Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer's Disease.

Long COVID (LongC) is associated with a myriad of symptoms including cognitive impairment. We reported at the beginning of the COVID-19 pandemic that neuronal-enriched or L1CAM+ extracellular vesicles (nEVs) from people with LongC contained proteins associated with Alzheimer's disease (AD). Since that time, a subset of people with prior COVID infection continue to report neurological problems more than three months after infection.

Blood Markers Show Neural Consequences of LongCOVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC).

Engineered induced-pluripotent stem cell derived monocyte extracellular vesicles alter inflammation in HIV humanized mice.

Aim: A peripheral inflammatory response can drive neuroinflammation in a number of infections including human immunodeficiency virus (HIV). Monocyte/macrophage (M/Mφ) activation is a hallmark of acute HIV infection and a source of chronic inflammation in a subset of HIV-infected individuals. We sought to decrease peripheral inflammation and M/Mφ transmigration after HIV infection by engineering extracellular vesicles (EV) to antagonize a microRNA (miR) associated with inflammation.

Using neuronal extracellular vesicles and machine learning to predict cognitive deficits in HIV.

Our objective was to predict HIV-associated neurocognitive disorder (HAND) in HIV-infected people using plasma neuronal extracellular vesicle (nEV) proteins, clinical data, and machine learning. We obtained 60 plasma samples from 38 women and 22 men, all with HIV infection and 40 with HAND. All underwent neuropsychological testing.

Hepatitis C Virus Cure in Human Immunodeficiency Virus Coinfection Dampens Inflammation and Improves Cognition Through Multiple Mechanisms.

Background: Chronic inflammation in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection increases cognitive impairment. With newer, direct-acting antiviral therapies for HCV, our objective was to determine whether chronic inflammation would be decreased and cognition improved with HCV sustained viral response (SVR) in coinfection.

Methods: We studied 4 groups longitudinally: 7 HCV-monoinfected and 12 HIV/HCV-coinfected persons before and after treatment for HCV, 12 HIV-monoinfected persons, and 9 healthy controls.

Inflammatory Mechanisms and Cascades Contributing to Neurocognitive Impairment in HIV/AIDS.

Neurocognitive impairment caused by chronic human immunodeficiency virus (HIV) infection is a growing concern. In this chapter we discuss the inflammatory mechanisms underlying the pathology of asymptomatic and mild neurocognitive impairment in the context of antiretroviral therapy. We discuss the role of HIV, viral proteins, and virally infected cells on the development of neuroinflammation and the effect of viral proteins on the cells of the central nervous system.

Profile of neuronal exosomes in HIV cognitive impairment exposes sex differences.

Objective: To use plasma neuron-derived exosomes (NDEs) to detect proteins that diagnose HIV-associated neurocognitive disorders (HAND). To compare NDE cargo from HAND with Alzheimer's disease.

Design: Eighty plasma samples were assayed including men (n = 29) and women (n = 51) with and without HAND.

Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer's disease.

Fluid biomarkers for cognitive impairment have the advantage of being relatively noninvasive and capable of monitoring neuronal and other brain cell health in real time. Biomarkers can predict the onset of dementing illness, but also correlate with cognition in a dynamic way allowing us to follow treatment responses and determine brain recovery. Chronic HIV infection causes cognitive impairment in a subset of individuals suggesting "premature aging.

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.

Immune activated monocyte exosomes alter microRNAs in brain endothelial cells and initiate an inflammatory response through the TLR4/MyD88 pathway.

The host immune response is critical for homeostasis; however, when chronic low level activation of the immune response with or without the driver continues, a cascade of events can trigger immunological dysfunction. Monocytes are key peripheral sensors of the immune response and their activation is instrumental in the development of cognitive impairment. Here, we show that monocytes activated by interferon alpha, lipopolysaccharide or a combination of both generate exosomes carrying significantly altered microRNA profiles compared to non-activated monocytes.

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

Extracellular vesicles (EVs) are globular, membrane bound nanovesicles (30-100 nm range) that are shed both during normal cellular functioning and under pathological conditions by most cell types. In recent years, there has been significant interest in the study of these vesicles as conduits for the delivery of information between cells from both analogous and disparate tissues. Their ability to carry specialised cargo including signalling mediators, proteins, messenger RNA and miRNAs characterises these vesicles as primary facilitators of cell-to-cell communication and regulation.

Blood neuron-derived exosomes as biomarkers of cognitive impairment in HIV.

Objective: To investigate proteins associated with neuronal damage in plasma neuron-derived exosomes (NDE) of HIV-infected study participants as a liquid biomarker for cognitive impairment.

Methods: Plasma NDE were isolated using precipitation and immunoadsorption with antibody to a cell surface-specific neuronal marker. Total exosomes and NDE were enumerated, characterized, and proteins extracted and targets quantified by ELISA.

Monocyte exosomes induce adhesion molecules and cytokines via activation of NF-κB in endothelial cells.

HIV-infected individuals have activated monocytes with an IFNα phenotype and elevated levels of circulating LPS. These individuals also have a risk of premature cardiovascular disease. The effect of activated monocyte exosomes (Exos) on endothelial cells is unknown.

Human plasma platelet-derived exosomes: effects of aspirin.

Platelet-derived exosomes mediate platelet atherogenic interactions with endothelial cells and monocytes. A new method for isolation of plasma platelet-derived exosomes is described and used to examine effects of aging and aspirin on exosome cargo proteins. Exosome secretion by purified platelets in vitro did not increase after exposure to thrombin or collagen, as assessed by exosome counts and quantification of the CD81 exosome marker.

Modulation of cellular function through immune-activated exosomes.

Extracellular vesicles classified as exosomes, microvesicles, or apoptotic bodies based on size are shed from most cells under normal as well as pathological conditions. They are released into the surrounding milieu, including plasma, urine, saliva, and tissues. Exosomes are highly enriched in microRNAs (miRs), which function in recipient cells by regulating posttranscriptional processing of targeted genes.

Cognitive consequences of a sustained monocyte type 1 IFN response in HIV-1 infection.

With successful antiretroviral therapy, HIV-1-infected subjects can achieve undetectable peripheral viral loads and immune homeostasis. However, in a subset of individuals on therapy, peripheral monocytes have a gene expression profile characteristic of a type 1 interferon α (IFN) response. This type 1 IFN response correlates with a number of pathogenic conditions including neural cell injury and in combination with HCV infection, cognitive impairment.

Monocyte activation from interferon-α in HIV infection increases acetylated LDL uptake and ROS production.

Atherosclerosis is an inflammatory disease that is accelerated in human immunodeficiency virus (HIV) infection. Individuals with HIV infection have an activated type I interferon (IFN) monocyte phenotype, which may enhance uptake of modified low-density lipoprotein (LDL) thereby initiating a prefoam cell pathology and recruitment into atherosclerotic plaques. In a sampling of HIV-infected subjects, an increase in monocyte activation genes, MX1 and CXCL10, correlated with monocyte expression of the scavenger receptor A (SR-A), a major receptor for lipid uptake and foam cell formation.

Exosomes as mediators of neuroinflammation.

Exosomes are membrane-bound nanovesicles that are shed by cells of various lineages under normal as well as pathological conditions. Previously thought to be 'extracellular debris', exosomes have recently generated immense interest following their discovery as mediators of intercellular communication by delivering functional proteins, mRNA transcripts as well as miRNAs to recipient cells. Although suggested to primarily serve as signaling organelles which also remove unwanted cellular components in the brain, accumulating evidence suggests that exosomes can also significantly contribute to the development of several neuropathologies.

Monocyte activation in HIV/HCV coinfection correlates with cognitive impairment.

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) effectively prolongs life and significantly improves immune function.

Global NeuroAIDS roundtable.

In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the "Global NeuroAIDS Roundtable" in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research.

Differential cognitive impairment in HCV coinfected men with controlled HIV compared to HCV monoinfection.

Background: Individuals infected with both HIV and hepatitis C virus (HCV) have shown impaired performance on different neuropsychological (NP) tests; however, whether coinfected individuals with controlled HIV and minimal liver damage in the era of antiretroviral therapy have impairment is understudied.

Methods: Nineteen HCV monoinfected, 17 HIV/HCV coinfected, and 17 control male participants were evaluated for depression, attention, executive function, information processing, fine motor speed, and verbal/visual learning/memory. Eleven controls and 14 HIV monoinfected participants with controlled viral load from a previous study were also included for comparison.

A peripheral monocyte interferon phenotype in HIV infection correlates with a decrease in magnetic resonance spectroscopy metabolite concentrations.

Objective: In spite of effective antiretroviral therapy (ART), cognition is impaired in upwards of 35% of the HIV-infected population. We investigated a possible link between peripheral immune activation and brain metabolite concentrations.

Design And Methods: Thirty-five HIV-seropositive (HIV+) and eight HIV-seronegative adults were recruited to this cross-sectional study.