{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:59:18Z","timestamp":1792803558851,"version":"4.5.0"},"reference-count":78,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T00:00:00Z","timestamp":1765584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["K99AA032220"],"award-info":[{"award-number":["K99AA032220"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["R01AA026086"],"award-info":[{"award-number":["R01AA026086"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["K08AA024512"],"award-info":[{"award-number":["K08AA024512"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01-HL158979"],"award-info":[{"award-number":["R01-HL158979"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K23AI134182"],"award-info":[{"award-number":["K23AI134182"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Veteran Health Administration","award":["IK2 CX000643"],"award-info":[{"award-number":["IK2 CX000643"]}],"id":[{"id":"https:\/\/ror.org\/05eq41471","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alcohol misuse is twice as prevalent among people living with HIV (PWH), and this increases the risk of pulmonary complications even in those receiving antiretroviral therapy. Our prior work showed that the alcohol metabolite, acetaldehyde, activates nuclear factor kappa B p65 (p65), leading to HIV replication and interleukin (IL)-1\u03b2 activation in alveolar macrophages (AMs). Since the aforementioned processes are energy-demanding, which conversely impair mitochondrial functions, we hypothesized that acetaldehyde-induced p65 drives AMs to a mitochondrial hyperactive state to promote HIV replication and IL-1\u03b2 release and induces oxidative stress and mitochondrial dysfunction. Since we found pioglitazone (PIO) to be a negative regulator of p65, we postulate that PIO suppresses HIV replication and IL-1\u03b2 activation in AMs by restricting p65-induced mitochondrial hyperactivation. Murine AMs were exposed to acetaldehyde via the acetaldehyde generating system (AGS) and infected in vitro with EcoHIV, a chimeric ecotropic HIV construct. AGS + EcoHIV activated p65, resulting in enhanced ATP-linked mitochondrial respiration, proton leak, non-mitochondrial respiration and the generation of reactive oxygen species (ROS) in AMs. Inhibition of mitochondrial ATP synthesis with low-dose oligomycin attenuated AGS-induced HIV replication and AGS + EcoHIV-induced IL-1\u03b2 release from AMs. PIO treatment, which attenuated AGS-induced p65 activation, suppressed proton leak, non-mitochondrial oxygen consumption, ROS, and IL-1\u03b2 and p24 release. While p65-induced mitochondrial hyperactivation represents AMs\u2019 adaptive response to the energy demands imposed by HIV replication and proinflammatory activation when exposed to acetaldehyde, PIO treatment may offer a novel therapeutic strategy to restore adequate mitochondrial bioenergetics in the AMs of PWH who misuse alcohol.<\/jats:p>","DOI":"10.3390\/biom15121737","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T10:11:23Z","timestamp":1765793483000},"page":"1737","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pioglitazone Modulates p65-Mediated Mitochondrial Bioenergetics: Implications for Acetaldehyde-Induced HIV Replication in Alveolar Macrophages"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5681-1185","authenticated-orcid":false,"given":"Moses","family":"New-Aaron","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Atlanta Veterans Affairs Health Care System, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Atlanta Veterans Affairs Health Care System, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7693-1907","authenticated-orcid":false,"given":"Xian","family":"Fan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0287-8653","authenticated-orcid":false,"given":"Ashish","family":"Mehta","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Atlanta Veterans Affairs Health Care System, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara C.","family":"Auld","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Grady Memorial Hospital, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bashar 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, GA 30322, USA"},{"name":"Grady Memorial Hospital, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5422-5614","authenticated-orcid":false,"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, GA 30322, USA"}],"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, GA 30322, USA"},{"name":"Atlanta Veterans Affairs Health Care System, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e38768","DOI":"10.1097\/MD.0000000000038768","article-title":"Toward a cure\u2014Advancing HIV\/AIDs treatment modalities beyond antiretroviral therapy: A Review","volume":"103","author":"Alum","year":"2024","journal-title":"Medicine"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Foka, F.E.T., and Mufhandu, H.T. 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