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Acetaldehyde, a metabolite of alcohol, circulates systemically and directly impacts alveolar macrophages (AMs), the primary reservoir of HIV in the lungs. Acetaldehyde promotes AM HIV replication and triggers IL-1\u03b2 release. We explored the mechanisms by which alcohol-derived acetaldehyde drives HIV replication and IL-1\u03b2 release in AMs. Furthermore, we tested if the transcription factor peroxisome proliferator-activated receptor (PPAR)\u03b3 agonist, pioglitazone, attenuates AM HIV replication and IL-1\u03b2 release. Primary mouse AMs, MH-S cells (an AM cell line), and THP-1 (human monocyte cell line)-derived macrophages were treated with alcohol-derived acetaldehyde (acetaldehyde-generating system [AGS]), HIV 1ADA, and EcoHIV, a chimeric HIV that infects murine cells. HIV expression was confirmed by HIV gag RNA (qRT-PCR) and p24 release (ELISA). IL-1\u03b2 was measured by qRT-PCR and ELISA. Extracellular hydrogen peroxide (H2O2) release was quantified by Amplex Red assay. Furthermore, immunoblot analysis of ERK1\/2, PPAR\u03b3, and NF-\u0138B\/p65 (p65) was used to identify how acetaldehyde potentiates HIV replication and IL-1\u03b2 activation in AMs. AGS increased H2O2, leading to ERK1\/2 phosphorylation, which deactivated PPAR\u03b3. AGS drove nuclear p65 translocation in HIV-infected cells, which enhanced HIV replication and IL-1\u03b2 release. Treatment with pioglitazone decreased nuclear p65, attenuating AGS-induced HIV replication and IL-1\u03b2 activation in AMs. We identified mechanisms underlying acetaldehyde-induced inflammatory activation and potentiation of HIV replication in AMs, which could be therapeutically targeted with pioglitazone to decrease HIV-related respiratory comorbidities among people living with HIV who misuse alcohol.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0448oc","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T19:27:51Z","timestamp":1746041271000},"page":"713-724","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":4,"title":["Pioglitazone Reverses Alcohol-induced Human Immunodeficiency Virus (HIV) Replication and IL-1\u03b2 Expression in Alveolar Macrophages"],"prefix":"10.1093","volume":"73","author":[{"given":"Moses","family":"New-Aaron","sequence":"first","affiliation":[{"name":"Division of Pulmonary, 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S.","family":"Staitieh","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Koval","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9309-0233","authenticated-orcid":false,"given":"Samantha M.","family":"Yeligar","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and"},{"name":"Atlanta Veterans Affairs Health Care System, Decatur, 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