Unraveling neuroHIV in the Presence of Substance Use Disorders.

This special issue contains 10 invited review papers that highlighted and extended the presentations at the NIDA-sponsored workshop "Unraveling NeuroAIDS in the Presence of Substance Use Disorders" at the 25th Society on NeuroImmune Pharmacology conference in 2019. The topics covered by these papers focused on the interactive, additive or synergistic effects of substance use disorders (SUD) with HIV infection on the immune system and on neuropathogenesis. These papers reviewed four categories of substances of abuse (opioids, tobacco, stimulants, and cannabis) and how comorbid HIV infection (including models with HIV proteins, HIV transgenic rodent models and SIV) might further impact the dysregulated dopaminergic and immune systems, and the subsequent neuropathogenesis and behavioral disorders known as HIV-associated neurological disorders (HAND). These reviews provided detailed background knowledge regarding how each of these addictive substances and HIV individually or collectively affected the immune system at the cellular, molecular and system levels, and the subsequent clinical and behavioral outcomes. The authors also identified gaps, confounds or constraints in the current disease models and approaches, and proposed future research directions.

Functional impact of HIV-1 Tat on cells of the CNS and its role in HAND.

Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat) is a potent mediator involved in the development of HIV-1-associated neurocognitive disorders (HAND). Tat is expressed even in the presence of antiretroviral therapy (ART) and is able to enter the central nervous system (CNS) through a variety of ways, where Tat can interact with microglia, astrocytes, brain microvascular endothelial cells, and neurons. The presence of low concentrations of extracellular Tat alone has been shown to lead to dysregulated gene expression, chronic cell activation, inflammation, neurotoxicity, and structural damage in the brain. The reported effects of Tat are dependent in part on the specific HIV-1 subtype and amino acid length of Tat used. HIV-1 subtype B Tat is the most common subtype in North American and therefore, most studies have been focused on subtype B Tat; however, studies have shown many genetic, biologic, and pathologic differences between HIV subtype B and subtype C Tat. This review will focus primarily on subtype B Tat where the full-length protein is 101 amino acids, but will also consider variants of Tat, such as Tat 72 and Tat 86, that have been reported to exhibit a number of distinctive activities with respect to mediating CNS damage and neurotoxicity.

Not a victim: How self-deception saved David.

This paper summarizes a course of psychotherapy in which the therapist integrated concepts and strategies from psychoanalytic and cognitive-behavioral orientations in treating a gay man with HIV-associated neurocognitive disorder and a history of sexual abuse. The article highlights the psychologically protective function that deception served in the treatment of this patient, and how the therapist navigated the fragility of these inner fictions. Further, it illustrates the way in which the therapist-patient dynamic was colored by a psychoanalytic process known as projective identification.

Screening for HIV-associated neurocognitive disorders in perinatally infected adolescents: youth-International HIV Dementia Scale validation.

CONTEXT: Perinatal HIV infection has adverse cognitive consequences into adolescence. However, there are no screening tools that assess risk for HIV-associated neurocognitive disorders in adolescent populations. Such screening tools are needed urgently for clinical care in resource-poor settings with a high prevalence of HIV. OBJECTIVE: To investigate the performance of the International HIV Dementia Scale (IHDS) as a screening tool for HIV-associated neurocognitive disorders in perinatally adolescents. DESIGN: The current study is a quantitative, quasiexperimental design. METHODS: Perinatally HIV-infected adolescents aged 9-12 years were recruited from community health clinics into the Cape Town Adolescent Antiretroviral Cohort; matched HIV-negative controls from the same communities were enrolled. Each participant completed the IHDS and a comprehensive neuropsychological battery. The adult version of the IHDS was performed, except for two minor modifications. We evaluated the diagnostic validity of this modified instrument, the youth-IHDS (y-IHDS), using a four-step process that included sensitivity and specificity calculations, and generating receiver operating characteristic curves. Validity was measured against the youth HIV-associated diagnostic criteria. RESULTS: At a cut-off score of 10 or less, the y-IHDS demonstrated good sensitivity (94%) but poor specificity (24%) for detecting all forms of neurocognitive disorders, with an acceptable area under the curve value of 0.695. CONCLUSION: The y-IHDS requires minimal resources and is based on a screening tool for adult HIV-associated cognitive disorders that is already widely used globally. Hence, this brief, cost-efficient, and valid screening tool may be a useful addition for clinicians working in resource-poor contexts in which adolescent HIV is highly prevalent.

HIV neuropathology.

Primary human immunodeficiency virus (HIV) neuropathologies can affect all levels of the neuraxis and occur in all stages of natural history disease. Some, like HIV encephalitis, HIV myelitis, and diffuse infiltrative lymphocytosis of peripheral nerve, reflect productive infection of the nervous system; others, like vacuolar myelopathy, distal symmetric polyneuropathy, and central and peripheral nervous system demyelination, are not clearly related to regional viral replication, and reflect more complex cascades of dysregulated host immunity and metabolic dysfunction. In pediatric patients, the spectrum of neuropathology is altered by the impacts of HIV on a developing nervous system, with microcephaly, abundant brain mineralization, and corticospinal tract degeneration as examples of this unique interaction. With efficacious therapies, CD8 T-cell encephalitis is emerging as a significant entity; often this is clinically recognized as immune reconstitution inflammatory syndrome, but has also been described in the context of viral escape and treatment interruption. The relationship of HIV neuropathology to clinical symptoms is sometimes straightforward, and sometimes mysterious, as individuals can manifest significant deficits in the absence of discrete lesions. However, at all stages of the natural history disease, neuroinflammation is abundant, and critical to the generation of clinical abnormality. Neuropathologic and neurobiologic investigations will be central to understanding HIV nervous system disorders in the era of efficacious therapies.

NeuroAIDS in children.

The human immunodeficiency virus-1 (HIV-1) enters the central nervous system compartment within the first few weeks of systemic HIV infection and may cause a spectrum of neurologic complications. Without combination antiretroviral therapy (cART), 50-90% of all HIV-infected infants and children develop some form of neuroAIDS. Of the estimated 2.3 million children less than 15 years of age who were living in sub-Saharan Africa at the end of 2014, only 30% were receiving cART, suggesting that there is a large burden of neuroAIDS among HIV-infected children in sub-Saharan Africa. There is complex interplay between the disease process itself, the child's immune reaction to the disease, the secondary complications, the side-effects of antiretroviral drugs, and inadequate antiretroviral drug uptake into the central nervous system. In addition there is the layering effect from the multiple socioeconomic challenges for children living in low- and middle-income countries. Adolescents may manifest with a range of neurocognitive sequelae from mild neurocognitive disorder through to severe neurocognitive impairment. Neuroimaging studies on white-matter tracts have identified dysfunction, especially in the frontostriatal networks needed for executive function. Psychiatric symptoms of depression, attention deficit hyperactivity disorder, and behavioral problems are also commonly reported in this age group. Antiretroviral drugs may cause treatment-limiting neurologic and neuropsychiatric adverse reactions. The following chapter addresses the neurologic complications known to be, and suspected of being, associated with HIV infection in children and adolescents.

Proceedings of the 2017 ISEV symposium on "HIV, NeuroHIV, drug abuse, & EVs".

Despite the success of combination antiretroviral therapy (cART), there is increased prevalence of HIV-associated neurocognitive disorders (HAND) in HIV-1-infected individuals on cART, which poses a major health care challenge. Adding further complexity to this long-term antiretroviral use is the comorbidity with drugs of abuse such as morphine, cocaine, and methamphetamine, which can in turn, exacerbate neurologic and cognitive deficits associated with HAND. Furthermore, HIV proteins, such as the transactivator of transcription (Tat) and the envelope protein (gp120), as well as antiretrovirals themselves can also contribute to the progression of neurodegeneration underlying HAND. In the field of NeuroHIV and drug addiction, EVs hold the potential to serve as biomarkers of cognitive dysfunction, targets of therapy, and as vehicles for therapeutic delivery of agents that can ameliorate disease pathogenesis. Based on the success of a previous Satellite Symposium in 2015 at the ISEV meeting in Washington, experts again expanded on their latest research findings in the field, shedding light on the emerging trends in the field of Extracellular Vesicle (EV) biology in NeuroHIV and drug abuse. The satellite symposium sought to align experts in the fields of NeuroHIV and drug abuse to share their latest insights on the role of EVs in regulating neuroinflammation, neurodegeneration, peripheral immune response, and HIV latency in HIV-infected individuals with or without the comorbidity of drug abuse.

[Evaluation of an outpatient multidisciplinary Neuro-HIV clinic by the patients and referring doctors]. / Evaluation de la plateforme Neuro-VIH d'un hôpital universitaire par les patients et les médecins traitants.

The neurocognitive complaints among HIV infected patients remain frequent, and to establish their etiology can be challenging. We created in 2011 an outpatient Neuro-HIV clinical platform that takes advantage of a multidisciplinary approach with 5 specialists (neuropsychologist, neurologist, psychiatrist, infectiologist and neuroradiologist). In order to estimate its utility, we conducted two questionnaire-based interviews by phone calls with the patients and their referring physicians. Three quarters of both the patients and the physicians interviewed consider the platform useful or essential. Even though there is often no immediate treatment for cognitive disorders, the patients receive from this multidisciplinary approach a better understanding of their disease, which may help them to better cope with their anxieties in daily life.

Les plaintes neurocognitives chez les patients infectés par le VIH sont fréquentes, et diagnostiquer leur étiologie est complexe. En 2011, nous avons créé une plateforme ambulatoire Neuro-VIH permettant une évaluation multidisciplinaire (neuropsychologues, neurologues, psychiatres, infectiologues, neuroradiologues) de ces patients. Afin d'évaluer l'utilité de cette plateforme, une enquête téléphonique auprès des patients ainsi que de leurs médecins traitants a été effectuée. Trois quarts des patients et médecins interrogés la considèrent utile, voire indispensable. Malgré l'absence de traitement immédiat des troubles cognitifs, les patients disent que bénéficier de cette approche multidisciplinaire leur a permis de clarifier la nature de leurs troubles et de mieux faire face à leurs angoisses sur les plans privé et professionnel.

HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment.

The modern antiretroviral treatment of human immunodeficiency virus (HIV-1) infection has considerably lowered the incidence of opportunistic infections. With the exception of the most severe dementia manifestations, the incidence and prevalence of HIV-associated neurocognitive disorders (HAND) have not decreased, and HAND continues to be relevant in daily clinical practice. Now, HAND occurs in earlier stages of HIV infection, and the clinical course differs from that before the widespread use of combination antiretroviral treatment (cART). The predominant clinical feature is a subcortical dementia with deficits in the domains concentration, attention, and memory. Motor signs such as gait disturbance and impaired manual dexterity have become less prominent. Prior to the advent of cART, the cerebral dysfunction could at least partially be explained by the viral load and by virus-associated histopathological findings. In subjects where cART has led to undetectable or at least very low viral load, the pathogenic virus-brain interaction is less direct, and an array of poorly understood immunological and probably toxic phenomena are discussed. This paper gives an overview of the current concepts in the field of HAND and provides suggestions for the diagnostic and therapeutic management.

Measuring and managing cognitive impairment in HIV.

: Cognitive impairment remains a frequently reported complaint in HIV-positive patients despite virologically suppressive antiretroviral therapy. Rates of cognitive impairment in antiretroviral treated HIV-positive cohorts vary and strongly depend on definitions utilized.The underlying pathogenesis is likely to be multifactorial and includes immune activation, neuroinflammation, antiretroviral neurotoxicity, the presence of noninfectious comorbidities such as vascular disease and depression and patient lifestyle factors such as recreational drug use.Contributing factors to cognitive impairment may change over time with ageing HIV-positive populations. Cerebrovascular disease and neurodegenerative causes of cognitive impairment may become more common with advancing age; how these factors interact with HIV-associated cognitive impairment is not yet known.Cerebrospinal fluid HIV RNA escape may occur in up to 10% of patients undergoing lumbar puncture clinically and can be associated with compartmentalized and resistant virus.Changes in antiretroviral therapy in patients with cognitive impairment should be based on current and historic resistance profiles of cerebrospinal fluid and plasma virus, or on potential antiretroviral drug neurotoxicity. Whether and how antiretroviral therapy should be changed in the absence of these factors is not known and requires study in adequately powered randomized trials in carefully selected clinical cohorts.

Guidelines for Evaluation and Management of Cognitive Disorders in HIV-Positive Individuals.

Antiretroviral therapy has revolutionised the treatment for people living with HIV (PLWH). Where antiretroviral coverage is high, the treatment paradigm for HIV-disease is now one of managing the long-term consequences of the virus and its treatment rather than the consequences of untreated HIV-disease such as immunosuppression and opportunistic infections. One such long-term consequence is HIV-associated cognitive impairment which is reported to occur in up to 50 % of treated PLWH and has been associated with poorer outcomes. Given the ageing cohort and increased frequency of comorbidities, the prevalence of symptomatic cognitive impairment may increase with time. High quality evidence for management strategies including screening, diagnosis and treatment of HIV-associated cognitive impairment are lacking and in general guidelines are based on best clinical practice. In this article, we assessed recent guidelines concerning the management of HIV-associated cognitive impairment by performing a systematic review of the MEDLINE database using PubMed. We report that, in general, guidelines from around the world regarding the management of HIV-associated cognitive impairment are converging. Screening is generally not recommended in asymptomatic PLWH. Diagnosis of HIV-associated cognitive impairment should be made only after a comprehensive assessment and exclusion of other potential causes. Antiretroviral therapy forms the cornerstone of management of HIV-associated cognitive impairment and should be guided by plasma and cerebrospinal fluid (CSF) genotype(s).

Magnetic nanotherapeutics for dysregulated synaptic plasticity during neuroAIDS and drug abuse.

The human immunodeficiency virus (HIV) is a neurotropic virus. It induces neurotoxicity and subsequent brain pathologies in different brain cells. Addiction to recreational drugs remarkably affects the initiation of HIV infections and expedites the progression of acquired immunodeficiency syndrome (AIDS) associated neuropathogenesis. Symptoms of HIV-associated neurocognitive disorders (HAND) are noticed in many AIDS patients. At least 50 % of HIV diagnosed cases show one or other kind of neuropathological signs or symptoms during different stages of disease progression. In the same line, mild to severe neurological alterations are seen in at least 80 % autopsies of AIDS patients. Neurological illnesses weaken the connections between neurons causing significant altercations in synaptic plasticity. Synaptic plasticity alterations during HIV infection and recreational drug abuse are mediated by complex cellular phenomena involving changes in gene expression and subsequent loss of dendritic and spine morphology and physiology. New treatment strategies with ability to deliver drugs across blood-brain barrier (BBB) are being intensively investigated. In this context, magnetic nanoparticles (MNPs) based nanoformulations have shown significant potential for target specificity, drug delivery, drug release, and bioavailability of desired amount of drugs in non-invasive brain targeting. MNPs-based potential therapies to promote neuronal plasticity during HIV infection and recreational drug abuse are being developed.

Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model.

HIV-associated neurocognitive disorder (HAND) consists of motor and cognitive dysfunction in a relatively large percentage of patients with AIDS. Prior work has suggested that at least part of the neuronal and synaptic damage observed in HAND may occur due to excessive stimulation of NMDA-type glutamate receptors (NMDARs). Here, we compared pharmacological and genetic manipulation of NMDAR activity using an improved derivative of the NMDAR antagonist memantine, termed NitroMemantine, and the modulatory NMDAR subunit GluN3A in the HIV/gp120 transgenic (tg) mouse model of HAND. Interestingly, we found that while both NitroMemantine and GluN3A have been shown to inhibit NMDAR activity, NitroMemantine protected synapses in gp120-tg mice, but overexpression of GluN3A augmented the damage. Given recent findings in the field, one explanation for this apparently paradoxical result is the location of the NMDARs primarily affected, with NitroMemantine inhibiting predominantly extrasynaptic pathologically activated NMDARs, but GluN3A disrupting normal NMDAR-mediated neuroprotective activity via inhibition of synaptic NMDARs.

[HIV- DEMENTIA. A REVIEW THIRTY FIVE YEARS AFTER (1981-2015)]. / Demencia por HIV. Una revisión 35 años después (1981-2015).

In this review, the intention is to present the four clinical models of HIV-1-brain damage, named with the diffuse category of HIV-encephalopathy. It contains the past three decades, since the first static-infectological model of Snider WD, developed in 1983, based in a great neuropathological trial with AIDS patients. The second one, maybe the most compact of them, was the AIDS-dementia complex, published by the Navia BA group, in two notable papers published in 1986. This resulted in a consistent HIV-neuropsychiatric condition, till 1996, when HAART era begun. In a third early-HAART evolving model, we can find good correlations between the different levels: clinical (mild-moderate/severe forms), neuropsychological (subcortical pattern), neuroimaging, and LCR-markers. In the last-current paradigm, coincident with the advanced HAART treatments, the original HIV-encephalopathy became in a hybrid-complex compartimentalized condition, in contact with other neurodegenerative entities, like Alzheimer disease, Parkinson disease or the CNS-immune reconstitution inflammatory syndrome, with a high prevalence, atypical clinical forms, and with the demand of a specific management, in parallel to the systemic HIV disease.

Development and in vivo evaluation of an implantable nano-enabled multipolymeric scaffold for the management of AIDS dementia complex (ADC).

This study reports the use of biocompatible and biodegradable polymers for the formulation and design of an implantable multipolymeric drug delivery device (MDDD) for the management of AIDS dementia complex (ADC), a debilitating condition affecting the cognitive, motor and behavioral systems in HIV+ individuals. A 3-factor Box-Behnken statistical design was employed for the optimization of nanoparticle and multipolymeric scaffold formulations. Fifteen formulations were generated using the Box-Behnken template, which were assessed for physicochemical and physicomechanical characterization. The optimised nanoparticle formulation yielded nanoparticles measuring 68.04nm in size and zeta potential (ZP) of -13.4mV was calculated for the colloidal system. In an attempt to further retard drug release and to formulate a device for implantation in the frontal lobe of the brain, nanoparticles were dispersed within a multipolymeric matrix. Matrix erosion was calculated at 28% for multipolymeric scaffold and a matrix resilience of 4.451% was observed 30 days post exposure to PBS, indicating slow degradation of the MDDD. In vivo studies showed 12.793ng/mL and 35.225ng/mL AZT level in plasma and CSF. In view of the physicomechanical properties, in vitro and in vivo drug release kinetics of MDDD makes it a potential candidate for the management of the ADC.

Controversies in HIV-associated neurocognitive disorders.

Cross-sectional studies show that around half of individuals infected with HIV-1 have some degree of cognitive impairment despite the use of antiretroviral drugs. However, prevalence estimates vary depending on the population and methods used to assess cognitive impairment. Whether asymptomatic patients would benefit from routine screening for cognitive difficulties is unclear and the appropriate screening method and subsequent management is the subject of debate. In some patients, HIV-1 RNA can be found at higher concentrations in CSF than in blood, which potentially results from the poor distribution of antiretroviral drugs into the CNS. However, the clinical relevance of so-called CSF viral escape is not well understood. The extent to which antiretroviral drug distribution and toxicity in the CNS affect clinical decision making is also debated.

CROI 2014: Neurologic complications of HIV infection.

A shift in focus in the field of neuroHIV was clearly manifest at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI), where a major emphasis was on the milder forms of neurologic morbidity, including cognitive impairment, seen in well-treated patients. Mechanisms of this persistent abnormality were investigated, including extensive analysis of the prevalence and associations of persistent HIV detection in cerebrospinal fluid (CSF) and characterization of persistent CNS immune activation. Another key emphasis was the early establishment of HIV replication and inflammation within the central nervous system (CNS) and the potentially salutary effect of very early HIV diagnosis and treatment in protecting the CNS from HIV-related injury. Mitochondrial function was identified as a potential mediator of a number of aspects of HIV-associated CNS dysfunction, including neurotoxicity associated with efavirenz, host genetic determinants of HIV-associated neurocognitive disorders (HAND), associations with direct measures of mitochondria in CSF, and metabolomic screening of CSF in HIV-infected subjects and those with HAND. Many studies employed laboratory rather than neuropsychologic end points, with a major focus on CSF biomarkers. Overall, neuroHIV presentations at CROI 2014 provided new insights into pathogenesis and treatment of the CNS, raising new challenges for researchers and practitioners aiming to optimize the status of the brain in people living with HIV infection.

Monocytes-derived macrophages mediated stable expression of human brain-derived neurotrophic factor, a novel therapeutic strategy for neuroAIDS.

HIV-1 associated dementia remains a significant public health burden. Clinical and experimental research has shown that reduced levels of brain-derived neurotrophic factor (BDNF) may be a risk factor for neurological complications associated with HIV-1 infection. We are actively testing genetically modified macrophages for their possible use as the cell-based gene delivery vehicle for the central nervous system (CNS). It can be an advantage to use the natural homing/migratory properties of monocyte-derived macrophages to deliver potentially neuroprotective BDNF into the CNS, as a non-invasive manner. Lentiviral-mediated gene transfer of human (h)BDNF plasmid was constructed and characterized. Defective lentiviral stocks were generated by transient transfection of 293T cells with lentiviral transfer plasmid together with packaging and envelope plasmids. High titer lentiviral vector stocks were harvested and used to transduce human neuronal cell lines, primary cultures of human peripheral mononocyte-derived macrophages (hMDM) and murine myeloid monocyte-derived macrophages (mMDM). These transduced cells were tested for hBDNF expression, stability, and neuroprotective activity. The GenomeLab GeXP Genetic Analysis System was used to evaluate transduced cells for any adverse effects by assessing gene profiles of 24 reference genes. High titer vectors were prepared for efficient transduction of neuronal cell lines, hMDM, and mMDM. Stable secretion of high levels of hBDNF was detected in supernatants of transduced cells using western blot and ELISA. The conditioned media containing hBDNF were shown to be protective to neuronal and monocytic cell lines from TNF-α and HIV-1 Tat mediated cytotoxicity. Lentiviral vector-mediated gene transduction of hMDM and mMDM resulted in high-level, stable expression of the neuroprotective factorBDNF in vitro. These findings form the basis for future research on the potential use of BDNF as a novel therapy for neuroAIDS.