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.

Health disparities in mortality among individuals with HIV-associated dementia in South Carolina.

HIV disproportionately affects the South compared to other regions of the US. Some people living with HIV (PLWH) may acquire HIV-associated neurocognitive disorders (HAND), of which HIV-associated dementia (HAD) is the most severe form. This study aimed to examine the disparities in mortality among individuals with HAD. Data were obtained from the South Carolina Alzheimer's Disease and Related Dementias Registry from 2010 to 2016 (HAD: n = 505; N = 164,982). Logistic regression and Cox proportional hazards models were used to determine mortality related to HIV-associated dementia and potential sociodemographic differences. Adjusted models controlled for age, gender, race, rurality, and place of diagnosis. Individuals diagnosed in a nursing facility were three times more likely to die with HAD compared to those diagnosed in the community (OR: 3.25; 95% CI: 2.08-5.08). Black populations were more likely to die with HAD compared to White populations (OR: 1.52; 95% CI: 0.953-2.42). Disparities in mortality among patients with HAD were found in place of diagnosis and by race. Future research should determine if mortality among individuals with HAD were as a result of HAD or non-HIV related decline.

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.

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

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

AIDS Dementia Complex: Neurotoxicity in AIDS Patients.

AIDS dementia complex (ADC) is a nervous system disorder that harms the neurons in different parts of the brain. Various features are involved in altering the normal activities of neurons. Neurotoxicity is induced due to HIV viral proteins such as gp120, SDF, Tat, etc. These proteins target macrophages, glial cells, astrocytes, and release neurotoxins. These neurotoxins proved harmful for the neurons, caused apoptotic cell death by raising calcium, glutamate level and by producing various free radicals such as nitric oxide (NO·). Lipid peroxidation and lipids rafts also play a vital role in producing toxicity and apoptotic cell death. Membrane associated oxidative stress, cognitive impairment, and high level of HNE (4-hydroxynonenal); all are involved in ADC pathogenesis.

Racial differences in scores on the HIV Dementia Scale: mediating effects of literacy and screening utility among Black and White persons with HIV disease.

There are many obstacles to screening for HIV-associated neurocognitive disorders (HAND), including the influence of various sociodemographic effects on screening measures. This study examined possible racial bias on the HIV Dementia Scale (HDS) in screening for HAND among 39 Black and 84 White persons living with HIV (PLWH). Black PLWH had significantly lower raw HDS scores than White PLWH, which was mediated by lower oral word reading scores. Nevertheless, HDS scores were comparably predictive of clinical HAND diagnoses for Black and White PLWH as determined by a comprehensive battery; overall, individuals who failed the HDS were three times as likely to have HAND as compared to those who performed within normal limits (sensitivity = .26, specificity = .94). Consistent with prior literature exploring race-group differences, findings suggest that lower scores among Black PLWH compared to White PLWH on a commonly-used screening measure for HAND are partly explained by reading scores, perhaps reflecting differences in educational quality and opportunities. However, race-group differences did not affect the classification accuracy of the HDS in detecting HAND, although overall diagnostic accuracy was modest in both groups. Future work should determine the optimal neurocognitive screening methods for Black PLWH and other under-represented ethnoracial groups.

Prevalence and 1-year incidence of HIV-associated neurocognitive disorder (HAND) in adults aged ≥50 years attending standard HIV clinical care in Kilimanjaro, Tanzania.

OBJECTIVES: HIV-associated neurocognitive disorders (HANDs) are prevalent in older people living with HIV (PLWH) worldwide. HAND prevalence and incidence studies of the newly emergent population of combination antiretroviral therapy (cART)-treated older PLWH in sub-Saharan Africa are currently lacking. We aimed to estimate HAND prevalence and incidence using robust measures in stable, cART-treated older adults under long-term follow-up in Tanzania and report cognitive comorbidities. DESIGN: Longitudinal study. PARTICIPANTS: A systematic sample of consenting HIV-positive adults aged ≥50 years attending routine clinical care at an HIV Care and Treatment Centre during March-May 2016 and followed up March-May 2017. MEASUREMENTS: HAND by consensus panel Frascati criteria based on detailed locally normed low-literacy neuropsychological battery, structured neuropsychiatric clinical assessment, and collateral history. Demographic and etiological factors by self-report and clinical records. RESULTS: In this cohort (n = 253, 72.3% female, median age 57), HAND prevalence was 47.0% (95% CI 40.9-53.2, n = 119) despite well-managed HIV disease (Mn CD4 516 (98-1719), 95.5% on cART). Of these, 64 (25.3%) were asymptomatic neurocognitive impairment, 46 (18.2%) mild neurocognitive disorder, and 9 (3.6%) HIV-associated dementia. One-year incidence was high (37.2%, 95% CI 25.9 to 51.8), but some reversibility (17.6%, 95% CI 10.0-28.6 n = 16) was observed. CONCLUSIONS: HAND appear highly prevalent in older PLWH in this setting, where demographic profile differs markedly to high-income cohorts, and comorbidities are frequent. Incidence and reversibility also appear high. Future studies should focus on etiologies and potentially reversible factors in this setting.

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

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

Neurocognitive Disorders in HIV-positive Patients.

Human immunodeficiency viruses (HIV) associated neurocognitive disorders (HAND) encompasses a group of syndromes of various degrees of impairment in cognition and daily functioning of HIV positive individuals. Although the widespread use of highly active antiretroviral therapy (HAART) has drastically reduced the prevalence of severe form of HAND, like HIV associated dementia (HAD), the prevalence of HAND and associated morbidity remains high. OBJECTIVES: (1) To know the prevalence of HAND in HIV-infected patients of a multi-ethnic population. (2) To describe various types of neurocognitive impairment among patients of HAND and study the factors affecting HAND. STUDY DESIGN: This study was a cross-sectional descriptive study conducted on 250 HIV-positive patients in outpatient department (OPD) of a tertiary care center in Mumbai, conducted over a period of 12 months. Patients with HIV-1 attending the OPD and having a minimal formal education of 4 years were included. Patients with concomitant delirium, any known central nervous system (CNS) disorder, any psychiatric disorder, and pregnant females were excluded. Outcome measures-the test batteries used were (1) International HIV Dementia Scale (IHDS) and (2) Addenbrookes cognitive examination-revised (ACE-R) scale. RESULTS: Of 250 subjects studied, 55.6% (139) were males and 44.4 % (111) were females. The mean age of study population was 39.42 years. The mean years of education were 8.32 years. The mean duration of infection (diagnosis of HIV-positive state) was 64.49 months and the mean duration of HAART intake in our patients was 52.30 months. The mean cluster of differentiation 4 (CD4) counts of our subjects were 527.13 per cumm [standard deviation (SD) of 234.13]. The mean nadir CD4 counts were 224.35 per cumm (SD of 115.09). Using the ACE-R scale, the prevalence of HAND was 71.60%, of which 37.20% had an asymptomatic neurological impairment, 29.60% had mild cognitive dysfunction, and 4.80% had HAD. Memory, verbal fluency and visuospatial abilities were the most affected domains on the ACE-R and memory recall and psychomotor speed were affected more on the IHDS. The prevalence of HAND was more with increasing age (p = 0.020), lesser education (p < 0.00) and lesser nadir CD4 counts (p < 0.00). However, it was not affected by the duration of the disease and the current CD4 counts (p > 0.05). CONCLUSION: Human immunodeficiency viruses (HIV) associated neurocognitive disorders HAND is common in HIV-positive patients, most of whom are asymptomatic. Older patients with less education and severe disease, having lower nadir counts are at the highest risk of HAND. Memory, verbal fluency, and visuospatial abilities were the most commonly affected domains.

Endolysosome Localization of ERα Is Involved in the Protective Effect of 17α-Estradiol against HIV-1 gp120-Induced Neuronal Injury.

Neurotoxic HIV-1 viral proteins contribute to the development of HIV-associated neurocognitive disorder (HAND), the prevalence of which remains high (30-50%) with no effective treatment available. Estrogen is a known neuroprotective agent; however, the diverse mechanisms of estrogen action on the different types of estrogen receptors is not completely understood. In this study, we determined the extent to which and mechanisms by which 17α-estradiol (17αE2), a natural less-feminizing estrogen, offers neuroprotection against HIV-1 gp120-induced neuronal injury. Endolysosomes are important for neuronal function, and endolysosomal dysfunction contributes to HAND and other neurodegenerative disorders. In hippocampal neurons, estrogen receptor α (ERα) is localized to endolysosomes and 17αE2 acidifies endolysosomes. ERα knockdown or overexpressing an ERα mutant that is deficient in endolysosome localization prevents 17αE2-induced endolysosome acidification. Furthermore, 17αE2-induced increases in dendritic spine density depend on endolysosome localization of ERα. Pretreatment with 17αE2 protected against HIV-1 gp120-induced endolysosome deacidification and reductions in dendritic spines; such protective effects depended on endolysosome localization of ERα. In male HIV-1 transgenic rats, we show that 17αE2 treatment prevents the development of enlarged endolysosomes and reduction in dendritic spines. Our findings demonstrate a novel endolysosome-dependent pathway that governs the ERα-mediated neuroprotective actions of 17αE2, findings that might lead to the development of novel therapeutic strategies against HAND.SIGNIFICANCE STATEMENT Extranuclear presence of membrane-bound estrogen receptors (ERs) underlie the enhancing effect of estrogen on cognition and synaptic function. The estrogen receptor subtype ERα is present on endolysosomes and plays a critical role in the enhancing effects of 17αE2 on endolysosomes and dendritic spines. These findings provide novel insight into the neuroprotective actions of estrogen. Furthermore, 17αE2 protected against HIV-1 gp120-induced endolysosome dysfunction and reductions in dendritic spines, and these protective effects of 17αE2 were mediated via endolysosome localization of ERα. Such findings provide a rationale for developing 17αE2 as a therapeutic strategy against HIV-associated neurocognitive disorders.

Cerebrospinal Fluid Viral Load Across the Spectrum of Untreated Human Immunodeficiency Virus Type 1 (HIV-1) Infection: A Cross-Sectional Multicenter Study.

BACKGROUND: The aim of this large multicenter study was to determine variations in cerebrospinal fluid (CSF) HIV-RNA in different phases of untreated human immunodeficiency virus type 1 (HIV-1) infection and its associations with plasma HIV-RNA and other biomarkers. METHODS: Treatment naive adults with available CSF HIV-RNA quantification were included and divided into groups representing significant disease phases. Plasma HIV-RNA, CSF white blood cell count (WBC), neopterin, and albumin ratio were included when available. RESULTS: In total, 1018 patients were included. CSF HIV-RNA was in median (interquartile range [IQR]) 1.03 log10 (0.37-1.86) copies/mL lower than in plasma, and correlated with plasma HIV-RNA (r = 0.44, P < .01), neopterin concentration in CSF (r = 0.49, P < .01) and in serum (r = 0.29, P < .01), CSF WBC (r = 0.34, P < .01) and albumin ratio (r = 0.25, P < .01). CSF HIV-RNA paralleled plasma HIV-RNA in all groups except neuroasymptomatic patients with advanced immunodeficiency (CD4 < 200) and patients with HIV-associated dementia (HAD) or opportunistic central nervous system (CNS) infections. Patients with HAD had the highest CSF HIV-RNA (in median [IQR] 4.73 (3.84-5.35) log10 copies/mL). CSF > plasma discordance was found in 126 of 972 individuals (13%) and varied between groups, from 1% in primary HIV, 11% in neuroasymptomatic groups, up to 30% of patients with HAD. CONCLUSIONS: Our study confirms previous smaller observations of variations in CSF HIV-RNA in different stages of HIV disease. Overall, CSF HIV-RNA was approximately 1 log10 copies/mL lower in CSF than in plasma, but CSF discordance was found in a substantial minority of subjects, most commonly in patients with HAD, indicating increasing CNS compartmentalization paralleling disease progression.

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

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

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

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

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

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

High-resolution intracranial vessel wall imaging in cerebral viral infections evaluations.

PURPOSE: Vascular complications can be seen in various viral CNS infections. Variable neuro-imaging findings have been described in the literature elucidating the parenchymal changes with vascular involvement. Vessel wall imaging (VWI) can help to detect these vascular involvements. We aimed to describe the role and usefulness of VWI in the evaluation of various viral CNS infections. METHODS: In this prospective study, we included 15 cases of various diagnosed viral CNS infections (varicella, HIV encephalopathy, HSV encephalitis, Japanese encephalitis, dengue, COVID-19). VWI and time-of-flight MR angiography (TOF MRA) were included in imaging protocol. All cases were evaluated for the presence of cerebral parenchymal changes, vascular enhancement, and vascular stenosis. RESULTS: We found infarctions in all 5 cases of varicella, 1 case of HIV encephalopathy, and 1 case of COVID-19 encephalopathy. All these cases also showed vascular enhancement and stenosis on VWI. The rest of the cases, including 1 case of HIV encephalopathy, 3 cases of herpes encephalitis, 2 cases of dengue, and 2 cases of Japanese encephalitis did not have any vascular complication, and also did not show vascular enhancement or stenosis. CONCLUSION: VWI can be useful in the detection of vascular involvement in various viral infections of CNS which show a relatively higher cerebrovascular complication rate like varicella, HIV encephalopathy, and COVID-19. However, VWI may not be useful in the routine evaluation of other viral infections like herpes, dengue, and Japanese encephalitis, which have a very low rate of cerebrovascular complication rate.

Reductions in Gray Matter Linked to Epigenetic HIV-Associated Accelerated Aging.

A growing literature suggests a relationship between HIV-infection and a molecular profile of age acceleration. However, despite the widely known high prevalence of HIV-related brain atrophy and HIV-associated neurocognitive disorder (HAND), epigenetic age acceleration has not been linked to HIV-related changes in structural MRI. We applied morphological MRI methods to study the brain structure of 110 virally suppressed participants with HIV infection and 122 uninfected controls age 22-72. All participants were assessed for cognitive impairment, and blood samples were collected from a subset of 86 participants with HIV and 83 controls to estimate epigenetic age. We examined the group-level interactive effects of HIV and chronological age and then used individual estimations of epigenetic age to understand the relationship between age acceleration and brain structure. Finally, we studied the effects of HAND. HIV-infection was related to gray matter reductions, independent of age. However, using epigenetic age as a biomarker for age acceleration, individual HIV-related age acceleration was associated with reductions in total gray matter. HAND was associated with decreases in thalamic and hippocampal gray matter. In conclusion, despite viral suppression, accentuated gray matter loss is evident with HIV-infection, and greater biological age acceleration specifically relates to such gray matter loss.

Normative scores for select neuropsychological battery tests for the detection of HIV-associated neurocognitive disorder amongst Nigerians.

Background: The study aimed to derive socio-demographic-corrected norms for selecting neuropsychological (NP) battery tests for people living with HIV (PLWHIV) in Nigeria. This cross-sectional study was conducted amongst patients who attended the general outpatient clinic and junior staff of the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla. Aims and Objectives: To determine the normative scores for select neuropsychological battery test for the detection of neurocognitive disorder amongst Nigerians PLWHIV. A sample of 92 individuals received voluntary HIV testing. Methods: Eligibility criteria were being HIV negative, aged 18-64 years and formal education. We undertook a brief neuromedical examination to identify putative exclusion criteria. We sampled four NP tests covering seven cognitive domains and the motor speed component of the International HIV Dementia Scale (IHDS-MS). We presented the normative scores using statistics of mean, median, standard deviation (SD), kurtosis and skewness. Results: All the participants were Nigerians aged 18-64 years. Most (74.1%) of the participants were females. The mean and median ages of the participants were 42.6 ± 11.42 years and 44 years, respectively. The effect of gender on NP performance was limited to the digit span test (DST)-forwards, while education affected all expect IHDS-MS and DST-backwards. The cut-off scores for defining mild and severe impairment varied (moving from 1SD to 2SD) for all cognitive domains except for IHDS-MS and DST. Conclusions: With these preliminary normative scores, it will be easier to identify and classify the severity of neurocognitive impairment amongst PLWHIV in Nigeria, thus facilitating the goal of keeping HIV-associated dementia to a minimum. The lack of variability in the IHDS-MS and DST is unfavourable.

The delicate balance between neurotoxicity and neuroprotection in the context of HIV-1 infection.

Human immunodeficiency virus type-1 (HIV-1) causes a spectrum of neurological impairments, termed HIV-associated neurocognitive disorder (HAND), following the infiltration of infected cells into the brain. Even though the implementation of antiretroviral therapy reduced the systemic viral load, the prevalence of HAND remains unchanged and infected patients develop persisting neurological disturbances affecting their quality of life. As a result, HAND have gained importance in basic and clinical researches, warranting the need of developing new adjunctive treatments. Nonetheless, a better understanding of the molecular and cellular mechanisms remains necessary. Several studies consolidated their efforts into elucidating the neurotoxic signaling leading to HAND including the deleterious actions of HIV-1 viral proteins and inflammatory mediators. However, the scope of these studies is not sufficient to address all the complexity related to HAND development. Fewer studies focused on an altered neuroprotective capacity of the brain to respond to HIV-1 infection. Neurotrophic factors are endogenous polyproteins involved in neuronal survival, synaptic plasticity, and neurogenesis. Any defects in the processing or production of these crucial factors might compose a risk factor rendering the brain more vulnerable to neuronal damages. Due to their essential roles, they have been investigated for their diverse interplays with HIV-1 infection. In this review, we present a complete description of the neurotrophic factors involved in HAND. We discuss emerging concepts for their therapeutic applications and summarize the complex mechanisms that down-regulate their production in favor of a neurotoxic environment. For certain factors, we finally address opposing roles that rather lead to increased inflammation.

Proteomics and metabolomics of HIV-associated neurocognitive disorders: A systematic review.

HIV-associated neurocognitive disorders (HAND) are common features of the effect of human immunodeficiency virus (HIV)-1 within the central nervous system (CNS). The underlying neuropathophysiology of HAND is incompletely known. Furthermore, there are no markers to effectively predict or stratify the risk of HAND. Recent advancements in the fields of proteomics and metabolomics have shown promise in addressing these concerns, however, it is not clear if these approaches may provide new insight into pathways and markers related to HAND. We therefore conducted a systematic review of studies using proteomic and/or metabolomic approaches in the aim of identifying pathways or markers associated with neurocognitive impairment in people living with HIV (PLWH). Thirteen studies were eligible, including 11 proteomic and 2 metabolomic investigations of HIV-positive clinical samples (cerebrospinal fluid (CSF), brain tissue, and serum). Across varying profiling techniques and sample types, the majority of studies found an association of markers with neurocognitive function in PLWH. These included metabolic marker myo-inositol and proteomic markers superoxide dismutase, gelsolin, afamin, sphingomyelin, and ceramide. Certain markers were found to be dysregulated across various sample types. Afamin and gelsolin overlapped in studies of blood and CSF and sphingomyelin and ceramide overlapped in studies of CSF and brain tissue. The association of these markers with neurocognitive functioning may indicate the activity of certain pathways, potentially those related to the underlying neuropathophysiology of HAND.

Improvement of HIV-associated neurocognitive disorders after antiretroviral therapy intensification: the Neuro+3 study.

OBJECTIVES: Despite the effectiveness of antiretroviral (ARV) therapy to control HIV infection, HIV-associated neurocognitive disorders (HAND) remain frequent. The Neuro+3 study assessed the cognitive improvement associated with ARV intensification based on increased CNS penetration effectiveness (CPE) scoring ≥+3 and total CPE score ≥9. METHODS: Thirty-one patients, aged 18-65 years, with confirmed diagnosis of HAND and effective ARV therapy were included. The cognitive improvement was measured using Frascati three-stage classification and global deficit score (GDS) after 48 and 96 weeks of ARV intensification. Ultrasensitive HIV-RNA, neopterin, soluble CD14, CCL2, CXCL10, IL6, IL8 and NF-L were measured in plasma and cerebrospinal fluid at Day 0 (baseline), Week 48 (W48) and W96. RESULTS: The intensified ARV was associated with a median (IQR) CPE score increase from 6 (4-7) at baseline to 10 (9-11). From baseline to W96, the median (IQR) GDS decreased from 1.4 (0.8-2.2) to 1.0 (0.6-2.0) (P = 0.009); HAND classification improved from 2 to 1 HIV-associated dementia, 22 to 8 mild neurocognitive disorders, 7 to 17 asymptomatic neurocognitive impairment and 0 to 5 patients without any neurocognitive alterations (P = 0.001). In multivariable linear regression analysis, GDS improvement at W96 was significantly associated with CPE score ≥9 after intensification (P = 0.014), CD4 lymphocyte increase at W48 (P < 0.001) and plasma CXCL10 decrease at W96 (P = 0.001). CONCLUSIONS: In patients with HAND, a significant cognitive improvement was observed after the ARV intensification strategy, with a higher CPE score. Cognitive improvement was more often observed in the case of a switch of two drug classes, arguing for better control of CNS HIV immune activation.