{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T19:23:44Z","timestamp":1771615424088,"version":"3.50.1"},"reference-count":24,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017837","name":"Wuxi Science and Technology Association","doi-asserted-by":"publisher","award":["Y20232005"],"award-info":[{"award-number":["Y20232005"]}],"id":[{"id":"10.13039\/100017837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"2025 Open Project of the Provincial Key Laboratory for Integrative Chinese-Western Prevention and Treatment of Geriatric Diseases at Yangzhou University","award":["202528"],"award-info":[{"award-number":["202528"]}]},{"name":"2025 Wuxi Aging Research Project","award":["WXLN25-A-24"],"award-info":[{"award-number":["WXLN25-A-24"]}]},{"name":"2025 Annual Scientific Research Project of the Jiangsu Provincial Association of Geriatrics","award":["JGS2025ZDM010"],"award-info":[{"award-number":["JGS2025ZDM010"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>CMV\/HIV coinfection markedly exacerbates disease progression, elevates treatment failure risk, and worsens patient outcomes, yet the underlying molecular mechanisms remain incompletely understood\u2014creating an urgent need for targeted host-focused research. This study identifies asparagine synthetase (ASNS) as a pivotal metabolic-signaling hub in coinfection pathogenesis, with critical interactions with the PI3K-AKT-mTOR pathway. Using integrated bioinformatics analyses of transcriptomic data, ASNS emerged as a central hub in protein-protein interaction networks, with robust positive co-expression alongside key PI3K-AKT-mTOR components (PIK3CA, MTOR, AKT2, AKT3), while machine learning validated AKT2 as a critical node. ASNS was consistently upregulated 48 hours following CMV infection and across all HIV disease stages, while single-cell RNA sequencing localized ASNS and MDM2 to plasma cells in HIV-positive individuals\u2014implicating their role in virus-driven immune responses. Transcription factor analysis identified RUNX1 as a central regulator: bioinformatics predictions confirmed RUNX1 binds to the ASNS promoter, and validation studies identified RUNX1 as the top biomarker for HIV treatment resistance (AUC\u2009=\u20090.714). Molecular docking and 200-ns dynamics simulations showed that cidofovir\u2014an approved antiviral agent\u2014binds ASNS with high affinity (\u22126.61 kcal\/mol) through nine hydrogen bonds, forming a more stable complex than ASNS-ONL, with VAL-51 and ASN-74 as key residues. Collectively, these findings establish ASNS as a host metabolic-signaling hub exploited by CMV and HIV, highlighting its potential as a novel therapeutic target. Targeting ASNS, particularly at residues VAL-51 and ASN-74, may offer a promising host-directed strategy to improve coinfection treatment outcomes. This work lays the groundwork for experimental validation and the development of targeted therapies for CMV\/HIV coinfection.<\/jats:p>","DOI":"10.1371\/journal.pone.0342050","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T18:39:06Z","timestamp":1771612746000},"page":"e0342050","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular interplay of ASNS and the PI3K-AKT-mTOR pathway in CMV and HIV co-infections: Therapeutic 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