Microwave &amp; magnetic proteomics of macrophages from patients with HIV-associated cognitive impairment

Cantres-Rosario, Yisel M.; Acevedo-Mariani, Frances M.; Pérez-Laspiur, Juliana; Haskins, William E.; Plaud, Marines; Cantres-Rosario, Yadira M.; Skolasky, Richard L.; Méndez-Bermúdez, Israel; Wojna, Valerie; Meléndez, Loyda M.

doi:10.1371/journal.pone.0181779

Cited by 4 publications

(4 citation statements)

References 68 publications

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“…However, this is the first study suggesting that HIV-1 infection in macrophages promotes lysosomal exocytosis and that it is attenuated by JWH-133 treatment, which is a significant advance for future treatment modalities. In a previous TMT-based proteomics study, we observed an increased CATB expression in macrophages from HIV-seropositive women with impaired cognition compared to asymptomatically impaired HIV-seropositive woman after 7 days in culture, suggesting that CATB protein expression is linked to cognitive impairment in HIV-seropositive women [ 96 ]. In this study, we found that intracellular CATB levels were increased by HIV-1 infection and decreased by JWH-133 treatment.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages

Rosario-Rodríguez,

Cantres-Rosario,

Carrasquillo-Carrión

et al. 2024

IJMS

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HIV-associated neurocognitive disorders (HAND) affect 15–55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain tissues of women with HAND. Increased CATB release from HIV-infected MDM leads to neurotoxicity, and their secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, CATB secretion, and neurotoxicity from HIV-infected MDM, but the mechanisms are not entirely understood. We hypothesized that HIV-1 infection upregulates the expression of proteins associated with oxidative stress and that a CB2R agonist could reverse these effects. MDM were isolated from healthy women donors (n = 3), infected with HIV-1ADA, and treated with JWH-133. After 13 days post-infection, cell lysates were labeled by Tandem Mass Tag (TMT) and analyzed by LC/MS/MS quantitative proteomics bioinformatics. While HIV-1 infection upregulated CATB, NF-κB signaling, Nrf2-mediated oxidative stress response, and lysosomal exocytosis, JWH-133 treatment downregulated the expression of the proteins involved in these pathways. Our results suggest that JWH-133 is a potential alternative therapy against HIV-induced neurotoxicity and warrant in vivo studies to test its potential against HAND.

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Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages

Rosario-Rodríguez,

Cantres-Rosario,

Carrasquillo-Carrión

et al. 2024

IJMS

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“…MOR increased expression of MICOS subunit MIC26 and Sorting and assembly machinery component 50 homolog (SAMM50), which maintain cristae morphology essential for proper ETC function and shunting of metabolites (Figure S3). 73,74 Other potential sources of increased ROS include phagocyte oxidative bursts and reduced ROS neutralization 21,75 …”

Section: Discussionmentioning

confidence: 99%

“…73,74 Other potential sources of increased ROS include phagocyte oxidative bursts and reduced ROS neutralization. 21,75 MOR significantly increased expression of CD38, a key enzyme that creates nicotinic acid adenine dinucleotide phosphate using NAD + (Figure 4A). This is implicated in metabolic aging since cells continuously need NAD + reserves to support glycolysis and the citric acid cycle.…”

Section: Discussionmentioning

confidence: 99%

Morphine disrupts macrophage functions even during HIV infection

Barbaro

Jaureguiberry‐Bravo

Berman

2022

Journal of Leukocyte Biology

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HIV‐associated neurocognitive impairment (HIV‐NCI) is a debilitating comorbidity that reduces quality of life in 15–40% of people with HIV (PWH) taking antiretroviral therapy (ART). Opioid use has been shown to increase neurocognitive deficits in PWH. Monocyte‐derived macrophages (MDMs) harbor HIV in the CNS even in PWH on ART. We hypothesized that morphine (MOR), a metabolite of heroin, further dysregulates functional processes in MDMs to increase neuropathogenesis. We found that, in uninfected and HIV‐infected primary human MDMs, MOR activates these cells by increasing phagocytosis and up‐regulating reactive oxygen species. Effects of MOR on phagocytosis were dependent on μ‐opioid receptor activity and were mediated, in part, by inhibited lysosomal degradation of phagocytized substrates. All results persisted when cells were treated with both MOR and a commonly prescribed ART cocktail, suggesting minimal impact of ART during opioid exposure. We then performed mass spectrometry in HIV‐infected MDMs treated with or without MOR to determine proteomic changes that suggest additional mechanisms by which opioids affect macrophage homeostasis. Using downstream pathway analyses, we found that MOR dysregulates ER quality control and extracellular matrix invasion. Our data indicate that MOR enhances inflammatory functions and impacts additional cellular processes in HIV‐infected MDMs to potentially increases neuropathogenesis in PWH using opioids.

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“…Previously, we demonstrated that HIV-infected women with cognitive impairment have higher levels of soluble insulin receptor (sIR) in plasma and cerebrospinal fluid (CSF), when compared to HIV-negative women, as well as lower levels of insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation in plasma ( 13 – 15 ). Metabolic enzymes are also altered in patients with HAND ( 16 , 17 ). The mechanisms responsible for the secretion of the full-length sIR to the plasma of HIV-infected women with HAND remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Soluble Insulin Receptor Levels in Plasma, Exosomes, and Urine and Its Association With HIV-Associated Neurocognitive Disorders

et al. 2022

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BackgroundHIV-associated neurocognitive disorders (HAND) are one of the HIV-associated comorbidities affecting 20–50% of the people with HIV (PWH) infection. We found that the soluble insulin receptor (sIR) levels in plasma and cerebrospinal fluid (CSF) were significantly higher in HIV-infected women. The mechanism of sIR release into the plasma remains unknown, but the detection of the sIR in exosomes may uncover novel mechanisms of sIR secretion from HIV-infected cells and its contribution to HIV disease progression and HAND development. Quantification of sIR in urine may represent a less invasive and more accessible diagnostic tool. Our objective was to quantify sIR levels in plasma, plasma-derived exosomes, and urine, and evaluate their association with HAND and renal function.MethodsWe measured full-length sIR in the plasma and urine of 38 controls and 76 HIV-infected women by ELISA, and sIR, HIV-1 Tat, and reactive oxygen species (ROS) in exosomes by flow cytometry.ResultsPlasma and exosomes with sIR were significantly higher in HIV-infected women when compared with controls and HAND. Exosomal sIR positively correlated with exosomal ROS and exosomal HIV-1 Tat in HIV-infected women. Exosomal ROS was significantly higher in HIV-infected women with more symptomatic cognitive impairment. Plasma-derived exosomes exhibited significantly higher levels of astrocyte (GFAP) and neuronal (L1CAM) markers in HIV-infected women, confirming the presence of circulating CNS-derived exosomes in the blood of HIV-infected women. Urine sIR positively correlated with eGFR in controls, but not in HIV-infected women, regardless there was no significant difference in renal function as determined by the estimated glomerular filtration rate (eGFR, p = 0.762). In HIV-infected women, higher plasma sIR correlated with lower urine sIR that could suggest sIR retention in blood or decreased renal filtration.DiscussionHigher plasma sIR levels and their correlation with ROS in plasma-derived exosomes with HAND suggest a combined role of metabolic disturbances, oxidative stress, exosome release, and cognitive decline. Communication between CNS and periphery is compromised in PWH, thus plasma-derived exosomes may shed light on disrupted cellular mechanisms in the brain of PWH. High plasma and low urine sIR levels could suggest sIR retention in blood or decreased renal filtration.

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Microwave & magnetic proteomics of macrophages from patients with HIV-associated cognitive impairment

Cited by 4 publications

References 68 publications

Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages

Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages

Morphine disrupts macrophage functions even during HIV infection

Soluble Insulin Receptor Levels in Plasma, Exosomes, and Urine and Its Association With HIV-Associated Neurocognitive Disorders

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