Developments in Neuroprotection for HIV-Associated Neurocognitive Disorders (HAND).
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ABSTRACT: 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.
SUBMITTER: Kolson DL
PROVIDER: S-EPMC9305687 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Despite an augmented research effort and scale-up of highly active antiretroviral therapy, a high prevalence of HIV-1-associated neurocognitive disorders (HAND) persists in the HIV-infected population. Nearly 50 % of all HIV-1-infected individuals suffer from a neurocognitive disorder due to neural and synaptodendritic damage. Challenges in HAND research, including limited availability of brain tissue from HIV patients, variation in HAND study protocols, and virus genotyping inconsistency and errors, however, have resulted in studies with insufficient power to delineate molecular mechanisms underlying HAND pathogenesis. There exists, therefore, a great need for a reliable and centralized resource specific to HAND research, particularly for epidemiological study and surveillance in resource-limited countries where severe forms of HAND persist.To address the aforementioned imperative need, here we present the HAND Database, a resource containing well-curated and up-to-date HAND virus information and associated clinical and epidemiological data. This database provides information on 5,783 non-redundant HIV-1 sequences from global HAND research published to date, representing a total of 163 unique individuals that have been assessed for HAND. A user-friendly interface allows for flexible searching, filtering, browsing, and downloading of data. The most comprehensive database of its kind, the HAND Database not only bolsters current HAND research by increasing sampling power and reducing study biases caused by protocol variation and genotyping inconsistency, it allows for comparison between HAND studies across different dimensions. Development of the HAND Database has also revealed significant knowledge gaps in HIV-driven neuropathology. These gaps include inadequate sequencing of viral genes beyond env, lack of HAND viral data from HIV epidemiologically important regions including Asian and Sub-Saharan African countries, and biased sampling toward the male gender, all factors that impede efforts toward providing an improved quality of life to HIV-infected individuals, and toward elimination of viruses in the brain.Our aim with the HAND database is to provide researchers in both the HIV and neuroscience fields a comprehensive and rigorous data source toward better understanding virus compartmentalization and to help in design of improved strategies against HAND viruses. We also expect this resource, which will be updated on a regular basis, to be useful as a reliable reference for further HAND epidemiology studies. The HAND Database is freely available and accessible online at http://www.handdatabase.org .
| S-EPMC4625622 | biostudies-literature
Project description:Advances in the treatment of the human immunodeficiency virus (HIV) have dramatically improved survival rates over the past 10 years, but HIV-associated neurocognitive disorders (HAND) remain highly prevalent and continue to represent a significant public health problem. This review provides an update on the nature, extent, and diagnosis of HAND. Particular emphasis is placed on critically evaluating research within the realm of cognitive neuropsychology that aims to elucidate the component processes of HAND across the domains of executive functions, motor skills, speeded information processing, episodic memory, attention/working memory, language, and visuoperception. In addition to clarifying the cognitive mechanisms of HAND (e.g., impaired cognitive control), the cognitive neuropsychology approach may enhance the ecological validity of neuroAIDS research and inform the development of much needed novel, targeted cognitive and behavioral therapies.
| S-EPMC2690857 | biostudies-other
Project description:To estimate the prevalence of HIV-associated neurocognitive disorders (HAND) among HIV patients in a multiethnic South Asian population, describe the pattern of neurocognitive impairment in HAND and the factors associated with HAND.A cross-sectional survey of HIV-positive outpatients and inpatients.The sole referral centre for HIV/AIDS treatment in Singapore.Inclusion criteria were HIV positive, age between 21 and 80 years old and at least 3 years of education. Exclusion criteria included concomitant delirium, serious systemic disease or major psychiatric illness. 265 patients did not meet criteria or declined to participate. The final sample size was 132.The primary outcome measure was cognitive impairment based on performance on the Montreal Cognitive Assessment, International HIV Dementia Scale and Instrumental Activities of Daily Living. The secondary outcome measure was the classification of impairment based on the 2007 updated research nosology for HAND.The prevalence of HAND was 22.7% of which 70% (15.9% of total) were asymptomatic neurocognitive impairment, 23.3% (5.3% of total) were mild neurocognitive disorder and 6.7% (1.5% of total) were HIV-associated dementia. Increasing age (OR 1.104, 95% CI 1.054 to 1.155, p<0.001), less education (OR 0.78, 95% CI 0.69 to 0.89, p<0.001) and low baseline CD4 count (OR 0.15, 95% CI 0.03 to 0.74, p=0.019) were associated with HAND. Delayed recall, language and abstract thinking were the domains most commonly affected, but impairment in visuospatial ability (RC 3.013, 95% CI 1.954 to 4.073, p<0.001) and attention (RC 2.205, 95% CI 1.043 to 3.367, p<0.001) were most strongly associated with HAND.HAND is common among HIV patients in a South Asian sample, most of whom are asymptomatic. Older patients with less education and severe illness at diagnosis are at highest risk of HAND. Delayed recall is most commonly affected, but visuospatial dysfunction is most strongly associated with prevalent HAND.
| S-EPMC3282293 | biostudies-other
Project description: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.
| S-EPMC4313542 | biostudies-literature
Project description:BackgroundThe prevalence of HIV-associated neurocognitive disorders (HAND), especially HIV-associated dementia (HAD) is influenced by several risk factors. The prevalence as well as risk factors for HAD are not well known in sub-Saharan Africa (SSA). We have shown that the International HIV Dementia Scale (IHDS) is a useful screening tool for HAND in Yaoundé [Njamnshi AK, Djientcheu VdP, Fonsah JY, Yepnjio FN, Njamnshi DM, Muna WFT. The IHDS is a useful screening tool for HAD/Cognitive Impairment in HIV-infected adults in Yaoundé-Cameroon. Journal of Acquired Immune Deficiency Syndromes 2008;49(4):393-397], but no study in Cameroon has yet investigated the risk factors for HAND or HAD.Patients and methodsA cross-sectional study was conducted in Yaoundé, the capital of Cameroon from September to December 2006. One hundred and eighty-five HIV-positive subjects were included. Diagnosis of HAND was done using the IHDS with a score < or = 10 considered as abnormal. Age, sex, level of education, IV drug use, body mass index (BMI), CDC clinical stage, CD4 counts, hemoglobin levels, administration of highly active antiretroviral therapy (HAART) and type of regimen used, were considered in univariate analysis, with level of significance set at P < or = 0.05. A binary logistic regression was used to determine independent risk factors.ResultsThe following factors were independent predictors of HAND: advanced clinical stage (OR=7.43, P=0.001), low CD4 count especially CD4 < or = 200 cells/microL (OR=4.88, P=0.045) and low hemoglobin concentration (OR=1.16, P=0.048).ConclusionThis first study of the risk factors for HAND in Yaoundé-Cameroon shows findings similar to those described in other studies. These results call for rapid action by policy makers to include HAND prevention strategies such as providing early universal access to HAART based on these risk factors, in the management of HIV patients at risk of HAND in resource-limited settings of SSA like ours.
| S-EPMC4906943 | biostudies-literature
Project description:The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to (1) evaluate the HIV-1 mRNA distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat, and (2) validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 h of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results that are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments and synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway and/or neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.
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Project description:PurposeThirty to 50% of HIV patients develop HIV-associated neurocognitive disorders (HANDs) despite combined antiretroviral therapy. HIV-1-infected macrophages release viral and cellular proteins that induce neuronal degeneration and death. We hypothesize that changes in the macrophage secretome of HIV-1 seropositive patients with HAND may dissect proteins related to neurotoxicity.Experimental designMonocyte-derived macrophages (MDMs) were isolated from the peripheral blood of 12 HIV+ and four HIV- women characterized for neurocognitive function. Serum-free MDM supernatants were collected for protein isolation and quantification with iTRAQ® labeling. Protein identification was performed using a LTQ Orbitrap Velos mass spectrometer and validated in MDM supernatants and in plasma using ELISA.ResultsThree proteins were different between normal cognition (NC) and asymptomatic neurocognitive disorders (ANI), six between NC and HIV-associated dementia (HAD), and six between NC and HAD. Among these, S100A9 was decreased in plasma from patients with ANI, and metalloproteinase 9 was decreased in the plasma of all HIV+ patients regardless of cognitive status, and was significantly reduced in supernatant of MDM isolated from patients with ANI.Conclusions and clinical relevanceS100A9 and metalloproteinase 9 have been associated with inflammation and cognitive impairment, and therefore represent potential targets for HAND treatment.
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Project description:While combination antiretroviral therapy (cART) has successfully increased the lifespan of individuals infected with HIV, a significant portion of this population remains affected by HIV-associated neurocognitive disorder (HAND). C-C chemokine receptor 5 (CCR5) has been well studied in immune response and as a co-receptor for HIV infection. HIV-infected (HIV+) patients experienced mild to significant amelioration of cognitive function when treated with different CCR5 antagonists, including maraviroc and cenicriviroc. Consistent with clinical results, Ccr5 knockout or knockdown rescued cognitive deficits in HIV animal models, with mechanisms of reduced microgliosis and neuroinflammation. Pharmacologic inhibition of CCR5 directly improved cerebral and hippocampal neuronal plasticity and cognitive function. By summarizing the animal and human studies of CCR5 in HIV-associated cognitive deficits, this review aims to provide an overview of the mechanistic role of CCR5 in HAND pathophysiology. This review also discusses the addition of CCR5 antagonists, such as maraviroc, to cART for targeted prevention and treatment of cognitive impairments in patients infected with HIV.
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Project description:Alzheimer's disease (AD) is characterized by progressive dysfunction of memory and higher cognitive functions with abnormal accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles throughout cortical and limbic brain regions. At present no curative treatment is available, and research focuses on drugs for slowing disease progression or providing prophylaxis. Withania somnifera (WS) also known as 'ashwagandha' is used widely in Ayurvedic medicine as a nerve tonic and memory enhancer. However, there is a paucity of data on the potential neuroprotective effects of W.somnifera against β-Amyloid (1-42)-induced neuropathogenesis. In the present study, we have tested the neuroprotective effects of methanol:Chloroform (3:1) extract of ashwagandha against β-amyloid induced toxicity and HIV-1Ba-L (clade B) infection using a human neuronal SK-N-MC cell line. Our results showed that β-amyloid induced cytotoxic effects in SK-N-MC cells as shown by decreased cell growth when tested individually. Also, confocal microscopic analysis showed decreased spine density, loss of spines and decreased dendrite diameter, total dendrite and spine area in clade B infected SK-N-MC cells compared to uninfected cells. However, when ashwagandha was added to β-amyloid treated and HIV-1 infected samples, the toxic effects were neutralized. Further, the MTT cell viability assays and the peroxisome proliferator-activated receptor-γ (PPARγ) levels supported these observations indicating the neuroprotective effect of WS root extract against β-amyloid and HIV-1Ba-L (clade B) induced neuro-pathogenesis.
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Project description:The current use of combined antiretroviral therapy (cART) is leading to a significant decrease in deaths and comorbidities associated with human immunodeficiency virus type 1 (HIV-1) infection. Nonetheless, none of these therapies can extinguish the virus from the long-lived cellular reservoir, including microglia, thereby representing an important obstacle to curing HIV. Microglia are the foremost cells infected by HIV-1 in the central nervous system (CNS) and are believed to be involved in the development of HIV-1-associated neurocognitive disorder (HAND). At present, the pathological mechanisms contributing to HAND remain unclear, but evidence suggests that removing these infected cells from the brain, as well as obtaining a better understanding of the specific molecular mechanisms of HIV-1 latency in these cells, should help in the design of new strategies to prevent HAND and achieve a cure for these diseases. The goal of this review was to study the current state of knowledge of the neuropathology and research models of HAND containing virus susceptible target cells (microglial cells) and potential pharmacological treatment approaches under investigation.
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