{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T17:17:12Z","timestamp":1764782232110,"version":"build-2065373602"},"reference-count":103,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T00:00:00Z","timestamp":1591660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG031782","5T32AI070117","R01DA048609","R01MH112391"],"award-info":[{"award-number":["AG031782","5T32AI070117","R01DA048609","R01MH112391"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>A significant number of people living with HIV (PLWH) develop HIV-associated neurocognitive disorders (HAND) despite highly effective antiretroviral therapy (ART). Dysregulated macroautophagy (autophagy) is implicated in HAND pathogenesis. The viral protein Nef, expressed even with suppressive ART, and certain antiretrovirals affect autophagy in non-CNS cells. Astrocytes, vital for CNS microenvironment homeostasis and neuronal health, require autophagy for their own homeostasis. We hypothesized that extracellular Nef and\/or ART impact astrocyte autophagy, thus contributing to HAND. We studied in-bulk and selective autophagic flux in primary human astrocytes treated with extracellular Nef and\/or a combination of tenofovir+emtricitabine+raltegravir (ART) using Western blotting, a tandem fluorescent LC3 reporter, and transmission electron microscopy\/morphometry. We show that after 24 h treatment, Nef and ART decrease autophagosomes through different mechanisms. While Nef accelerates autophagosome degradation without inducing autophagosome formation, ART inhibits autophagosome formation. Combination Nef+ART further depletes autophagosomes by inducing both abnormalities. Additionally, extracellular Nef and\/or ART inhibit lysosomal degradation of p62, indicating Nef and\/or ART affect in-bulk and selective autophagy differently. Dysregulation of both autophagic processes is maintained after 7 days of Nef and\/or ART treatment. Persistent autophagy dysregulation due to chronic Nef and\/or ART exposure may ultimately result in astrocyte and neuronal dysfunction, contributing to HAND.<\/jats:p>","DOI":"10.3390\/cells9061426","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T06:34:16Z","timestamp":1591684456000},"page":"1426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["HIV Nef and Antiretroviral Therapy Have an Inhibitory Effect on Autophagy in Human Astrocytes that May Contribute to HIV-Associated Neurocognitive Disorders"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3794-5289","authenticated-orcid":false,"given":"Laura","family":"Cheney","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4655-8280","authenticated-orcid":false,"given":"Hillary","family":"Guzik","sequence":"additional","affiliation":[{"name":"Analytical Imaging Facility, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank P.","family":"Macaluso","sequence":"additional","affiliation":[{"name":"Analytical Imaging Facility, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA"},{"name":"Department of Anatomy and Structural Biology, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Macian","sequence":"additional","affiliation":[{"name":"Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Maria","family":"Cuervo","sequence":"additional","affiliation":[{"name":"Department of Developmental and Molecular Biology, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan W.","family":"Berman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1212\/WNL.0b013e318200d727","article-title":"HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study","volume":"75","author":"Heaton","year":"2010","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1007\/s13365-011-0021-x","article-title":"Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression","volume":"17","author":"Cysique","year":"2011","journal-title":"J. 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