HIV-Associated Neurotoxicity: The Interplay of Host and Viral Proteins.

HIV-1 can incite activation of chemokine receptors, inflammatory mediators, and glutamate receptor-mediated excitotoxicity. The mechanisms associated with such immune activation can disrupt neuronal and glial functions. HIV-associated neurocognitive disorder (HAND) is being observed since the beginning of the AIDS epidemic due to a change in the functional integrity of cells from the central nervous system (CNS). Even with the presence of antiretroviral therapy, there is a decline in the functioning of the brain especially movement skills, noticeable swings in mood, and routine performance activities. Under the umbrella of HAND, various symptomatic and asymptomatic conditions are categorized and are on a rise despite the use of newer antiretroviral agents. Due to the use of long-lasting antiretroviral agents, this deadly disease is becoming a manageable chronic condition with the occurrence of asymptomatic neurocognitive impairment (ANI), symptomatic mild neurocognitive disorder, or HIV-associated dementia. In-depth research in the pathogenesis of HIV has focused on various mechanisms involved in neuronal dysfunction and associated toxicities ultimately showcasing the involvement of various pathways. Increasing evidence-based studies have emphasized a need to focus and explore the specific pathways in inflammation-associated neurodegenerative disorders. In the current review, we have highlighted the association of various HIV proteins and neuronal cells with their involvement in various pathways responsible for the development of neurotoxicity.

Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders.

The neurovascular units (NVU) are the minimal functional units of the blood-brain barrier (BBB), composed of endothelial cells, pericytes, astrocytes, microglia, neurons, and the basement membrane. The BBB serves as an important interface for immune communication between the brain and peripheral circulation. Disruption of the NVU by the human immunodeficiency virus-1 (HIV-1) induces dysfunction of the BBB and triggers inflammatory responses, which can lead to the development of neurocognitive impairments collectively known as HIV-1-associated neurocognitive disorders (HAND). Methamphetamine (METH) use disorder is a frequent comorbidity among individuals infected with HIV-1. METH use may be associated not only with rapid HIV-1 disease progression but also with accelerated onset and increased severity of HAND. However, the molecular mechanisms of METH-induced neuronal injury and cognitive impairment in the context of HIV-1 infection are poorly understood. In this review, we summarize recent progress in the signaling pathways mediating synergistic impairment of the BBB and neuronal injury induced by METH and HIV-1, potentially accelerating the onset or severity of HAND in HIV-1-positive METH abusers. We also discuss potential therapies to limit neuroinflammation and NVU damage in HIV-1-infected METH abusers.

Early prediction of putamen imaging features in HIV-associated neurocognitive impairment syndrome.

BACKGROUND: To explore the correlation between the volume of putamen and brain cognitive impairment in patients with HIV and to predict the feasibility of early-stage HIV brain cognitive impairment through radiomics. METHOD: Retrospective selection of 90 patients with HIV infection, including 36 asymptomatic neurocognitive impairment (ANI) patients and 54 pre-clinical ANI patients in Beijing YouAn Hospital. All patients received comprehensive neuropsychological assessment and MRI scanning. 3D Slicer software was used to acquire volume of interest (VOI) and radiomics features. Clinical variables and volume of putamen were compared between patients with ANI and pre-clinical ANI. The Kruskal Wallis test was used to analysis multiple comparisons between groups. The relationship between cognitive scores and VOI was compared using linear regression. For radiomics, principal component analysis (PCA) was used to reduce model overfitting and calculations and then a support vector machine (SVM) was used to build a binary classification model. For model performance evaluation, we used an accuracy, sensitivity, specificity and receiver operating characteristic curve (ROC). RESULT: There were no significant differences in clinical variables between ANI group and pre-clinical-ANI group (P>0.05). The volume of bilateral putamen was significantly different between AHI group and pre-clinical group (P<0.05), but there was only a trend in the left putamen between ANI-treatment group and pre-clinical treatment group(P = 0.063). Reduced cognitive scores in Verbal Fluency, Attention/Working Memory, Executive Functioning, memory and Speed of Information Processing were negatively correlated with the increased VOI (P<0.05), but the correlation was relatively low. In diagnosing the ANI from pre-clinical ANI, the mean area under the ROC curves (AUC) were 0.85 ± 0.22, the mean sensitivity and specificity were 63.12 ± 5.51 and 94.25% ± 3.08%. CONCLUSION: The volumes of putamen in patients with ANI may be larger than patients with pre-clinical ANI, the change of the volume of the putamen may have a certain process; there is a relationship between putamen and cognitive impairment, but the exact mechanism is unclear. Radiomics may be a useful tool for predicting early stage HAND in patients with HIV.

A comprehensive data-driven analysis framework for detecting impairments in brain function networks with resting state fMRI in HIV-infected individuals on cART.

Central nervous system (CNS) sequelae continue to be common in HIV-infected individuals despite combination antiretroviral therapy (cART). These sequelae include HIV-associated neurocognitive disorder (HAND) and virologic persistence in the CNS. Resting state functional magnetic resonance imaging (rsfMRI) is a widely used tool to examine the integrity of brain function and pathology. In this study, we examined 16 HIV-positive (HIV+) subjects and 12 age, sex, and race matched HIV seronegative controls (HIV-) whole-brain high-resolution rsfMRI along with a battery of neurocognitive tests. A comprehensive data-driven analysis of rsfMRI revealed impaired functional connectivity, with very large effect sizes in executive function, language, and multisensory processing networks in HIV+ subjects. These results indicate the potential of high-resolution rsfMRI in combination with advanced data analysis techniques to yield biomarkers of neural impairment in HIV.

Greater Sensorimotor Deficits and Abnormally Lower Globus Pallidus Fractional Anisotropy in HIV+ Women than in HIV+ Men.

AIMS: Cognitive impairment may be greater in HIV-positive (HIV+) women than in HIV+ men. Whether sex-specific differences exist in brain microstructure of HIV+ individuals is unknown and was evaluated. METHOD: 39 HIV+ (21 men, 18 women) and 45 seronegative (SN, 20 men, 25 women) participants were assessed with brain diffusion tensor imaging and cognitive assessments (7 neuropsychological domains). Fractional anisotropy (FA) and mean diffusivity (MD) were measured with an automated atlas in selected brain regions. Group comparisons were assessed with linear mixed effects models, with sub-regions and hemisphere (left/right) as repeated factors for each region. RESULTS: HIV+ women, but not HIV+ men, were slower than sex-matched SN controls on sensorimotor function (Dominant-hand: interaction-p = 0.007; Non-dominant hand: interaction-p = 0.039). Similarly, only HIV+ women had lower FA in the globus pallidus (GP, interaction-p = 0.011). Additionally, regardless of sex, the HIV+ group had poorer Fluency, Speed, and Attention than SN-controls (p = 0.006-0.008), as well as lower FA and higher MD in multiple brain regions (p = <0.001-0.044). Across all participants, performance on Attention was predicted by uncinate-FA (p < 0.001, r = 0.5) and corpus callosum (CC)-FA (p = 0.038, r = 0.23), while the Speed of Information Processing was predicted by CC-FA (p = 0.009, r = 0.3). Furthermore, faster sensorimotor function correlated with higher CC-FA and uncinate-FA in men but not in women (Sex*DTI-interaction-p = 0.03-0.06). CONCLUSIONS: The relatively poorer sensorimotor function and abnormally lower GP_FA, suggesting lesser neuronal integrity, in HIV+ women demonstrate sex-specific effects from HIV-infection on these measures. These findings may be related to the greater immune activation and neuroinflammation in HIV+ women compared to HIV+ men. Graphical Abstract.

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).

Recovery of HIV encephalopathy in perinatally infected children on antiretroviral therapy.

AIM: To describe the trajectory of clinical signs in children who developed human immunodeficiency virus encephalopathy (HIVE) after starting early antiretroviral therapy (ART). METHOD: This was a retrospective case-cohort description of HIVE among Cape Town participants from the Children with HIV Early AntiRetroviral treatment (CHER) trial. Criteria for HIVE diagnosis were at least two of: (1) acquired central motor deficit, (2) impaired brain growth, and (3) failure to attain or loss of developmental milestones in the absence of an alternative aetiology. RESULTS: Of 133 surviving participants who initiated ART at a median age of 9 weeks and who were followed until a median age of 6 years, 20 (12%) developed HIVE at a median age 31 months (interquartile range 19-37). In these, the first neurological deterioration was noticed at a median age of 19 months, when 16 were on ART and nine had undetectable HIV viral load for a median of 12 months. Signs of upper motor neurons were present in 18, of whom 12 resolved and four had persistent spastic diplegia; 19 had motor delay, of whom 14 resolved; 12 had language delay, of whom 11 resolved; and 16 had impaired brain growth, of whom only five recovered. For the 16 participants already on ART at HIVE diagnosis, regimens were not altered in response to diagnosis. INTERPRETATION: HIVE may occur despite early ART initiation and virological suppression and then resolve on unchanged ART, most likely as intrathecal inflammation subsides. WHAT THIS PAPER ADDS: Despite suppressive antiretroviral therapy, children can develop human immunodeficiency virus encephalopathy, The most common manifestations are motor deficits and impaired brain growth. Most experience improvement, with many resolving without additional intervention.

Movement disorder in a patient with Human Immunodeficiency Virus on an anti-retroviral therapy: A Case Report.

Human Immunodeficiency Virus associated neurocognitive dysfunction can present as a case of movement disorder in a patient with prolonged antiretroviral therapy. Diagnosis was made after ruling out space occupying lesions, nutritional deficiencies and infectious causes through brain imaging and cerebrospinal fluid analysis. With multidisciplinary care and change of antiretroviral therapy to drugs with higher cerebrospinal fluid penetration, symptoms of the patient improved over a span of six months. Delayed neurological damage due to Human Immunodeficiency Virus can present with isolated cerebellar symptoms.

Region-specific effects of HIV-1 Tat on intrinsic electrophysiological properties of pyramidal neurons in mouse prefrontal cortex and hippocampus.

Human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) is a viral protein that promotes transcription of the HIV genome and possesses cell-signaling properties. Long-term exposure of central nervous system (CNS) tissue to HIV-1 Tat is theorized to contribute to HIV-associated neurodegenerative disorder (HAND). In the current study, we sought to directly evaluate the effect of HIV-1 Tat expression on the intrinsic electrophysiological properties of pyramidal neurons located in layer 2/3 of the medial prefrontal cortex and in area CA1 of the hippocampus. Toward that end, we drove Tat expression with doxycycline (100 mg·kg-1·day-1 ip) in inducible Tat (iTat) transgenic mice for 7 days and then performed single-cell electrophysiological studies in acute tissue slices made through the prefrontal cortex and hippocampus. Control experiments were performed in doxycycline-treated G-tg mice, which retain the tetracycline-sensitive promoter but do not express Tat. Our results indicated that the predominant effects of HIV-1 Tat expression are excitatory in medial prefrontal cortical pyramidal neurons yet inhibitory in hippocampal pyramidal neurons. Notably, in these two populations, HIV-1 Tat expression produced differential effects on neuronal gain, membrane time constant, resting membrane potential, and rheobase. Similarly, we also observed distinct effects on action potential kinetics and afterhyperpolarization, as well as on the current-voltage relationship in subthreshold voltage ranges. Collectively, these data provide mechanistic evidence of complex and region-specific changes in neuronal physiology by which HIV-1 Tat protein may promote cognitive deficits associated with HAND.NEW & NOTEWORTHY We drove expression of human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) protein in inducible Tat (iTat) transgenic mice for 7 days and then examined the effects on the intrinsic electrophysiological properties of pyramidal neurons located in the medial prefrontal cortex (mPFC) and in the hippocampus. Our results reveal a variety of specific changes that promote increased intrinsic excitability of layer II/III mPFC pyramidal neurons and decreased intrinsic excitability of hippocampal CA1 pyramidal neurons, highlighting both cell type and region-specific effects.

Detecting cognitive impairment in HIV-infected individuals using mutual connectivity analysis of resting state functional MRI.

It is estimated that more than 50% of the individuals affected with Human Immunodeficiency Virus (HIV) present deficits in multiple cognitive domains, collectively known as HIV-associated neurocognitive disorder (HAND). Early stages of brain injury may be clinically silent but potentially measurable via neuroimaging. A total of 40 subjects (20 HIV positive and 20 age-matched controls) volunteered for the study. All subjects underwent a standard battery of neuropsychological tests used for the clinical diagnosis of HAND. Fourteen HIV+ and five healthy subjects showed signs of neurological impairment. Connectivity was computed using mutual connectivity analysis (MCA) with generalized radial basis function neural network, a framework for quantifying non-linear connectivity as well as conventional correlation from 160 regional time-series that were extracted based on the Dosenbach (DOS) atlas. We subsequently applied graph theoretic as well as network analysis approaches for characterizing the connectivity matrices obtained and localizing between-group differences. We focused on trying to detect cognitive impairment using the subset of 29 (14 subjects with HAND and 15 cognitively normal controls) subjects. For the global analysis, significant differences (p < 0.05) were seen in the variance in degree, modularity and Smallworldness. Regional analysis revealed changes occurring mainly in portions of the lateral occipital cortex and the cingulate cortex. Furthermore, using Network Based Statistics (NBS), we uncovered an affected sub-network of 19 nodes comprising predominantly of regions of the default mode network. Similar analysis using the conventional correlation method revealed no significant results at a global scale, while regional analysis shows some differences spread across resting state networks. These results suggest that there is a subtle reorganization occurring in the topology of brain networks in HAND, which can be captured using improved connectivity analysis.

An Empirical Mediation Analysis of Mechanisms Underlying HIV-1-Associated Neurocognitive Disorders.

HIV-1-associated neurocognitive disorders (HAND), characterized by alterations in the core components of cognitive function and age-related disease progression, persist in the post-cART era. However, the neurobehavioral mechanisms that mediate alterations in the core components of cognitive function and the progression of neurocognitive impairments have yet to be systematically evaluated. To address this knowledge gap, statistical mediation analysis was assessed, providing a critical opportunity to empirically evaluate putative neurobehavioral mechanisms underlying HAND. Neurocognitive assessments, conducted in HIV-1 transgenic (Tg) and control animals across the functional lifespan (i.e., Postnatal Day (PD) 30 to PD 600), tapped multiple cognitive domains including preattentive processes, learning, sustained attention, and long-term episodic memory. Three longitudinal mediation models were utilized to assess whether deficits in preattentive processes mediate alterations in learning, sustained attention and/or long-term episodic memory over time. Preattentive processes partially mediated the relationship between genotype and learning, genotype and sustained attention, and genotype and long-term episodic memory across the functional lifespan, explaining between 44% and 58% of the HIV-1 transgene effect. Understanding the neurobehavioral mechanisms mediating alterations in HAND may provide key targets for the development of a diagnostic biomarker, novel therapeutics, and cure/restoration strategies.

The impact of substance abuse on HIV-mediated neuropathogenesis in the current ART era.

Approximately 37 million people worldwide are infected with human immunodeficiency virus (HIV). One highly significant complication of HIV infection is the development of HIV-associated neurocognitive disorders (HAND) in 15-55% of people living with HIV (PLWH), that persists even in the antiretroviral therapy (ART) era. The entry of HIV into the central nervous system (CNS) occurs within 4-8 days after peripheral infection. This establishes viral reservoirs that may persist even in the presence of ART. Once in the CNS, HIV infects resident macrophages, microglia, and at low levels, astrocytes. In response to chronic infection and cell activation within the CNS, viral proteins, inflammatory mediators, and host and viral neurotoxic factors produced over extended periods of time result in neuronal injury and loss, cognitive deficits and HAND. Substance abuse is a common comorbidity in PLWH and has been shown to increase neuroinflammation and cognitive disorders. Additionally, it has been associated with poor ART adherence, and increased viral load in the cerebrospinal fluid (CSF), that may also contribute to increased neuroinflammation and neuronal injury. Studies have examined mechanisms that contribute to neuroinflammation and neuronal damage in PLWH, and how substances of abuse exacerbate these effects. This review will focus on how substances of abuse, with an emphasis on methamphetamine (meth), cocaine, and opioids, impact blood brain barrier (BBB) integrity and transmigration of HIV-infected and uninfected monocytes across the BBB, as well as their effects on monocytes/macrophages, microglia, and astrocytes within the CNS. We will also address how these substances of abuse may contribute to HIV-mediated neuropathogenesis in the context of suppressive ART. Additionally, we will review the effects of extracellular dopamine, a neurotransmitter that is increased in the CNS by substances of abuse, on HIV neuropathogenesis and how this may contribute to neuroinflammation, neuronal insult, and HAND in PLWH with active substance use. Lastly, we will discuss some potential therapies to limit CNS inflammation and damage in HIV-infected substance abusers.

Reduced intrinsic excitability of CA1 pyramidal neurons in human immunodeficiency virus (HIV) transgenic rats.

The hippocampus is involved in key neuronal circuits that underlie cognition, memory, and anxiety, and it is increasingly recognized as a vulnerable structure that contributes to the pathogenesis of HIV-associated neurocognitive disorder (HAND). However, the mechanisms responsible for hippocampal dysfunction in neuroHIV remain unknown. The present study used HIV transgenic (Tg) rats and patch-clamp electrophysiological techniques to study the effects of the chronic low-level expression of HIV proteins on hippocampal CA1 pyramidal neurons. The dorsal and ventral areas of the hippocampus are involved in different neurocircuits and thus were evaluated separately. We found a significant decrease in the intrinsic excitability of CA1 neurons in the dorsal hippocampus in HIV Tg rats by comparing neuronal spiking induced by current step injections and by dynamic clamp to simulate neuronal spiking activity. The decrease in excitability in the dorsal hippocampus was accompanied by a higher rate of excitatory postsynaptic currents (EPSCs), whereas CA1 pyramidal neurons in the ventral hippocampus in HIV Tg rats had higher EPSC amplitudes. We also observed a reduction of hyperpolarization-activated nonspecific cationic current (Ih) in both the dorsal and ventral hippocampus. Neurotoxic HIV proteins have been shown to increase neuronal excitation. The lower excitability of CA1 pyramidal neurons that was observed herein may represent maladaptive homeostatic plasticity that seeks to stabilize baseline neuronal firing activity but may disrupt neural network function and contribute to HIV-associated neuropsychological disorders, such as HAND and depression.

White matter loss and oligodendrocyte dysfunction in HIV: A consequence of the infection, the antiretroviral therapy or both?

While the severe cognitive effects of HIV-associated dementia have been reduced by combined antiretroviral therapy (cART), nearly half of HIV-positive (HIV+) patients still suffer from some form of HIV-Associated Neurocognitive Disorders (HAND). While frank neuronal loss has been dramatically reduced in HAND patients, white matter loss, including dramatic thinning of the corpus callosum, and loss of volume and structural integrity of myelin persists despite viral control by cART. It remains unclear whether changes in white matter underlie the clinical manifestation seen in patients or whether they are the result of persistent viral reservoirs, remnant damage from the acute infection, the antiretroviral compounds used to treat HIV, secondary effects due to peripheral toxicities or other associated comorbid conditions. Both HIV infection itself and its treatment with antiretroviral drugs can induce metabolic syndrome, lipodystrophy, atherosclerosis and peripheral neuropathies by increased oxidative stress, induction of the unfolded protein response and dysregulation of lipid metabolism. These virally and/or cART-induced processes can also cause myelin loss in the CNS. This review aims to highlight existing data on the contribution of white matter damage to HAND and explore the mechanisms by which HIV infection and its treatment contribute to persistence of white matter changes in people living with HIV currently on cART.

Aging sensitizes male mice to cognitive dysfunction induced by central HIV-1 gp120.

Although highly active antiretroviral therapy has led to improved prognosis and alleviation of some HIV-related disease complications, it has not provided complete protection against HIV-associated dementia. As the population of persons living with HIV grows older and aged persons represent a significant number of new infections, it is important to understand how HIV may affect the aged brain. In the current study, both adult and aged mice were treated with HIV gp120 and trained in a reference memory version of the water maze. Analysis of probe data revealed that aged animals treated with gp120 demonstrated profound decrements in water maze performance compared to gp120 treated young animals and saline treated aged or young animals. Additionally, we examined the neuroinflammatory responses in the aged and adult brain 4 h after treatment with gp120. Pro-inflammatory cytokines associated with neuroinflammation are known to be antagonistic to learning and memory processes and aged and adult animals treated with gp120 demonstrated similar increases in IL-1ß and IL-6 in the hippocampus and cortex. Additionally, gp120 treatment was associated with an increase in MHCII gene expression, a marker of microglial activation, in the hippocampus. Although, the aged brain demonstrated a similar inflammatory profile at the time point measured, aged animals were more sensitive to cognitive dysfunction related to gp120 treatment. This finding supports the theory that aging may be a significant risk factor in the development of HIV-associated dementia.

Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment.

HIV causes neurodegeneration and dementia in AIDS patients, but its function in milder cognitive impairments in virologically suppressed patients on antiretroviral therapy is unknown. Such patients are immunocompetent, have low peripheral and brain HIV burdens, and show minimal brain neuropathology. Using the model of HIV-related memory impairment in EcoHIV-infected conventional mice, we investigated the neurobiological and cognitive consequences of efficient EcoHIV expression in the mouse brain after intracerebral infection. HIV integrated and persisted in an expressed state in brain tissue, was detectable in brain monocytic cells, and caused neuroinflammatory responses and lasting spatial, working, and associative memory impairment. Systemic antiretroviral treatment prevented direct brain infection and memory dysfunction indicating the requirement for HIV expression in the brain for disease. Similarly inoculated murine leukemia virus used as a control replicated in mouse brain but not in monocytic cells and was cognitively benign, linking the disease to HIV-specific functions. Memory impairment correlated in real time with hippocampal dysfunction shown by defective long-term potentiation in hippocampal slices ex vivo and with diffuse synaptodendritic injury in the hippocampus reflected in significant reduction in microtubule-associated protein 2 and synapsin II staining. In contrast, there was no evidence of overt neuronal loss in this region as determined by neuron-specific nuclear protein quantification, TUNEL assay, and histological observations. Our results reveal a novel capacity of HIV to induce neuronal dysfunction and memory impairment independent of neurotoxicity, distinct from the neurotoxicity of HIV infection in dementia.IMPORTANCE HIV neuropathogenesis has been attributed in large measure to neurotoxicity of viral proteins and inflammatory factors produced by infected monocytic cells in the brain. We show here that HIV expression in mouse brain causes lasting memory impairment by a mechanism involving injury to hippocampal synaptodendritic arbors and neuronal function but not overt neuronal loss in the region. Our results mirror the observation of minimal neurodegeneration in cognitively impaired HIV patients on antiretroviral therapy and demonstrate that HIV is nonneurotoxic in certain brain abnormalities that it causes. If neurons comprising the cognition-related networks survive HIV insult, at least for some time, there is a window of opportunity for disease treatment.

Heterogeneity in neurocognitive change trajectories among people with HIV starting antiretroviral therapy in Rakai, Uganda.

Considerable heterogeneity exists in patterns of neurocognitive change in people with HIV (PWH). We examined heterogeneity in neurocognitive change trajectories from HIV diagnosis to 1-2 years post-antiretroviral therapy (ART). In an observational cohort study in Rakai, Uganda, 312 PWH completed a neuropsychological (NP) test battery at two-time points (ART-naïve, 1-2 years post-ART initiation). All NP outcomes were used in a latent profile analysis to identify subgroups of PWH with similar ART-related neurocognitive change profiles. In a subset, we examined subgroup differences pre-ART on cytokine and neurodegenerative biomarkers CSF levels. We identified four ART-related change subgroups: (1) decline-only (learning, memory, fluency, processing speed, and attention measures), (2) mixed (improvements in learning and memory but declines in attention and executive function measures), (3) no-change, or (4) improvement-only (learning, memory, and attention measures). ART-related NP outcomes that are most likely to change included learning, memory, and attention. Motor function measures were unchanged. Subgroups differed on eight of 34 pre-ART biomarker levels including interleukin (IL)-1ß, IL-6, IL-13, interferon-γ, macrophage inflammatory protein-1ß, matrix metalloproteinase (MMP)-3, MMP-10, and platelet-derived growth factor-AA. The improvement-only and mixed subgroups showed lower levels on these markers versus the no-change subgroup. These findings provide support for the need to disentangle heterogeneity in ART-related neurocognitive changes, to focus on higher-order cognitive processes (learning, memory, attention) as they were most malleable to change, and to better understand why motor function remained unchanged despite ART treatment. Group differences in pre-ART CSF levels provide preliminary evidence of biological plausibility of neurocognitive phenotyping.

CROI 2019: neurologic complications of HIV disease.

Investigators reported many new neuroHIV research findings at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI). These findings included confirmation that HIV-associated neurocognitive disorder (HAND) remains common with an increasingly recognized role for comorbidities (eg, obesity) and neurodegenerative conditions (eg, Alzheimer's disease), especially as persons living with HIV (PLWH) advance into their seventh decade of life and beyond. HAND is increasingly recognized as a heterogeneous disorder that differs between individuals (eg, by sex) in the trajectory of specific neurocognitive abilities (eg, executive functioning). A more recent focus at this year's conference was toxicity of combination antiretroviral therapy: neurocognitive performance and neuroimaging data from several studies were presented but did not consistently support that integrase strand transfer inhibitors are associated with worse neurologic outcomes. Neuroimaging studies found that white matter changes reflect a combination of the effects of HIV and comorbidities (including cerebrovascular small vessel disease) and best correlate with blood markers of inflammation. The pathogenesis of HIV in the central nervous system (CNS) was the focus of a plenary lecture and numerous presentations on HIV compartmentalization in the CNS and cerebrospinal fluid viral escape. Novel findings were also presented on associations between HIV-associated neurologic complications and glycomics, neuron-derived exosomes, and DNA methylation in monocytes. This summary will review findings from CROI and identify new research and clinical opportunities.

HIV Infection Induces Extracellular Cathepsin B Uptake and Damage to Neurons.

HIV-associated neurocognitive disorders prevail in 20-50 percent of infected individuals. Macrophages transmigrate through the blood brain barrier during HIV-1 infection, triggering neuronal dysfunction. HIV-infected macrophages secrete cathepsin B (CATB), and serum amyloid p component (SAPC), inducing neuronal apoptosis by an unknown mechanism. We hypothesized that HIV infection facilitates CATB/SAPC secretion from macrophages followed by neuronal internalization, promoting dysfunction. SK-N-SH neuronal cells were exposed to active recombinant histidine-tagged cathepsin B (His-CATB). His-CATB entry was tracked by intracellular flow cytometry, and neuronal dysfunction was verified by western blot. Macrophage-derived extracellular vesicles (EVs) were tested for the presence of CATB and SAPC. Neurons internalized His-CATB, an effect that was partially decreased by pre-treatment with anti-CATB antibody. Pre-treatment with CATB and SAPC antibodies decreased cleavage of caspase-3 and restored synaptophysin in neurons. Neurons exposed to macrophage-conditioned media differentially internalized His-CATB, dependent on the HIV replication levels. Finally, CATB and SAPC were secreted in EVs. We report for the first time that CATB is secreted from macrophages both free and in EVs, and is internalized by neurons. Moreover, HIV-replication levels modulate the amount of CATB neuronal uptake, and neuronal dysfunction can be decreased with CATB antibodies. In conclusion, the CATB/SAPC complex represents a novel target against HIV-associated neurocognitive disorders.