Transformation of brain myeloid cell populations by SIV in rhesus macaques revealed by multiomics.

The primary immune constituents in the brain, microglia and macrophages, are the target for HIV in people and simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological dysfunction, known as HIV-associated neurocognitive disorder (HAND). Given the gaps in our knowledge on how these cells respond in vivo to CNS infection, we perform single-cell multiomic sequencing, including gene expression and ATAC-seq, on myeloid cells from the brains of rhesus macaques with SIV-induced encephalitis (SIVE) as well as uninfected controls.

Transformation of brain myeloid cell populations by SIV in rhesus macaques revealed by multiomics.

The primary immune constituents in the brain, microglia and macrophages, are the target for HIV in people and simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological dysfunction, known as HIV-associated neurocognitive disorder (HAND). Given the gaps in our knowledge on how these cells respond in vivo to CNS infection, we performed single-cell multiomic sequencing, including gene expression and ATAC-seq, on myeloid cells from the brains of rhesus macaques with SIV-induced encephalitis (SIVE) as well as uninfected controls.

Microglia and macrophages alterations in the CNS during acute SIV infection: A single-cell analysis in rhesus macaques.

Human Immunodeficiency Virus (HIV) is widely acknowledged for its profound impact on the immune system. Although HIV primarily affects peripheral CD4 T cells, its influence on the central nervous system (CNS) cannot be overlooked. Within the brain, microglia and CNS-associated macrophages (CAMs) serve as the primary targets for HIV and the simian immunodeficiency virus (SIV) in nonhuman primates.

Pink1/Parkin deficiency alters circulating lymphocyte populations and increases platelet-T cell aggregates in rats.

Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Pink1 and Parkin are proteins that function together in mitochondrial quality control, and when they carry loss-of-function mutations lead to familial forms of PD. While much research has focused on central nervous system alterations in PD, peripheral contributions to PD pathogenesis are increasingly appreciated.

Microglia and macrophages alterations in the CNS during acute SIV infection: a single-cell analysis in rhesus macaques.

Human Immunodeficiency Virus (HIV) is widely acknowledged for its profound impact on the immune system. Although HIV primarily affects peripheral CD4 T cells, its influence on the central nervous system (CNS) cannot be overlooked. Within the brain, microglia and CNS-associated macrophages (CAMs) serve as the primary targets for HIV, as well as for the simian immunodeficiency virus (SIV) in nonhuman primates.

Parkinson's disease relevant pathological features are manifested in male Pink1/Parkin deficient rats.

Animal disease models are important for neuroscience experimentation and in the study of neurodegenerative disorders. The major neurodegenerative disorder leading to motor impairments is Parkinson's disease (PD). The identification of hereditary forms of PD uncovered gene mutations and variants, such as loss-of-function mutations in PTEN-induced putative kinase 1 (Pink1) and the E3 ubiquitin ligase Parkin, two proteins involved in mitochondrial quality control, that could be harnessed to create animal models.

Morphine suppresses peripheral responses and transforms brain myeloid gene expression to favor neuropathogenesis in SIV infection.

The twin pandemics of opioid abuse and HIV infection can have devastating effects on physiological systems, including on the brain. Our previous work found that morphine increased the viral reservoir in the brains of treated SIV-infected macaques. In this study, we investigated the interaction of morphine and SIV to identify novel host-specific targets using a multimodal approach.

Deprenyl reduces inflammation during acute SIV infection.

In the era of antiretroviral therapy, inflammation is a central factor in numerous HIV-associated comorbidities, such as cardiovascular disease, cognitive impairment, and neuropsychiatric disorders. This highlights the value of developing therapeutics that both reduce HIV-associated inflammation and treat associated comorbidities. Previous research on monoamine oxidase inhibitors (MAOIs) suggests this class of drugs has anti-inflammatory properties in addition to neuropsychiatric effects.

Physiologically Relevant Concentrations of Dolutegravir, Emtricitabine, and Efavirenz Induce Distinct Metabolic Alterations in HeLa Epithelial and BV2 Microglial Cells.

Microglia, the resident brain phagocytes, likely play a key role in human immunodeficiency virus (HIV) infection of the central nervous system (CNS) and subsequent neuropathogenesis; however, the nature of the infection-induced changes that yield damaging CNS effects and the stimuli that provoke microglial activation remains elusive, especially in the current era of using antiretroviral (ARV) drugs for ARV therapy (ART). Altered microglial metabolism can modulate cellular functionality and pathogenicity in neurological disease. While HIV infection itself alters brain energy metabolism, the effect of ARV drugs, particularly those currently used in treatment, on metabolism is understudied.

Cryopreservation of microglia enables single-cell RNA sequencing with minimal effects on disease-related gene expression patterns.

Microglia play a key role in brain development, normal homeostasis, and neurodegenerative disorders. Single-cell technologies have led to important findings about microglia, with many animal model studies using single-cell RNA sequencing (scRNA-seq), whereas most human specimen studies using archived frozen brains for single-nucleus RNA sequencing (snRNA-seq). However, microglia compose a small proportion of the total brain tissue; snRNAseq depletes expression of microglia activation genes that characterize many diseases.

Applying the RatWalker System for Gait Analysis in a Genetic Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. Gait abnormalities, including decreased arm swing, slower walking speed, and shorter steps are common in PD patients and appear early in the course of disease. Thus, the quantification of motor patterns in animal models of PD will be important for phenotypic characterization during disease course and upon therapeutic treatment.

Chronic morphine administration differentially modulates viral reservoirs in SIVmac251 infected rhesus macaque model.

HIV persists in cellular reservoirs despite effective combined antiretroviral therapy (cART) and there is viremia flare up upon therapy interruption. Opioids modulate the immune system and suppress antiviral gene responses, which significantly impact people living with HIV (PLWH). However, the effect of opioids on viral reservoir dynamics remain elusive.

Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages, Alters Metabolic Pathways, and Elevates Cell Death Pathways: A Single-Cell Analysis.

Both substance use disorder and HIV infection continue to affect many individuals. Both have untoward effects on the brain, and the two conditions often co-exist. In the brain, macrophages and microglia are infectable by HIV, and these cells are also targets for the effects of drugs of abuse, such as the psychostimulant methamphetamine.

Deletion of DJ-1 in rats affects protein abundance and mitochondrial function at the synapse.

DJ-1 is a multifunctional protein affecting different biological and cellular processes. In addition, DJ-1 has roles in regulating mitochondrial function. Loss-of-function mutations in DJ-1 were found to cause an autosomal recessive form of Parkinson's disease.

A year-long extended release nanoformulated cabotegravir prodrug.

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles.

Creation of a long-acting rilpivirine prodrug nanoformulation.

Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative, long-acting (LA) antiretrovirals can sustain therapeutic drug concentrations in blood for prolonged time periods. The success of recent clinical trials for LA parenteral cabotegravir and rilpivirine highlight the emergence of these new therapeutic options.

Quantitative Proteomics of Presynaptic Mitochondria Reveal an Overexpression and Biological Relevance of Neuronal MitoNEET in Postnatal Brain Development.

Although it has been recognized that energy metabolism and mitochondrial structure and functional activity in the immature brain differs from that of the adult, few studies have examined mitochondria specifically at the neuronal synapse during postnatal brain development. In this study, we examined the presynaptic mitochondrial proteome in mice at postnatal day 7 and 42, a period that involves the formation and maturation of synapses. Application of two independent quantitative proteomics approaches - SWATH-MS and super-SILAC - revealed a total of 40 proteins as significantly differentially expressed in the presynaptic mitochondria.

Pharmacokinetic testing of a first-generation cabotegravir prodrug in rhesus macaques.

: Long-acting antiretrovirals can improve therapy and prevention for HIV-1 infection. Current long-acting cabotegravir (CAB LAP) can be administered every other month. Previously, we demonstrated that a myristoylated CAB prodrug encased in poloxamer 407 provided extended plasma drug concentrations.

Correction: MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease.

[This corrects the article DOI: 10.1371/journal.ppat.

Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution.

Rationale: Long-acting slow effective release antiretroviral therapy (LASER ART) was developed to improve patient regimen adherence, prevent new infections, and facilitate drug delivery to human immunodeficiency virus cell and tissue reservoirs. In an effort to facilitate LASER ART development, "multimodal imaging theranostic nanoprobes" were created. These allow combined bioimaging, drug pharmacokinetics and tissue biodistribution tests in animal models.

Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques.

A nanoformulated myristoylated dolutegravir prodrug (NMDTG) was prepared using good laboratory practice protocols. Intramuscular injection of NMDTG (118 ± 8 mg/ml, 25.5 mg of DTG equivalents/kg of body weight) to three rhesus macaques led to plasma DTG levels of 86 ± 12 and 28 ± 1 ng/ml on days 35 and 91, respectively.

Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles.

Long-acting parenteral (LAP) antiretroviral drugs have generated considerable interest for treatment and prevention of HIV-1 infection. One new LAP is cabotegravir (CAB), a highly potent integrase inhibitor, with a half-life of up to 54 days, allowing for every other month parenteral administrations. Despite this excellent profile, high volume dosing, injection site reactions and low body fluid drug concentrations affect broad use for virus infected and susceptible people.

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals.

The use of antiretroviral (ARV) drugs with central nervous system (CNS) penetration effectiveness (CPE) may be useful in the treatment of HIV-associated neurocognitive disorder (HAND) as well as targeting a CNS reservoir in strategies to achieve a functional cure for HIV. However, increased cognitive deficits are linked to at least one of these drugs (efavirenz). As mitochondrial dysfunction has been found with a number of ARVs, and as such can affect neuronal function, the objective of this study was to assess the effects of ARV with high CPE for toxicological profiles on presynaptic nerve terminal energy metabolism.