{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:57:04Z","timestamp":1790092624897,"version":"4.0.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013296","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000}}],"reference-count":27,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/PR22881 and BT\/PR22985"],"award-info":[{"award-number":["BT\/PR22881 and BT\/PR22985"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    We previously reported that Tibetan-specific variant of prolyl-hydroxylase-2 (PHD2)\n                    <jats:sup>D4E;C127S<\/jats:sup>\n                    protects highlanders from hypoxia-triggered pathologies by destabilizing hypoxia-inducible factor (HIF)-1\u03b1. Others have reported that stabilized HIF1\u03b1 negatively regulates interferon (IFN)-regulating factor (IRF)-3 under hypoxia. We examined the role of PHD2\n                    <jats:sup>D4E;C127S<\/jats:sup>\n                    variant in IFN synthesis in immune cells during viral infections. Primary monocytes and cells engineered to express the PHD2\n                    <jats:sup>D4E;C127S<\/jats:sup>\n                    variant displayed protection against dengue virus (DENV)-2 infection by suppressing HIF1\u03b1, in turn promoting IRF-3 and IFN\u03b1\/\u03b2 synthesis in hypoxia (3% O\n                    <jats:sub>2<\/jats:sub>\n                    ) in vitro. However, under normoxia (21% O\n                    <jats:sub>2<\/jats:sub>\n                    ), these mutant cells increased reactive oxygen species (ROS) generation following DENV2 infection. Increased ROS then suppressed PHD2\n                    <jats:sup>D4E;C127S<\/jats:sup>\n                    activity, reflected by reduced hydroxylation and concomitant stabilization of HIF1\u03b1, resulting in suppressed IFN synthesis and higher DENV2 replication. The PHD2\n                    <jats:sup>WT<\/jats:sup>\n                    cells demonstrated the opposite trend. Our data further confirmed the inverse correlation between HIF1\u03b1 and IFN pathways. CAY10585, a HIF1\u03b1-inhibitor, decreased the DENV2 infection by increasing\n                    <jats:italic>IFN-A\/B<\/jats:italic>\n                    and\n                    <jats:italic>IRF-3\/7\/9<\/jats:italic>\n                    expression. HIF1\u03b1-depleted monocytes also showed a similar response to the infection. We extended our findings to COVID-19 infection. The CD4\/CD8 T-cells collected from Tibetans with PHD2\n                    <jats:sup>D4E;C127S<\/jats:sup>\n                    variant and exposed to SARS-CoV-2 infection showed elevated expression of IFN-\u03b3 in response to exposure to SARS-CoV-2 receptor-binding domain (RBD) peptide under hypoxia, and a lesser expression under normoxia. The study thus highlights a unique crosstalk of PHD2\n                    <jats:sup>D4E;C127S<\/jats:sup>\n                    variant with HIF1\u03b1-IFN axis under environmental pO\n                    <jats:sub>2<\/jats:sub>\n                    in protecting or predisposing Tibetans to viral infections.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013296","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T13:59:56Z","timestamp":1750946396000},"page":"e1013296","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tibetan PHD2D4E;C127S variant protects from viral diseases in hypoxia, but predispose to infections in normoxia via HIF\u03b1:IFN axis"],"prefix":"10.1371","volume":"21","author":[{"given":"Riya","family":"Ghosh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garima","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishith M.","family":"Shrimali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanchan","family":"Bhardwaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsewang","family":"Chorol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tashi","family":"Thinlas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvaiz A.","family":"Koul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef T.","family":"Prchal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6601-6692","authenticated-orcid":true,"given":"Prasenjit","family":"Guchhait","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"issue":"11","key":"ppat.1013296.ref001","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1086\/324163","article-title":"Infections at high altitude","volume":"33","author":"B Basnyat","year":"2001","journal-title":"Clin Infect Dis"},{"issue":"2","key":"ppat.1013296.ref002","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1542\/peds.2004-2795","article-title":"Effect of altitude on hospitalizations for respiratory syncytial virus infection","volume":"117","author":"JA 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