Cannabinoid Receptor Type 2 Agonist JWH-133 Stimulates Antiviral Factors and Decreases Proviral, Inflammatory, and Neurotoxic Proteins in HIV-Infected Macrophage Secretome

ABSTRACT: Although antiviral therapy has improved quality of life, around 50% of people with HIV (PWH) experience neurodegeneration and cognitive decline. This is prompted in part by migration of HIV-infected monocyte-derived macrophages (MDM) to the brain, leading to neuronal death. Previous studies in our lab have shown that HIV-infected MDM secrete cathepsin B (CATB), which is a pro-inflammatory neurotoxic enzyme that is reduced by the addition of cannabinoid receptor-2 (CB2R) agonist JWH-133 to cell cultures. In this study, we aimed to identify the secreted proteins (secretome) by HIV-infected macro-phages exposed to JWH-133 and quantify them using Tandem Mass Tag (TMT) mass spectrometry. Frozen 13-day MDM supernatants from: (1) MDM negative control; (2) HIV-MDM; and (3) MDM-HIV-JWH-133, were compared in triplicates by mass spectrometry (LC/MS/MS) and analyzed for protein identification. Subsequently, the same samples were labeled by TMT labeling and quantified by LC/MS/MS. After database search, 528 proteins were identified from all groups. Thereafter, proteins with more than 3 unique peptides and more than 10% coverage were selected for protein ID. Venn diagrams revealed 1 unique protein secreted by MDM-HIV, 10 unique proteins in MDM-HIV JWH-133, and 15 common proteins in the three groups. CATB was unique to MDM-HIV. MDM-HIV exposed to JWH-133 showed proteins related to metabolism, cell organization, anti-viral activity, and stress response. TMT analysis revealed 1,454 proteins with abundance for statistical analysis based on FC ≥ |1.5| and p-value ≤ 0.05, of which Ruvb-like 1 and Hornerin decreased significantly with JWH-133 treatment. Both proteins stimulate HIV replication. In addition, HIV infection upregulated proteins associated with pathways of HIV latency that were inhibited by JWH-133. In conclusion, JWH-133 treatment in HIV-infected macrophages leads to the secretion of antiviral host factors and decreases the secretion of proviral, inflammatory, and neurotoxic host factors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Macrophage

DISEASE(S): Human Immunodeficiency Virus Infectious Disease

SUBMITTER: Loyda Melendez  

LAB HEAD: Loyda Melendez

PROVIDER: PXD069890 | Pride | 2025-11-24

REPOSITORIES: Pride