Dataset Information

Quantitative proteomics reveal that CB2R agonist JWH-133 downregulates NF-κB activation, oxidative stress, and lysosomal exocytosis from HIV-infected macrophages

ABSTRACT: HIV-associated neurocognitive disorders (HAND) affect 15-55% of HIV-positive patients, with no therapy. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated 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 its secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, was shown to decrease 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. To test our hypothesis 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 Tags (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 their expression. Our results suggest that JWH-133 is a potential alternative therapy against HIV-1 induced neurotoxicity and warrant in vivo studies to test its potential against HAND.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood, Macrophage

DISEASE(S): Human Immunodeficiency Virus Infectious Disease

SUBMITTER: Loyda Melendez

LAB HEAD: Loyda Melendez

PROVIDER: PXD048464 | Pride | 2024-06-22

REPOSITORIES: Pride

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Publications

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

Rosario-Rodríguez Lester J LJ Cantres-Rosario Yadira M YM Carrasquillo-Carrión Kelvin K Rodríguez-De Jesús Ana E AE Cartagena-Isern Luz J LJ García-Requena Luis A LA Roche-Lima Abiel A Meléndez Loyda M LM

International journal of molecular sciences 20240313 6

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 ...[more]

PMID: 38542221

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Project description:We assessed correlates of protection from disease progression in a rare subset of HIV-infected individuals, viremic non-progressors (VNPs). These individuals have high viral load for several years, but in contrast to the majority of infected individuals, they do not progress to AIDS. Here we found this lack of progression was associated with selective preservation of two essential subsets of memory CD4+ T cells, central memory (TCM) and stem-cell memory (TSCM) cells. Compared to HIV-infected putative progressors, VNPs had higher proliferation of these indispensable subsets of memory cells, which was associated with the number of TCM. In addition, the long-lived CD4+ TCM and TSCM cells in VNPs had decreased HIV infection compared to the less critical effector memory CD4+ T cells, which indicates a possible mechanism by which VNPs maintain their CD4+ T cell pool after several years of infection, and remain free from AIDS progression. 6 HIV-infected patients fitting the clinical criteria of Viremic Non-Progressors were identified. VNPs were defined as having confirmed HIV-1 infection for at least 9 years with sustained plasma HIV RNA levels >10,000 copies/ml and maintenance of peripheral blood CD4+ T cell counts >500 cells/mm3 and a CD4% (of all lymphocytes) >15%. As controls, 7 HIV-infected Putative Progressors were identified. PPs were defined as having plasma HIV RNA levels >10,000 copies/mL, CD4+ T cell counts >400 cells/mm3 and having been initially infected with HIV 2-24 months prior to the index visit. The estimated date of initial HIV infection was calculated according to published algorithms that incorporate âde-tunedâ anti-HIV-1 antibody ELISA results or by a documented sero-conversion window of <6 months. All participants were required to be antiretroviral therapy (ART)-naÃ¯ve. RNA from 6 VNP and 7 PPs was purified from PAXgene whole blood tubes and hybridized to Affymetrix U133 Plus 2.0 arrays. During data analysis, one VNP patient (PID 4015) was determined to be an outlier and removed from further analysis. Thus, 5 VNPs and 7 PPs are represented in this Series.

Dataset Information

Quantitative proteomics reveal that CB2R agonist JWH-133 downregulates NF-κB activation, oxidative stress, and lysosomal exocytosis from HIV-infected macrophages

Publications

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

Similar Datasets

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