A helping HAND: therapeutic potential of MAGL inhibition against HIV-1-associated neuroinflammation.

Background: Human immunodeficiency virus (HIV) affects nearly 40 million people globally, with roughly 80% of all people living with HIV receiving antiretroviral therapy. Antiretroviral treatment suppresses viral load in peripheral tissues but does not effectively penetrate the blood-brain barrier. Thus, viral reservoirs persist in the central nervous system and continue to produce low levels of inflammatory factors and early viral proteins, including the transactivator of transcription (Tat). HIV Tat is known to contribute to chronic neuroinflammation and synaptodendritic damage, which is associated with the development of cognitive, motor, and/or mood problems, collectively known as HIV-associated neurocognitive disorders (HAND). Cannabinoid anti-inflammatory effects are well documented, but therapeutic utility of cannabis remains limited due to its psychotropic effects, including alterations within brain regions encoding reward processing and motivation, such as the nucleus accumbens. Alternatively, inhibiting monoacylglycerol lipase (MAGL) has demonstrated therapeutic potential through interactions with the endocannabinoid system. Methods: The present study utilized a reward-related operant behavioral task to quantify motivated behavior in female Tat transgenic mice treated with vehicle or MAGL inhibitor MJN110 (1 mg/kg). Brain tissue was collected to assess dendritic injury and neuroinflammatory profiles, including dendritic microtubule-associated protein (MAP2ab) intensity, microglia density, microglia morphology, astrocyte density, astrocytic interleukin-1ß (IL-1ß) colocalization, and various lipid mediators. Results: No significant behavioral differences were observed; however, MJN110 protected against Tat-induced dendritic injury by significantly upregulating MAP2ab intensity in the nucleus accumbens and in the infralimbic cortex of Tat(+) mice. No or only minor effects were noted for Iba-1+ microglia density and/or microglia morphology. Further, Tat increased GFAP+ astrocyte density in the infralimbic cortex and GFAP+ astrocytic IL-1ß colocalization in the nucleus accumbens, with MJN110 significantly reducing these measures in Tat(+) subjects. Lastly, selected HETE-related inflammatory lipid mediators in the striatum were downregulated by chronic MJN110 treatment. Conclusions: These findings demonstrate anti-inflammatory and neuroprotective properties of MJN110 without cannabimimetic behavioral effects and suggest a promising alternative to cannabis for managing neuroinflammation.

Unravelling the triad of neuroinvasion, neurodissemination, and neuroinflammation of human immunodeficiency virus type 1 in the central nervous system.

Since the identification of human immunodeficiency virus type 1 (HIV-1) in 1983, many improvements have been made to control viral replication in the peripheral blood and to treat opportunistic infections. This has increased life expectancy but also the incidence of age-related central nervous system (CNS) disorders and HIV-associated neurodegeneration/neurocognitive impairment and depression collectively referred to as HIV-associated neurocognitive disorders (HAND). HAND encompasses a spectrum of different clinical presentations ranging from milder forms such as asymptomatic neurocognitive impairment or mild neurocognitive disorder to a severe HIV-associated dementia (HAD). Although control of viral replication and suppression of plasma viral load with combination antiretroviral therapy has reduced the incidence of HAD, it has not reversed milder forms of HAND. The objective of this review, is to describe the mechanisms by which HIV-1 invades and disseminates in the CNS, a crucial event leading to HAND. The review will present the evidence that underlies the relationship between HIV infection and HAND. Additionally, recent findings explaining the role of neuroinflammation in the pathogenesis of HAND will be discussed, along with prospects for treatment and control.

Genomic Factors and Therapeutic Approaches in HIV-Associated Neurocognitive Disorders: A Comprehensive Review.

HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of patients affected by HANDs ranges from (30 to 50) % of HIV-infected individuals. The pathological mechanisms contributing to HANDs and the most serious manifestation of the disease, HIV-associated dementia (HAD), are not yet well understood. Evidence suggests that these mechanisms are likely multifactorial, producing neurocognitive complications involving disorders such as neurogenesis, autophagy, neuroinflammation, and mitochondrial dysfunction. Over the years, multiple pharmacological approaches with specific mechanisms of action acting upon distinct targets have been approved. Although these therapies are effective in reducing viral loading to undetectable levels, they also present some disadvantages such as common side effects, the need for administration with a very high frequency, and the possibility of drug resistance. Genetic studies on HANDs provide insights into the biological pathways and mechanisms that contribute to cognitive impairment in people living with HIV-1. Furthermore, they also help identify genetic variants that increase susceptibility to HANDs and can be used to tailor treatment approaches for HIV-1 patients. Identification of the genetic markers associated with disease progression can help clinicians predict which individuals require more aggressive management and by understanding the genetic basis of the disorder, it will be possible to develop targeted therapies to mitigate cognitive impairment. The main goal of this review is to provide details on the epidemiological data currently available and to summarise the genetic (specifically, the genetic makeup of the immune system), transcriptomic, and epigenetic studies available on HANDs to date. In addition, we address the potential pharmacological therapeutic strategies currently being investigated. This will provide valuable information that can guide clinical care, drug development, and our overall understanding of these diseases.

Imaging of Brain Structural and Functional Effects in People With Human Immunodeficiency Virus.

Before the introduction of antiretroviral therapy, human immunodeficiency virus (HIV) infection was often accompanied by central nervous system (CNS) opportunistic infections and HIV encephalopathy marked by profound structural and functional alterations detectable with neuroimaging. Treatment with antiretroviral therapy nearly eliminated CNS opportunistic infections, while neuropsychiatric impairment and peripheral nerve and organ damage have persisted among virally suppressed people with HIV (PWH), suggesting ongoing brain injury. Neuroimaging research must use methods sensitive for detecting subtle HIV-associated brain structural and functional abnormalities, while allowing for adjustments for potential confounders, such as age, sex, substance use, hepatitis C coinfection, cardiovascular risk, and others. Here, we review existing and emerging neuroimaging tools that demonstrated promise in detecting markers of HIV-associated brain pathology and explore strategies to study the impact of potential confounding factors on these brain measures. We emphasize neuroimaging approaches that may be used in parallel to gather complementary information, allowing efficient detection and interpretation of altered brain structure and function associated with suboptimal clinical outcomes among virally suppressed PWH. We examine the advantages of each imaging modality and systematic approaches in study design and analysis. We also consider advantages of combining experimental and statistical control techniques to improve sensitivity and specificity of biotype identification and explore the costs and benefits of aggregating data from multiple studies to achieve larger sample sizes, enabling use of emerging methods for combining and analyzing large, multifaceted data sets. Many of the topics addressed in this article were discussed at the National Institute of Mental Health meeting "Biotypes of CNS Complications in People Living with HIV," held in October 2021, and are part of ongoing research initiatives to define the role of neuroimaging in emerging alternative approaches to identifying biotypes of CNS complications in PWH. An outcome of these considerations may be the development of a common neuroimaging protocol available for researchers to use in future studies examining neurological changes in the brains of PWH.

HIV-Associated Dementia: Associated Factors and Characteristics of Cognitive Domain Abnormalities in Elderly People Living with HIV Treated with Highly Active Antiretroviral Therapy.

This study aimed to evaluate the prevalence and associated factors of HIV-associated dementia (HAD) in people living with HIV (PLWH) aged ≥ 60 years who are currently treated with highly active antiretroviral therapy. A cross-sectional study was conducted on adult (age ≥ 60 years) PLWH at the infectious clinic, Vajira Hospital, Navamindradhiraj University, Thailand, between August 2019 and March 2021. We collected the patients' characteristics and performed Montreal Cognitive Assessment and Instrumental Activities of Daily Living test to determine whether they have HIV-associated neurocognitive disorders (HAND), which we further classified into asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HAD. Finally, we evaluated the prevalence, associated factors, and characteristics of cognitive domain abnormalities in these patients. We enrolled 84 elderly PLWH patients consisting of 43 (51.2%) males. The mean patient age was 63 years (SD ± 3.9), and the median duration of HIV infection was 13 (SD ± 5.7) years. All the patients had undetectable HIV viral load. Among them, seven (8.3%) had no neurocognitive impairment, 61 (72.6%) had ANI, three (3.6%) had MND, and 13 (15.5%) had HAD. After confounder adjustment, the patient age of ≥ 65 years was found to be significantly associated with dementia (odds ratio = 5.97, 95% CI: 1.51-23.57). Significant difference in the mean score of all cognitive domains was observed between the patients with HAD and those with normal cognitive status. HAND is common in PLWH. Age older than ≥ 65 years is a risk factor of HAD.

[Rapidly progressive dementia as the initial presentation of human immunodeficiency virus infection].

Dementia associated with human immunodeficiency virus (HIV) is currently a rare cause of rapidly progressive dementia. Its appearance is not only limited to the late phases of the disease, but can sometimes be the presenting symptom. We present the case of a patient who debuted with anxious-depressive symptoms and rapid cognitive deteri-oration with early repercussions on his daily functionality. HIV was detected in the study, with a higher viral load in cerebrospinal fluid than in plasma. Despite a torpid course at the beginning, antiretroviral therapy brought about a progressive improvement in the cognitive sphere, consistent with the decrease in the viral load. Although rare, HIV continues to be a cause of dementia that primary care and hospital care professionals should not forget. The relevance of its early diagnosis lies in its potentially reversible nature.

Developments in Neuroprotection for HIV-Associated Neurocognitive Disorders (HAND).

PURPOSE OF REVIEW: Reducing the risk of HIV-associated neurocognitive disorders (HAND) is an elusive treatment goal for people living with HIV. Combination antiretroviral therapy (cART) has reduced the prevalence of HIV-associated dementia, but milder, disabling HAND is an unmet challenge. As newer cART regimens that more consistently suppress central nervous system (CNS) HIV replication are developed, the testing of adjunctive neuroprotective therapies must accelerate. RECENT FINDINGS: Successes in modifying cART regimens for CNS efficacy (penetrance, chemokine receptor targeting) and delivery (nanoformulations) in pilot studies suggest that improving cART neuroprotection and reducing HAND risk is achievable. Additionally, drugs currently used in neuroinflammatory, neuropsychiatric, and metabolic disorders show promise as adjuncts to cART, likely by broadly targeting neuroinflammation, oxidative stress, aerobic metabolism, and/or neurotransmitter metabolism. Adjunctive cognitive brain therapy and aerobic exercise may provide additional efficacy. Adjunctive neuroprotective therapies, including available FDA-approved drugs, cognitive therapy, and aerobic exercise combined with improved cART offer plausible strategies for optimizing the prevention and treatment of HAND.

Biotypes of HIV-associated neurocognitive disorders based on viral and immune pathogenesis.

PURPOSE OF REVIEW: HIV-associated neurocognitive disorders (HAND) continues to be prevalent in people living with HIV despite antiretroviral therapy. However, understanding disease mechanisms and identifying therapeutic avenues has been challenging. One of the challenges is that HAND is a heterogeneous disease and that patients identified with similar impairments phenotypically may have very different underlying disease processes. As the NeuroAIDS field is re-evaluating the approaches used to identify patients with HIV-associated neurological impairments, we propose the subtyping of patients into biotypes based on viral and immune pathogenesis. RECENT FINDINGS: Here we review the evidence supporting subtyping patients with HIV-associated neurological complications into four biotypes: macrophage-mediated HIV encephalitis, CNS viral escape, T-cell-mediated HIV encephalitis, and HIV protein-associated encephalopathy. SUMMARY: Subtyping patients into subgroups based on biotypes has emerged as a useful approach for studying heterogeneous diseases. Understanding biotypes of HIV-associated neurocognitive impairments may therefore enable better understanding of disease mechanisms, allow for the development of prognostic and diagnostic markers, and could ultimately guide therapeutic decisions.

Demencia rápidamente progresiva como forma de presentación de infección por el virus de la inmunodeficiencia humana / Rapidly progressive dementia as the initial presentation of human immunodeficiency virus infection

La demencia asociada a virus de la inmunodeficiencia humana (VIH) es una causa de demencia rápidamente progresiva poco frecuente en la actualidad. Su aparición no se limita a las fases tardías de la enfermedad, sino que en ocasiones puede ser el síntoma de presentación. Presentamos el caso de un paciente que debutó con síntomas ansioso-depresivos y un rápido deterioro cognitivo con repercusión precoz en su funcionalidad diaria. En el estudio se detectó VIH con mayor carga viral en líquido cefalorraquídeo que en plasma. La terapia antirretroviral logró, a pesar de la tórpida evolución inicial, una mejora progresiva en la esfera cognitiva, congruente con la disminución de la carga viral. Aunque poco frecuente, el VIH sigue siendo una causa de demencia que los profesionales de atención primaria y hospitalaria no debemos olvidar. La importancia de su diagnóstico precoz radica en su carácter potencialmente reversible.(AU)

Dementia associated with human immunodeficiency virus (HIV) is currently a rare cause of rapidly progressive dementia. Its appearance is not only limited to the late phases of the disease, but can sometimes be the presenting symptom. We present the case of a patient who debuted with anxious-depressive symptoms and rapid cognitive deterioration with early repercussions on his daily functionality. HIV was detected in the study, with a higher viral load in cerebrospinal fluid than in plasma. Despite a torpid course at the beginning, antiretroviral therapy brought about a progressive improvement in the cognitive sphere, consistent with the decrease in the viral load. Although rare, HIV continues to be a cause of dementia that primary care and hospital care professionals should not forget. The relevance of its early diagnosis lies in its potentially reversible nature.(AU)

HIV-Associated Neurocognitive Disorders: The First Longitudinal Follow-Up of a cART-Treated Cohort of Older People in Sub-Saharan Africa.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) are a highly prevalent chronic complication in older people living with HIV (PLWH) in high-income countries. Although sub-Saharan Africa has a newly emergent population of older combination antiretroviral therapy (cART)-treated PLWH, HAND have not been studied longitudinally. We assessed longitudinal prevalence of HAND and have identified possible modifiable factors in a population of PLWH aged 50 years or older, over 3 years of follow-up. METHODS: Detailed neuropsychological and clinical assessment was completed annually in the period 2016-2019 in a systematic sample of cART-treated PLWH in Kilimanjaro, Tanzania. A consensus panel defined HAND using American Academy of Neurology criteria for asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia. HIV disease severity and other factors associated with HAND progression, improvement, and stability were evaluated in individuals fully assessed at baseline and in 2019. RESULTS: At baseline, 47% of the cohort (n = 253, 72.3% female individuals) met HAND criteria despite good HIV disease control [Y1 59.5% (n = 185), Y2 61.7% (n = 162), and Y3 57.9% (n = 121)]. Of participants fully assessed at baseline and year 3 (n = 121), HAND remained stable in 54% (n = 57), improved in 15% (n = 16), and declined in 31% (n = 33). Older age and lower education level significantly predicted HAND progression, whereas HIV-specific factors did not. Male sex and shorter cART duration were associated with improvement. CONCLUSIONS: In this first longitudinal study characterizing clinical course of HAND in older cART-treated PLWH in sub-Saharan Africa, HAND was highly prevalent with variable progression and reversibility. Progression may be more related to cognitive reserve than HIV disease in cART-treated PLWH.

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.

HIV Encephalopathy in ART-Naïve, Hospitalized Infants in Mozambique.

INTRODUCTION: The neurodevelopmental impact of HIV infection in older children has been well-described, with characterization of HIV-associated encephalopathy (HIVE) and associated cognitive defects. HIVE is relatively common in older children who were vertically infected. The sparse literature on HIVE in infants suggests that incidence may be up to 10% in the first year of life, but no studies were identified that specifically evaluated hospitalized infants. METHODS: A descriptive study of routine inpatient data from two central referral hospitals in Mozambique was conducted. Inclusion criteria were infants with confirmed HIV infection aged <12 months, not on ART, admitted between 1 January 2019 and 30 June 2019. Presumptive HIVE was defined as having delayed developmental milestones in addition to microcephaly and/or pathological reflexes. RESULTS: Seven out of 27 patients (26%) were classified as presumptive HIVE. Delayed milestones were seen in 18 patients (67%) and the prevalence was approximately two times higher in the HIVE (+) group across all milestone categories. Delayed or no maternal ART (p = 0.03) and the infant not having received postnatal nevirapine prophylaxis (p = 0.02) were significantly associated with HIVE. CONCLUSIONS: HIVE prevalence is high in ART naïve hospitalized infants, particularly in those with risk factors for in-utero transmission. Thorough neurologic and developmental assessments can help identify HIV-infected infants and can be of particular utility in pediatric wards without access to point-of-care virologic testing where presumptive HIV diagnosis is still needed. Infants with HIVE need comprehensive care that includes antiretroviral therapy and physical/occupational therapy.

Contemporary trends in HIV-associated neurocognitive disorders in Ghana.

BACKGROUND: Widespread introduction of early combination antiretroviral therapy (cART) for People Living with HIV (PLWH) will influence the burden, profile, and trajectory of HIV-associated neurocognitive disorders (HAND) in the 21st century. OBJECTIVES: To assess the prevalence and trajectory of HAND among PLWH in a Ghanaian tertiary medical center. METHODS: We analyzed the dataset of a study involving PLWH established on cART (n = 256) and PLWH not initially on cART (n = 244). HIV-negative individuals (n = 246) served as normative controls for neurocognitive assessments. HAND was defined according to the Frascati criteria into asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated dementia (HAD) at enrollment and at month 12. Multivariate logistic regression models were fitted to identify factors associated with HAND. RESULTS: Among PLWH on cART, 21.5%, 3.5% and 0.0% had ANI, MND and HAD respectively compared with 20.1%, 9.8% and 2.0% among PLWH cART naïve, p < 0.0001. Overall, 71.6%, 20.8%, 6.6% and 1.0% had no cognitive impairment, ANI, MND and HAD at baseline. Among participants who completed month 12 follow-up, 55.2% had no cognitive impairment, 43.5%, 1.2%, 0.0% had ANI, MND and HAD respectively, p < 0.0001. Adjusted odds ratio (95% CI) of six independent predictors of HAND at month 12 were no education (3.29;1.81-6.00), stage 4 disease (4.64;1.37-15.69), hypertension (2.28;1.10-4.73), nevirapine use (2.05;1.04-4.05), baseline viral load (0.66;0.56-0.77), and cigarette use (0.10; 0.03-0.42). CONCLUSION: Most Ghanaian patients in the post-cART era with HAND had mild neurocognitive impairments. The impact of hypertension on progression of HAND warrants further evaluation in our settings.

Interrogating the impact of combination antiretroviral therapies on HIV-associated neurocognitive disorders.

OBJECTIVES: Although the advent of Combination Antiretroviral Therapy (cART) has greatly reduced the prevalence of HIV-Associated Dementia, the most severe form of HIV-Associated Neurocognitive Disorder (HAND), the incidence of the milder forms of HAND have risen. The explanations proposed include persistent central nervous system (CNS) viraemia and the neurotoxicity of chronic cART regimens. Nonetheless, controversies in HAND prevalence estimates, alongside a lack of consensus on the significance of CNS Penetration Effectiveness (CPE) have added to the complexity of elucidating the role of cART in HAND. The present review will evaluate the evidence underlying these explanations, as well as highlighting the need for improved trial designs and the incorporation of emerging biomarkers and neuroimaging tools. METHODS: A review of the current literature investigating cART neurotoxicity, controversies in HAND prevalence estimates, CNS Penetration Effectiveness, and neuroprotective adjuvant therapies. CONCLUSIONS: Ultimately, the inadequacy of cART in achieving complete preservation of the CNS underscores the imminent need for neuroprotective adjuvant therapies, where the efficacy of combining multiple adjuvant classes presents a potential therapeutic frontier which must be interrogated.

Associations between plasma nucleoside reverse transcriptase inhibitors concentrations and cognitive function in people with HIV.

OBJECTIVES: To investigate the associations of plasma lamivudine (3TC), abacavir (ABC), emtricitabine (FTC) and tenofovir (TFV) concentrations with cognitive function in a cohort of treated people with HIV (PWH). METHODS: Pharmacokinetics (PK) and cognitive function (Cogstate, six domains) data were obtained from PWH recruited in the POPPY study on either 3TC/ABC or FTC/tenofovir disoproxil fumarate (TDF)-containing regimens. Association between PK parameters (AUC0-24: area under the concentration-time curve over 24 hours, Cmax: maximum concentration and Ctrough: trough concentration) and cognitive scores (standardized into z-scores) were evaluated using rank regression adjusting for potential confounders. RESULTS: Median (IQR) global cognitive z-scores in the 83 PWH on 3TC/ABC and 471 PWH on FTC/TDF were 0.14 (-0.27, 0.38) and 0.09 (-0.28, 0.42), respectively. Higher 3TC AUC0-24 and Ctrough were associated with better global z-scores [rho = 0.29 (p = 0.02) and 0.27 (p = 0.04), respectively], whereas higher 3TC Cmax was associated with poorer z-scores [rho = -0.31 (p<0.01)], independently of ABC concentrations. Associations of ABC PK parameters with global and domain z-scores were non-significant after adjustment for confounders and 3TC concentrations (all p's>0.05). None of the FTC and TFV PK parameters were associated with global or domain cognitive scores. CONCLUSIONS: Whilst we found no evidence of either detrimental or beneficial effects of ABC, FTC and TFV plasma exposure on cognitive function of PWH, higher plasma 3TC exposures were generally associated with better cognitive performance although higher peak concentrations were associated with poorer performance.

Plasma anti-CD4 IgG is associated with brain abnormalities in people with HIV on antiretroviral therapy.

Anti-CD4 IgG autoantibodies have been implicated in CD4+ T cell reconstitution failure, leaving people with HIV (PWH) at heightened risk of HIV-associated comorbidities, such as neurocognitive impairment. Seventeen PWH on stable anti-retroviral therapy (ART) and 10 HIV seronegative controls had plasma anti-CD4 IgG antibodies measured by enzyme-linked immunosorbent assay. Neuropsychological (NP) tests assessed cognitive performance, and brain volumes were measured by structural magnetic resonance imaging. Anti-CD4 IgG levels were elevated (p = 0.04) in PWH compared with controls. Anti-CD4 IgG correlated with global NP z-scores (rho = - 0.51, p = 0.04). A relationship was observed between anti-CD4 IgG and putamen (ß = - 0.39, p = 0.02), pallidum (ß = - 0.38, p = 0.03), and amygdala (ß = - 0.42, p = 0.05) regional brain volumes. The results of this study suggest the existence of an antibody-mediated relationship with neurocognitive impairment and brain abnormalities in an HIV-infected population.

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.

Beneficial and Adverse Effects of cART Affect Neurocognitive Function in HIV-1 Infection: Balancing Viral Suppression against Neuronal Stress and Injury.

HIV-associated neurocognitive disorders (HAND) persist despite the successful introduction of combination antiretroviral therapy (cART). While insufficient concentration of certain antiretrovirals (ARV) may lead to incomplete viral suppression in the brain, many ARVs are found to cause neuropsychiatric adverse effects, indicating their penetration into the central nervous system (CNS). Several lines of evidence suggest shared critical roles of oxidative and endoplasmic reticulum stress, compromised neuronal energy homeostasis, and autophagy in the promotion of neuronal dysfunction associated with both HIV-1 infection and long-term cART or ARV use. As the lifespans of HIV patients are increased, unique challenges have surfaced. Longer lives convey prolonged exposure of the CNS to viral toxins, neurotoxic ARVs, polypharmacy with prescribed or illicit drug use, and age-related diseases. All of these factors can contribute to increased risks for the development of neuropsychiatric conditions and cognitive impairment, which can significantly impact patient well-being, cART adherence, and overall health outcome. Strategies to increase the penetration of cART into the brain to lower viral toxicity may detrimentally increase ARV neurotoxicity and neuropsychiatric adverse effects. As clinicians attempt to control peripheral viremia in an aging population of HIV-infected patients, they must navigate an increasingly complex myriad of comorbidities, pharmacogenetics, drug-drug interactions, and psychiatric and cognitive dysfunction. Here we review in comparison to the neuropathological effects of HIV-1 the available information on neuropsychiatric adverse effects and neurotoxicity of clinically used ARV and cART. It appears altogether that future cART aiming at controlling HIV-1 in the CNS and preventing HAND will require an intricate balancing act of suppressing viral replication while minimizing neurotoxicity, impairment of neurocognition, and neuropsychiatric adverse effects. Graphical abstract Schematic summary of the effects exerted on the brain and neurocognitive function by HIV-1 infection, comorbidities, psychostimulatory, illicit drugs, therapeutic drugs, such as antiretrovirals, the resulting polypharmacy and aging, as well as the potential interactions of all these factors.