid in the treatment of HIV-related nervous system dysfunction.

Activation of α7 nicotinic acetylcholine receptor ameliorates HIV-associated neurology and neuropathology.

HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy are primarily manifested as impaired behaviours, glial activation/neuroinflammation and compromised neuronal integrity, for which there are no effective treatments currently available. In the current study, we used doxycycline-inducible astrocyte-specific HIV Tat transgenic mice (iTat), a surrogate HAND model, and determined effects of PNU-125096, a positive allosteric modulator of α7 nicotinic acetylcholine receptor (α7 nAChR) on Tat-induced behavioural impairments and neuropathologies. We showed that PNU-125096 treatment significantly improved locomotor, learning and memory deficits of iTat mice while inhibited glial activation and increased PSD-95 expression in the cortex and hippocampus of iTat mice. Using α7 nAChR knockout mice, we showed that α7 nAChR knockout eliminated the protective effects of PNU-125096 on iTat mice. In addition, we showed that inhibition of p38 phosphorylation by SB239063, a p38 MAPK-specific inhibitor exacerbated Tat neurotoxicity in iTat mice. Last, we used primary mouse cortical individual cultures and neuron-astrocytes co-cultures and in vivo staining of iTat mouse brain tissues and showed that glial activation was directly involved in the interplay among Tat neurotoxicity, α7 nAChR activation and the p38 MAPK signalling pathway. Taken together, these findings demonstrated for the first time that α7 nAChR activation led to protection against HAND and suggested that α7 nAChR modulator PNU-125096 holds significant promise for development of therapeutics for HAND.

HIV-1 Vpr protein impairs lysosome clearance causing SNCA/alpha-synuclein accumulation in neurons.

Despite the promising therapeutic effects of combinatory antiretroviral therapy (cART), 20% to 30% of HIV/AIDS patients living with long term infection still exhibit related cognitive and motor disorders. Clinical studies in HIV-infected patients revealed evidence of basal ganglia dysfunction, tremors, fine motor movement deficits, gait, balance, and increased risk of falls. Among older HIV+ adults, the frequency of cases with SNCA/α-synuclein staining is higher than in older healthy persons and may predict an increased risk of developing a neurodegenerative disease. The accumulation of SNCA aggregates known as Lewy Bodies is widely described to be directly linked to motor dysfunction. These aggregates are naturally removed by Macroautophagy/autophagy, a cellular housekeeping mechanism, that can be disturbed by HIV-1. The molecular mechanisms involved in linking HIV-1 proteins and autophagy remain mostly unclear and necessitates further exploration. We showed that HIV-1 Vpr protein triggers the accumulation of SNCA in neurons after decreasing lysosomal acidification, deregulating lysosome positioning, and the expression levels of several proteins involved in lysosomal maturation. Viruses and retroviruses such as HIV-1 are known to manipulate autophagy in order to use it for their replication while blocking the degradative final step, which could destroy the virus itself. Our study highlights how the suppression of neuronal autophagy by HIV-1 Vpr is a mechanism leading to toxic protein aggregation and neurodegeneration.Abbreviations: BLOC1: Biogenesis of Lysosome-related Organelles Complex 1; CART: combinatory antiretroviral therapy; CVB: coxsackievirus; DAPI: 4',6-diamidino-2-phenylindole; DENV: dengue virus; GFP: green fluorescent protein; HCV: hepatitis C virus; HCMV: human cytomegalovirus; HIV: human immunodeficiency virus; Env: HIV-1 envelope glycoproteins; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; VSV: Indiana vesiculovirus; LTR: Long Terminal Repeat; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MLBs: multilamellar bodies; RIPA: Radioimmunoprecipitation assay buffer; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; Tat: transactivator of TAR; TEM: transmission electron microscope; Vpr: Viral protein R.

IgG intrathecal synthesis in HIV-associated neurocognitive disorder (HAND) according to the HIV-1 subtypes and pattern of HIV RNA in CNS and plasma compartments.

We hypothesized that humoral immunity stimulation in the CNS in HIV-1C patients would be lower than that in HIV-1B due to a defective Tat chemokine dimotif (C30C31) that might influence cellular trafficking and CNS inflammation. Sixty-eight paired CSF and blood samples from people with HIV (PWH), free of CNS opportunistic infections, were included, HIV-1B (n = 27), HIV-1C (n = 26), and HIV negative (n = 25). IgG intrathecal synthesis was assayed using quantitative and qualitative methods. IgG oligoclonal bands (OCB) in CSF were observed in 51% of PWH, comparable between HIV-1B and HIV-1C, as well as the medians of IgG intrathecal synthesis formulas. The group with HIV infection aviremic in CSF and blood showed 75% of OCB. There was a poor positive correlation between the IgG quotient and GDS. The impact of HIV-1 on IgG intrathecal production was not subtype dependent. Low-grade CNS intrathecal IgG production persists in HIV CNS infection even in PWH with CSF and blood HIV RNA controlled.

Altered expression of fractalkine in HIV-1-infected astrocytes and consequences for the virus-related neurotoxicity.

HIV-1 infection in the central nervous system (CNS) causes the release of neurotoxic products from infected cells which trigger extensive neuronal loss. Clinically, this results in HIV-1-associated neurocognitive disorders (HAND). However, the effects on neuroprotective factors in the brain remain poorly understood and understudied in this situation. HAND is a multifactorial process involving several players, and the complex cellular mechanisms have not been fully elucidated yet. In this study, we reported that HIV-1 infection of astrocytes limits their potential to express the protective chemokine fractalkine in response to an inflammatory environment. We next confirmed that this effect was not due to a default in its shedding from the cell surface. We then investigated the biological mechanism responsible for this reduced fractalkine expression and found that HIV-1 infection specifically blocks the interaction of transcription factor NF-κB on its promoter with no effect on other cytokines. Moreover, we demonstrated that fractalkine production in astrocytes is regulated in response to immune factors secreted by infected/activated microglia and macrophages. In contrast, we observed that conditioned media from these infected cells also trigger neuronal apoptosis. At last, we demonstrated a strong neuroprotective action of fractalkine on human neurons by reducing neuronal damages. Taken together, our results indicate new relevant interactions between HIV-1 and fractalkine signaling in the CNS. This study provides new information to broaden the understanding of HAND and possibly foresee new therapeutic strategies. Considering its neuro-protective functions, reducing its production from astrocytes could have important outcomes in chronic neuroinflammation and in HIV-1 neuropathogenesis.

Mini-review: The therapeutic role of cannabinoids in neuroHIV.

In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease with an inflammatory component that specifically targets the brain and causes a high prevalence of HIV-1-associated neurocognitive disorders (HAND). The endocannabinoid (eCB) system has attracted interest as a target for treatment of neurodegenerative disorders, due to the potential anti-inflammatory and neuroprotective properties of cannabinoids, including its potential therapeutic use in HIV-1 neuropathogenesis. In this review, we summarize what is currently known about the structural and functional changes of the eCB system under conditions of HAND. This will be followed by summarizing the current clinical and preclinical findings on the effects of cannabis use and cannabinoids in the context of HIV-1 infection, with specifically focusing on viral load, cognition, inflammation, and neuroprotection. Lastly, we present some potential future directions to better understand the involvement of the eCB system and the role that cannabis use and cannabinoids play in neuroHIV.

Sphingolipids as Regulators of Neuro-Inflammation and NADPH Oxidase 2.

Neuro-inflammation accompanies numerous neurological disorders and conditions where it can be associated with a progressive neurodegenerative pathology. In a similar manner, alterations in sphingolipid metabolism often accompany or are causative features in degenerative neurological conditions. These include dementias, motor disorders, autoimmune conditions, inherited metabolic disorders, viral infection, traumatic brain and spinal cord injury, psychiatric conditions, and more. Sphingolipids are major regulators of cellular fate and function in addition to being important structural components of membranes. Their metabolism and signaling pathways can also be regulated by inflammatory mediators. Therefore, as certain sphingolipids exert distinct and opposing cellular roles, alterations in their metabolism can have major consequences. Recently, regulation of bioactive sphingolipids by neuro-inflammatory mediators has been shown to activate a neuronal NADPH oxidase 2 (NOX2) that can provoke damaging oxidation. Therefore, the sphingolipid-regulated neuronal NOX2 serves as a mechanistic link between neuro-inflammation and neurodegeneration. Moreover, therapeutics directed at sphingolipid metabolism or the sphingolipid-regulated NOX2 have the potential to alleviate neurodegeneration arising out of neuro-inflammation.

Emerging Role of Nef in the Development of HIV Associated Neurological Disorders.

Despite adherence to treatment, individuals living with HIV have an increased risk for developing cognitive impairments, referred to as HIV-associated neurological disorders (HAND). Due to continued growth in the HIV population, particularly amongst the aging cohort, the neurobiological mechanisms of HAND are increasingly relevant. Similar to other viral proteins (e.g. Tat, Gp120, Vpr), the Negative Factor (Nef) is associated with numerous adverse effects in the CNS as well as cognitive impairments. In particular, emerging data indicate the consequences of Nef may be facilitated by the modulation of cellular autophagy as well as its inclusion into extracellular vesicles (EVs). The present review examines evidence for the molecular mechanisms by which Nef might contribute to neuronal dysfunction underlying HAND, with a specific focus on autophagy and EVs. Based on the these data, we propose an integrated model by which Nef may contribute to underlying neuronal dysfunction in HAND and highlight potentially novel therapeutic targets for HAND. Graphical abstract.

NLRP3 and IL-1ß Gene Expression Is Elevated in Monocytes From HIV-Treated Patients With Neurocognitive Disorders.

BACKGROUND: Systemic immune activation and inflammation in chronic HIV infection are driving factors of non-AIDS-related events, including neurocognitive impairment. The role of inflammasome in monocytes from patients with HIV infection has been extensively studied, but its association with the extent of neurocognitive dysfunction has been poorly investigated. METHODS: We enrolled 79 HIV-positive patients; 44 with varying levels of HIV-associated neurocognitive disorder (HAND) and 35 without and 8 healthy donors. HAND subtypes included asymptomatic neurocognitive impairment (asymptomatic neurocognitive impairment; n = 19), mild neurocognitive disorder (MND; n = 17), and HIV-associated dementia (n = 8). We quantified plasmatic concentrations of proinflammatory cytokines (TNF-α, IL-6, IL-17A, IL-1ß, and IFN-γ) for all HIV patients, and the mRNA expression of genes involved in the inflammasome activity (NLRP3, PYCARD, NAIP, AIM2, IL-1ß, and IL-18) in monocytes of a subgroup of 28 HIV patients and 8 healthy donors. RESULTS: HIV patients' plasma concentrations of IFN-γ, IL-1ß, and IL-17A were undetectable. Levels of TNF-α and IL-6 were similar among the HIV patient groups. A trend toward an increased expression of inflammasome genes according to neurocognitive disorder severity was observed. Of note, the NLRP3 mRNA relative expression was higher in MND compared with other groups, and IL-1ß was lower in MND than HIV-associated dementia patients. CONCLUSIONS: Changes in inflammasome components in circulating monocytes according to different HAND severity suggest that NLRP3 may be a possible biomarker or target to better understand and treat the link between systemic inflammation and neurocognitive impairment in HIV infection.

Cross-talk between lipid homeostasis and endoplasmic reticulum stress in neurodegeneration: Insights for HIV-1 associated neurocognitive disorders (HAND).

The dysregulation of lipid homeostasis is emerging as a hallmark of many CNS diseases. As aberrant protein regulation is suggested to be a shared pathological feature amongst many neurodegenerative conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), disruptions in neuronal lipid processing may contribute to disease progression in the CNS. Specifically, given the endoplasmic reticulum (ER) dual role in lipid homeostasis as well as protein quality control (PQC) via unfolded protein response (UPR), lipid dysregulation in the CNS may converge on ER functioning and constitute a crucial mechanism underlying aberrant protein aggregation. In the current review, we discuss the diverse roles of lipid species as essential components of the CNS. Moreover, given the importance of both lipid dysregulation and protein aggregation in pathology of CNS diseases, we attempt to assess the potential downstream cross-talk between lipid dysregulation and ER dependent PQC mechanisms, with special focus on HIV-associated neurodegenerative disorders (HAND).

Extracellular Vesicles in HIV, Drug Abuse, and Drug Delivery.

Extracellular vesicles (EVs) are known to perform important biological functions and have been implicated in multiple disease pathogeneses, including HIV and drugs of abuse. EVs can carry biological molecules via biofluids such as plasma and cerebrospinal fluids (CSF) from healthy or disease organs to distant organs and deliver biomolecules to recipient cells that subsequently alter the physiology of the recipient organs. As biocarriers, EVs have the potential to be developed as non-invasive biomarkers for disease pathogenesis and drug abuse, as the level of specific EV components can be altered under disease/drug abuse conditions. Since many drugs don't cross the blood-brain barrier, EVs have shown the potential to encapsulate small drug molecules, including nucleotides, and carry these drugs to brain cells and enhance brain drug bioavailability. Through this special issue, we have covered several studies related to the role of EVs in altering biological functions via cell-cell interactions in healthy, HIV, and drug of abuse conditions. We have also included studies on the role of EVs as potential biomarkers for HIV pathogenesis and drugs of abuse. Further, the potential role of EVs in drug delivery in the CNS for diseases, including HIV-associated neurocognitive disorders and other neurological disorders, are covered in this issue.

A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1.

BACKGROUND: HIV-1 infection remains a major public health concern despite effective combination antiretroviral therapy (cART). The virus enters the central nervous system (CNS) early in infection and continues to cause HIV-associated neurocognitive disorders (HAND). The pathogenic mechanisms of HIV-associated brain injury remain incompletely understood. Since HIV-1 activates the type I interferon system, which signals via interferon-α receptor (IFNAR) 1 and 2, this study investigated the potential role of IFNAR1 in HIV-induced neurotoxicity. METHODS: We cross-bred HIVgp120-transgenic (tg) and IFNAR1 knockout (IFNAR1KO) mice. At 11-14 months of age, we performed a behavioral assessment and subsequently analyzed neuropathological alterations using deconvolution and quantitative immunofluorescence microscopy, quantitative RT-PCR, and bioinformatics. Western blotting of brain lysates and an in vitro neurotoxicity assay were employed for analysis of cellular signaling pathways. RESULTS: We show that IFNAR1KO results in partial, sex-dependent protection from neuronal injury and behavioral deficits in a transgenic model of HIV-induced brain injury. The IFNAR1KO rescues spatial memory and ameliorates loss of presynaptic terminals preferentially in female HIVgp120tg mice. Similarly, expression of genes involved in neurotransmission reveals sex-dependent effects of IFNAR1KO and HIVgp120. In contrast, IFNAR1-deficiency, independent of sex, limits damage to neuronal dendrites, microgliosis, and activation of p38 MAPK and restores ERK activity in the HIVgp120tg brain. In vitro, inhibition of p38 MAPK abrogates neurotoxicity caused similarly by blockade of ERK kinase and HIVgp120. CONCLUSION: Our findings indicate that IFNAR1 plays a pivotal role in both sex-dependent and independent processes of neuronal injury and behavioral impairment triggered by HIV-1.

Purinergic signaling in infectious diseases of the central nervous system.

The incidence of infectious diseases affecting the central nervous system (CNS) has been increasing over the last several years. Among the reasons for the expansion of these diseases and the appearance of new neuropathogens are globalization, global warming, and the increased proximity between humans and wild animals due to human activities such as deforestation. Neurotropism affecting normal brain function is shared by organisms such as viruses, bacteria, fungi, and parasites. Neuroinfections caused by these agents activate immune responses, inducing neuroinflammation, excitotoxicity, and neurodegeneration. Purinergic signaling is an evolutionarily conserved signaling pathway associated with these neuropathologies. During neuroinfections, host cells release ATP as an extracellular danger signal with pro-inflammatory activities. ATP is metabolized to its derivatives by ectonucleotidases such as CD39 and CD73; ATP and its metabolites modulate neuronal and immune mechanisms through P1 and P2 purinergic receptors that are involved in pathophysiological mechanisms of neuroinfections. In this review we discuss the beneficial or deleterious effects of various components of the purinergic signaling pathway in infectious diseases that affect the CNS, including human immunodeficiency virus (HIV-1) infection, herpes simplex virus type 1 (HSV-1) infection, bacterial meningitis, sepsis, cryptococcosis, toxoplasmosis, and malaria. We also provide a description of this signaling pathway in emerging viral infections with neurological implications such as Zika and SARS-CoV-2.

HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System.

Antiretroviral therapy (ART) has transformed HIV into a chronic condition, lengthening and improving the lives of individuals living with this virus. Despite successful suppression of HIV replication, people living with HIV (PLWH) are susceptible to a growing number of comorbidities, including neuroHIV that results from infection of the central nervous system (CNS). Alterations in the dopaminergic system have long been associated with HIV infection of the CNS. Studies indicate that changes in dopamine concentrations not only alter neurotransmission, but also significantly impact the function of immune cells, contributing to neuroinflammation and neuronal dysfunction. Monocytes/macrophages, which are a major target for HIV in the CNS, are responsive to dopamine. Therefore, defining more precisely the mechanisms by which dopamine acts on these cells, and the changes in cellular function elicited by this neurotransmitter are necessary to develop therapeutic strategies to treat neuroHIV. This is especially important for vulnerable populations of PLWH with chemically altered dopamine concentrations, such as individuals with substance use disorder (SUD), or aging individuals using dopamine-altering medications. The specific neuropathologic and neurocognitive consequences of increased CNS dopamine remain unclear. This is due to the complex nature of HIV neuropathogenesis, and logistical and technical challenges that contribute to inconsistencies among cohort studies, animal models and in vitro studies, as well as lack of demographic data and access to human CNS samples and cells. This review summarizes current understanding of the impact of dopamine on HIV neuropathogenesis, and proposes new experimental approaches to examine the role of dopamine in CNS HIV infection. Graphical abstract HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System. Both substance abuse disorders and the use of dopaminergic medications for age-related diseases are associated with changes in CNS dopamine concentrations and dopaminergic neurotransmission. These changes can lead to aberrant immune function, particularly in myeloid cells, which contributes to the neuroinflammation, neuropathology and dysfunctional neurotransmission observed in dopamine-rich regions in HIV+ individuals. These changes, which are seen despite the use antiretroviral therapy (ART), in turn lead to further dysregulation of the dopamine system. Thus, in individuals with elevated dopamine, the bi-directional interaction between aberrant dopaminergic neurotransmission and HIV infection creates a feedback loop contributing to HIV associated neurocognitive dysfunction and neuroHIV. However, the distinct contributions and interactions made by HIV infection, inflammatory mediators, ART, drugs of abuse, and age-related therapeutics are poorly understood. Defining more precisely the mechanisms by which these factors influence the development of neurological disease is critical to addressing the continued presence of neuroHIV in vulnerable populations, such as HIV-infected older adults or drug abusers. Due to the complexity of this system, understanding these effects will require a combination of novel experimental modalities in the context of ART. These will include more rigorous epidemiological studies, relevant animal models, and in vitro cellular and molecular mechanistic analysis.

HIV Infection and Neurocognitive Disorders in the Context of Chronic Drug Abuse: Evidence for Divergent Findings Dependent upon Prior Drug History.

The fronto-striatal circuitry, involving the nucleus accumbens, ventral tegmental area, and prefrontal cortex, mediates goal-directed behavior and is targeted by both drugs of abuse and HIV-1 infection. Acutely, both drugs and HIV-1 provoke increased dopamine activity within the circuit. However, chronic exposure to drugs or HIV-1 leads to dysregulation of the dopamine system as a result of fronto-striatal adaptations to oppose the effects of repeated instances of transiently increased dopamine. Specifically, chronic drug use leads to reduced dopaminergic tone, upregulation of dopamine transporters, and altered circuit connectivity, sending users into an allosteric state in which goal-directed behaviors are dysregulated (i.e., addiction). Similarly, chronic exposure to HIV-1, even with combination antiretroviral therapy (cART), dysregulates dopamine and dopamine transporter function and alters connectivity of the fronto-striatal circuit, contributing to apathy and clinical symptoms of HIV-1 associated neurocognitive disorders (HAND). Thus, in a drug user also exposed to HIV-1, dysregulation of the fronto-striatal dopamine circuit advances at an exacerbated rate and appears to be driven by mechanisms unique from those seen with chronic drug use or HIV-1 exposure alone. We posit that the effects of drug use and HIV-1 infection on microglia interact to drive the progression of motivational dysfunction at an accelerated rate. The current review will therefore explore how the fronto-striatal circuit adapts to drug use (using cocaine as an example), HIV-1 infection, and both together; emphasizing proper methods and providing future directions to develop treatments for pathologies disrupting goal-directed behaviors and improve clinical outcomes for affected patients. Graphical Abstract Drug use and HIV-1 in the fronto-striatal circuit. Drugs of abuse and HIV-1 infection both target the fronto-striatal circuit which mediates goal-directed behavior. Acutely, drugs and HIV-1 increase dopamine activity; in contrast chronic exposure produces circuit adaptions leading to dysregulation, addiction and/or apathy. Comorbid drug use and HIV-1 infection may interact with microglia to exacerbate motivational dysregulation.

Targeting Cannabinoid Receptor 2 on Peripheral Leukocytes to Attenuate Inflammatory Mechanisms Implicated in HIV-Associated Neurocognitive Disorder.

HIV infection affects an estimated 38 million people. Approximately 50% of HIV patients exhibit neurocognitive dysfunction termed HIV-Associated Neurocognitive Disorder (HAND). HAND is a consequence of chronic low-level neuroinflammation due to HIV entry into the brain. Initially, monocytes become activated in circulation and traffic to the brain. Monocytes, when activated, become susceptible to infection by HIV and can then carry the virus across the blood brain barrier. Once in the brain, activated monocytes secrete chemokines, which recruit virus-specific CD8+ T cells into the brain to further promote neuroinflammation. HAND is closely linked to systemic inflammation driven, in part, by HIV but is also due to persistent translocation of microorganisms across the GI tract. Persistent anti-viral responses in the GI tract compromise microbial barrier integrity. Indeed, HIV patients can exhibit remarkably high levels of activated (CD16+) monocytes in circulation. Recent studies, including our own, show that HIV patients using medical marijuana exhibit lower levels of circulating CD16+ monocytes than non-cannabis using HIV patients. Cannabis is a known immune modulator, including anti-inflammatory properties, mediated, in part, by ∆9-tetrahydrocannabinol (THC), as well as less characterized minor cannabinoids, such as cannabidiol (CBD), terpenes and presumably other cannabis constituents. The immune modulating activity of THC is largely mediated through cannabinoid receptors (CB) 1 and 2, with CB1 also responsible for the psychotropic properties of cannabis. Here we discuss the anti-inflammatory properties of cannabinoids in the context of HIV and propose CB2 as a putative therapeutic target for the treatment of neuroinflammation. Graphical Abstract HIV-associated neurocognitive disorder is a systemic inflammatory disease leading to activation of plasmacytoid dendritic cells, monocytes and T cells. Monocyte and CD8 T cell migration across the BBB and interaction with astrocytes promotes neurotoxic inflammatory mediators release. CB2 ligands are proposed as therapeutics capable of suppressing systemic and localized inflammation.

Brain amyloid in virally suppressed HIV-associated neurocognitive disorder.

OBJECTIVE: To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition. METHODS: A total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46-68 years, underwent 11C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal individuals (aged 60-74 years), 7 individuals with mild cognitive impairment (MCI) (aged 64-71 years), and 11 individuals with Alzheimer disease (AD) (aged 55-74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV sample. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV sample, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8-10 years of long-term health outcomes in 100%. RESULTS: HAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD-like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8-9 years after the study PET, then progression to severe dementia within 2-3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas. CONCLUSIONS: Relative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur.