CD14+CD16+ monocyte transmigration across the blood-brain barrier is associated with HIV-NCI despite viral suppression.

HIV-associated neurocognitive impairment (HIV-NCI) affects 15%-50% of people with HIV (PWH), despite viral suppression with antiretroviral therapy (ART). HIV neuropathogenesis is mediated, in part, by transmigration of infected CD14+CD16+ monocytes across the blood-brain barrier (BBB) into the central nervous system (CNS). In the CNS, CD14+CD16+ monocytes contribute to infection and activation of parenchymal cells, resulting in production of neurotoxic viral and host factors that cause neuronal damage. Mechanisms by which CD14+CD16+ monocytes contribute to HIV-NCI have not been characterized in a study population of PWH on ART without contribution from confounders that affect cognition (e.g., substance use, hepatitis C virus coinfection). We assessed cognitive function, PBMC transmigration across the BBB, and neuronal health markers in a well-defined cohort of 56 PWH on ART using stringent criteria to eliminate confounding factors. We demonstrated that PWH on ART with HIV-NCI have significantly increased transmigration of their CD14+CD16+ monocytes across the BBB compared with those with normal cognition. We showed that hypertension and diabetes may be effect modifiers on the association between CD14+CD16+ monocyte transmigration and cognition. This study underscored the persistent role of CD14+CD16+ monocytes in HIV-NCI, even in PWH with viral suppression, suggesting them as potential targets for therapeutic interventions.

Switching to Low Neurotoxic Antiretrovirals to Improve Neurocognition Among People Living With HIV-1-Associated Neurocognitive Disorder: The MARAND-X Randomized Clinical Trial.

BACKGROUND: The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited. METHODS: Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models. RESULTS: Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed. CONCLUSIONS: In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.

The magnitude of neurocognitive disorders and associated factors among people living with HIV AIDS facilities in Bahir Dar City Ethiopia.

Neurocognitive disorders are mental health conditions that are caused by medical illnesses and can lead to several acquired cognitive deficits, which represent a decline from a previously attained level of functioning. The principal domains of cognitive functions include complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. Studies have shown that people living with human immunodeficiency virus (HIV) are at a heightened risk of experiencing cognitive challenges across multiple domains. Given that, a substantial number of people live in Amhara region, assessing cognitive domains to estimate the current magnitude and factors associated with neurocognitive disorders among HIV/AIDS patients is crucial. An institutional-based cross-sectional study was conducted among 569 participants adults living with HIV attending the city's selected health facilities from March 20 to April 30, 2023. A multistage sampling technique was used. The International HIV Dementia Scale (IHDS) was used to measure the outcome of interest. The data were collected using a structured questionnaire and document review. The data were analyzed using STATA version 14. Multiple binary logistic regressions were used as the final model. A total of 501 individuals, with a response rate of 88.04% participated in the study. The overall proportion of HIV patients with neurocognitive impairment was 54.7% (95% CI 50.62-58.77). Factors associated with the neurocognitive impairment were: being widowed AOR = 3.05 (95% CI 1.47-6.31), divorced AOR = 1.95 (1.16-3.28), rural residence AOR = 2.28 (95% CI 1.02-5.09), CD4 count below 500 cells/dl AOR = 1.61 (95% CI 1.03-2.50), history of opportunistic infection AOR = 2.21 (95% CI 1.42-3.41), being in first-line drug regimen AOR = 2.92 (95% CI 1.22-7.00), being in a first-line regimen with Efavirenz AOR = 4.36 (95% CI 1.07-17.73), and impairment in daily living AOR = 2.64 (95% CI 1.39-4.99). In this study, the proportion of neurocognitive impairment was greater than that in most previous studies conducted in Ethiopia. The factors associated with the disorder were: being widowed or divorced, living in a rural area, having low CD4, having a history of opportunistic infection, receiving a first-line drug regimen, receiving efavirenz-containing drugs, and having impaired daily living. Hence, routine neuropsychological screenings should be integrated into comprehensive ART care by the regional health bureau and implemented by hospitals and health centers.

Infectious Diseases.

Microglia, brain-resident innate immune cells, have been extensively studied in neurodegenerative contexts like Alzheimer's disease. The Coronavirus disease 2019 (COVID-19) pandemic highlighted how peripheral infection and inflammation can be detrimental to the neuroimmune milieu and initiate microgliosis driven by peripheral inflammation. Microglia can remain deleterious to brain health by sustaining inflammation in the central nervous system even after the clearance of the original immunogenic agents. In this chapter, we discuss how pulmonary infection with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) can lead to neurovascular and neuroimmune inflammation causing the neurological syndrome of post-acute sequelae of COVID-19 (PASC). Further, we incorporate lessons from the Human Immunodeficiency Virus' (HIV's) effects on microglial functioning in the era of combined antiretroviral therapies (cART) that contribute to HIV-1 associated neurocognitive disorders (HAND). Finally, we describe roles for mixed lineage kinase 3 (MLK3) and leucine-rich repeat kinase (LRRK2) as key regulators of multiple inflammatory and apoptotic pathways important to the pathogenesis of PASC and HAND. Inhibition of these pathways provides a therapeutically synergistic method of treating both PASC and HAND.

Levetiracetam Prevents Neurophysiological Changes and Preserves Cognitive Function in the Human Immunodeficiency Virus (HIV)-1 Transactivator of Transcription Transgenic Mouse Model of HIV-Associated Neurocognitive Disorder.

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) affects nearly half of the 39 million people living with HIV. HAND symptoms range from subclinical cognitive impairment to dementia; the mechanisms that underlie HAND remain unclear and there is no treatment. The HIV protein transactivator of transcription (TAT) is thought to contribute to HAND because it persists in the central nervous system and elicits neurotoxicity in animal models. Network hyperexcitability is associated with accelerated cognitive decline in neurodegenerative disorders. Here we show that the antiepileptic drug levetiracetam (LEV) attenuated aberrant excitatory synaptic transmission, protected synaptic plasticity, reduced seizure susceptibility, and preserved cognition in inducible TAT (iTAT) transgenic male mice. iTAT mice had an increased frequency of spontaneous excitatory postsynaptic currents in hippocampal slice recordings and impaired long-term potentiation, a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV by osmotic minipump prevented both impairments. Kainic acid administered to iTAT mice induced a higher maximum behavioral seizure score, longer seizure duration, and shorter latency to first seizure, consistent with a lower seizure threshold. LEV treatment prevented these in vivo signs of hyperexcitability. Lastly, in the Barnes maze, iTAT mice required more time to reach the goal, committed more errors, and received lower cognitive scores relative to iTAT mice treated with LEV. Thus, TAT expression drives functional deficits, suggesting a causative role in HAND. As LEV not only prevented aberrant synaptic activity in iTAT mice but also prevented cognitive dysfunction, it may provide a promising pharmacological approach to the treatment of HAND. SIGNIFICANCE STATEMENT: Approximately half of people living with human immunodeficiency virus (HIV) also suffer from HIV-associated neurocognitive disorder (HAND), for which there is no treatment. The HIV protein transactivator of transcription (TAT) causes toxicity that is thought to contribute to HAND. Here, the antiepileptic drug levetiracetam (LEV) prevented synaptic and cognitive impairments in a TAT-expressing mouse. LEV is widely used to treat seizures and is well-tolerated in humans, including those with HIV. This study supports further investigation of LEV-mediated neuroprotection in HAND.

A 2-Year, Randomized, Clinical Trial Examining the Effects of Speed of Processing Cognitive Training on Quality-of-Life Indicators in Adults With HIV-Associated Neurocognitive Disorder in Birmingham, Alabama: Results of the Think Fast Study.

ABSTRACT: Speed of processing (SOP) cognitive training may improve indicators of the quality of life (QoL) in people living with HIV. In this 2-year, longitudinal, randomized, controlled trial, 216 participants ages 40 years and older with HIV-associated neurocognitive disorder or borderline HIV-associated neurocognitive disorder were assigned to one of three groups: (a) 10 hr of SOP training (n = 70); (b) 20 hr of SOP training (n = 73), or (c) 10 hr of internet navigation control training (a contact control group; n = 73). Participants completed several QoL measures at baseline, posttest, and Year 1 and Year 2 follow-ups. Using linear mixed-effect models, no strong pattern of training effects across QoL outcomes was apparent, with small-magnitude, nonsignificant, between-group differences in depression, locus of control, and Medical Outcomes Study-HIV scales. In conclusion, despite prior work showing some transfer of SOP cognitive training improving QoL, that was not observed. Implications for research and practice are posited.

Central Nervous System Effects of Early HIV Infection and Consequences of Antiretroviral Therapy Initiation during Acute HIV.

HIV infection is a multi-organ disease that involves the central nervous system (CNS). While devastating CNS complications such as HIV-associated dementia and CNS opportunistic infection typically manifest years after HIV acquisition, HIV RNA is readily detected in the cerebrospinal fluid in untreated neuroasymptomatic people with HIV, highlighting that HIV neuroinvasion predates overt clinical manifestations. Over the past two decades, increased awareness of HIV infection within the at-risk population, coupled with the accessibility of nucleic acid testing and modern HIV immunoassays, has made the detection of acute and early HIV infection readily achievable. This review aims to summarize research findings on CNS involvement during acute and early HIV infection, as well as the outcomes following the immediate initiation of antiretroviral therapy during this early stage of infection. The knowledge gap in long-term neuroprotection through early ART within the first year of infection will be discussed.

Lack of Association of Vascular Risk Factors with HIV-Associated Neurocognitive Disorders in cART-Treated Adults Aged ≥ 50 Years in Tanzania.

HIV-associated neurocognitive disorders (HAND) are highly prevalent in those ageing with HIV. High-income country data suggest that vascular risk factors (VRFs) may be stronger predictors of HAND than HIV-disease severity, but data from sub-Saharan Africa are lacking. We evaluated relationships of VRFs, vascular end-organ damage and HAND in individuals aged ≥ 50 in Tanzania. c-ART-treated individuals were assessed for HAND using consensus criteria. The prevalence of VRFs and end organ damage markers were measured. The independent associations of VRFs, end organ damage and HAND were examined using multivariable logistic regression. Data were available for 153 individuals (median age 56, 67.3% female). HAND was highly prevalent (66.7%, 25.5% symptomatic) despite well-managed HIV (70.5% virally suppressed). Vascular risk factors included hypertension (34%), obesity (10.5%), hypercholesterolemia (33.3%), diabetes (5.3%) and current smoking (4.6%). End organ damage prevalence ranged from 1.3% (prior myocardial infarction) to 12.5% (left ventricular hypertrophy). Measured VRFs and end organ damage were not independently associated with HAND. The only significant association was lower diastolic BP (p 0.030, OR 0.969 (0.943-0.997). Our results suggest that vascular risk factors are not major drivers of HAND in this setting. Further studies should explore alternative aetiologies such as chronic inflammation.

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.

Caffeine upregulates SIRT3 expression to ameliorate astrocytes-mediated HIV-1 Tat neurotoxicity via suppression of EGR1 signaling pathway.

Caffeine is one of the most popular consumed psychostimulants that mitigates several neurodegenerative diseases. Nevertheless, the roles and molecular mechanisms of caffeine in HIV-associated neurocognitive disorders (HAND) remain largely unclear. Transactivator of transcription (Tat) is a major contributor to the neuropathogenesis of HAND in the central nervous system. In the present study, we determined that caffeine (100 µM) treatment significantly ameliorated Tat-induced decreased astrocytic viability, oxidative stress, inflammatory response and excessive glutamate and ATP release, thereby protecting neurons from apoptosis. Subsequently, SIRT3 was demonstrated to display neuroprotective effects against Tat during caffeine treatment. In addition, Tat downregulated SIRT3 expression via activation of EGR1 signaling, which was reversed by caffeine treatment in astrocytes. Overexpression of EGR1 entirely abolished the neuroprotective effects of caffeine against Tat. Furthermore, counteracting Tat or caffeine-induced differential expression of SIRT3 abrogated the neuroprotection of caffeine against Tat-triggered astrocytic dysfunction and neuronal apoptosis. Taken together, our study establishes that caffeine ameliorates astrocytes-mediated Tat neurotoxicity by targeting EGR1/SIRT3 signaling pathway. Our findings highlight the beneficial effects of caffeine on Tat-induced astrocytic dysfunction and neuronal death and propose that caffeine might be a novel therapeutic drug for relief of HAND.

Limited HIV-associated neuropathologies and lack of immune activation in sub-saharan African individuals with late-stage subtype C HIV-1 infection.

Although previous studies have suggested that subtype B HIV-1 proviruses in the brain are associated with physiological changes and immune activation accompanied with microgliosis and astrogliosis, and indicated that both HIV-1 subtype variation and geographical location might influence the neuropathogenicity of HIV-1 in the brain. The natural course of neuropathogenesis of the most widespread subtype C HIV-1 has not been adequately investigated, especially for people living with HIV (PLWH) in sub-Saharan Africa. To characterize the natural neuropathology of subtype C HIV-1, postmortem frontal lobe and basal ganglia tissues were collected from nine ART-naïve individuals who died of late-stage AIDS with subtype C HIV-1 infection, and eight uninfected deceased individuals as controls. Histological staining was performed on all brain tissues to assess brain pathologies. Immunohistochemistry (IHC) against CD4, p24, Iba-1, GFAP, and CD8 in all brain tissues was conducted to evaluate potential viral production and immune activation. Histological results showed mild perivascular cuffs of lymphocytes only in a minority of the infected individuals. Viral capsid p24 protein was only detected in circulating immune cells of one infected individual, suggesting a lack of productive HIV-1 infection of the brain even at the late-stage of AIDS. Notably, similar levels of Iba-1 or GFAP between HIV + and HIV- brain tissues indicated a lack of microgliosis and astrogliosis, respectively. Similar levels of CD8 + cytotoxic T lymphocyte (CTL) infiltration between HIV + and HIV- brain tissues indicated CTL were not likely to be involved within subtype C HIV-1 infected participants of this cohort. Results from this subtype C HIV-1 study suggest that there is a lack of productive infection and limited neuropathogenesis by subtype C HIV-1 even at late-stage disease, which is in contrast to what was reported for subtype B HIV-1 by other investigators.

Cognitive impairment and neurocognitive profiles among people living with HIV and HIV-negative individuals older over 50 years: a comparison of IHDS, MMSE and MoCA.

We aimed to examine the l differences in the assessment of neurocognitive impairment (NCI) using cognitive screening tools between PLWH and HIV-negative individuals and further compare the neurocognitive profiles between the two groups. This was baseline evaluation of Pudong HIV Aging Cohort, including 465 people living with HIV (PLWH) and 465 HIV-negative individuals aged over 50 years matched by age (± 3 years), sex and education. NCI was assessed using the Chinese version of Mini-mental State Examination (MMSE), the International HIV Dementia Scale (IHDS) and Beijing version of Montreal Cognitive Assessment (MoCA). In total, 258 (55.5%), 91 (19.6%), 273 (58.7%) of PLWH were classified as having NCI by the IHDS, MMSE and MoCA, compared to 90 (19.4%), 25 (5.4%), 135 (29.0%) of HIV-negative individuals, respectively (p < 0.05); such associations remained significant in multivariable analysis. PLWH showed a larger overlap of NCI detected by IHDS, MMSE, and MoCA. IHDS and MoCA detected almost all of the NCI detected by MMSE. IHDS-motor and psychomotor speeds and MoCA-executive function showed the greatest disparities between two groups. In multivariable analysis, older age and more depressive symptoms were positively associated with NCI regardless of the screening tools or HIV serostatus. PLWH over 50 years old display a higher prevalence of NCI and distinct neurocognitive profiles compared to HIV-negative individuals, despite viral suppression. Given the more considerable overlap in NCI classification in PLWH, it is advisable to choose one screening tool such as IHDS or MoCA to identify those potentially having NCI and then refer to more comprehensive neuropsychological assessment.

Dysregulation of Gut Microbiota-Derived Neuromodulatory Amino Acid Metabolism in Human Immunodeficiency Virus-Associated Neurocognitive Disorder: An Integrative Metagenomic and Metabolomic Analysis.

OBJECTIVE: Although accumulating evidence implicating altered gut microbiota in human immunodeficiency virus (HIV) infection and neurodegenerative disorders; however, the association between dysbiosis of the gut microbiota and metabolites in the pathogenesis of HIV-associated neurocognitive disorder (HAND) remains unclear. METHODS: Fecal and plasma samples were obtained from 3 cohorts (HAND, HIV-non-HAND, and healthy controls), metagenomic analysis and metabolomic profiling were performed to investigate alterations in the gut microbial composition and circulating metabolites in HAND. RESULTS: The gut microbiota of people living with HIV (PLWH) had an increased relative abundance of Prevotella and a decreased relative abundance of Bacteroides. In contrast, Prevotella and Megamonas were substantially decreased, and Bacteroides and Phocaeicola were increased in HAND patients. Moreover, untargeted metabolomics identified several neurotransmitters and certain amino acids associated with neuromodulation, and the differential metabolic pathways of amino acids associated with neurocognition were depleted in HAND patients. Notably, most neuromodulatory metabolites are associated with an altered abundance of specific gut bacteria. INTERPRETATION: Our findings provide new insights into the intricate interplay between the gut and microbiome-brain axis in the pathogenesis of HAND, highlighting the potential for developing novel therapeutic strategies that specifically target the gut microbiota. ANN NEUROL 2024;96:306-320.

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.

Prevalence and associated factors of neurocognitive disorder among people living with HIV/AIDS in the South Gondar zone primary hospitals, North-West Ethiopia: an institution-based cross-sectional study.

OBJECTIVE: To assess the prevalence and associated factors of neurocognitive disorder among people living with HIV/AIDS in South Gondar primary hospitals, North-West Ethiopia, 2023. DESIGN: Institution-based cross-sectional study design. SETTING: South Gondar primary hospitals, North-West Ethiopia. PARTICIPANTS: 608 participants were recruited using the systematic random sampling technique. MEASUREMENT: Data were collected using an interviewer-administered questionnaire and medical chart reviews. The International HIV Dementia Scale was used to screen for neurocognitive disorder. The data were entered through EPI-DATA V.4.6 and exported to SPSS V.21 statistical software for analysis. In the bivariable logistic regression analyses, variables with a value of p<0.25 were entered into a multivariable logistic regression analysis to identify factors independently associated with neurocognitive disorder. Statistical significance was declared at a value of p<0.05. RESULTS: The prevalence of neurocognitive disorder among HIV-positive participants was 39.1%. In multivariable logistic regression, lower level of education (adjusted OR (AOR)=2.94; 95% CI 1.29 to 6.82), unemployment (AOR=2.74; 95% CI 1.29 to 6.84) and comorbid medical illness (AOR=1.80; 95% CI 1.03 to 3.14) were significantly associated with neurocognitive disorder. CONCLUSION: HIV-associated neurocognitive problems affected over a third of the participants. According to the current study, comorbid medical conditions, unemployment and low educational attainment are associated with an increased risk of neurocognitive disorder. Therefore, early detection and treatment are essential.

Awareness and Knowledge of HIV-Associated Neurocognitive Disorder Among Middle-Aged and Older People Living With HIV/AIDS in Southern Nevada: Implications for HIV/AIDS Community-Based Education Programs.

Although a significant amount of biomedical research has been conducted to study HIV-associated neurocognitive disorder (HAND), there has been scant research done to assess the awareness and knowledge of this public health concern among middle-aged and older people living with HIV/AIDS (PLWH). Our qualitative community-based participatory research study sought to address this research gap by examining the awareness and knowledge of HAND among relevant stakeholders in southern Nevada, USA. We conducted 15 semistructured interviews with middle-aged and older PLWH to examine their awareness and knowledge of HAND and access to pertinent resources. After our thematic analysis of our interviews, we identified two overarching themes: (1) limited awareness and knowledge of HAND among PLWH, and (2) southern Nevada social determinants of health. Our findings underscore the importance of raising awareness and knowledge of HAND among PLWH through community-based education programs, and improving access to resources related to social determinants of health.

HIV associated neurocognitive disorder screening and diagnosis pathways in Australia: a scoping review and international implications.

Symptomatic HIV-associated neurocognitive disorder (HAND) is a complication of HIV (cognitive impairment, difficulties with everyday functioning). If detected early, interventions assist with optimizing care, avoiding rapid decline and enhancing coping. There remains inconsistency surrounding screening/diagnosis information within Australian healthcare professionals and community settings. A scoping review of academic literature, government policies and non-government organisations (NGOs) was conducted to map existing screening/diagnosis information using the guidelines of Joanna Briggs Institute. A literature search of EBSCOhost and Medline (dates: 2015-2021), the Australian government NGO web domains, Google and unpublished academic works was conducted (July 2021) and updated (December 2022) to identify Australian items (past 5 years). Seventeen items met the inclusion criteria. No government guidelines were identified. Various HIV-related organisations proposed different diagnostic guidelines. Most HAND research originated in Sydney. The most accessible information was from Dementia Australia, with some inaccuracies noted. There is scant Australian research/information on HAND screening/diagnosis. HAND translational research and screening/diagnosis standards are urgently needed to inform best practices. The Australian context is used to discuss international implications regarding higher-income countries with similar patterns/healthcare.

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.

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.