{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T17:41:30Z","timestamp":1767634890201,"version":"3.48.0"},"reference-count":93,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T00:00:00Z","timestamp":1767484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["1R01HL164306-02\/03"],"award-info":[{"award-number":["1R01HL164306-02\/03"]}]},{"name":"National Institute of Health","award":["R56HL151602-01A1"],"award-info":[{"award-number":["R56HL151602-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The REPRIEVE Trial recently reported high rates of sudden cardiac death (SCD) middle-aged people living with HIV-1 infection (PWH) using the WHO\/NIH-recommended two nucleoside reverse transcriptase inhibitors (NRTIs)\/one integrase strand inhibitor (INSTI) regimen to manage HIV-1 viremia. To date, clinically relevant animal models to delineate underlying causes for this remain limited. Here, we assessed if HIV-1-infected NOD.Cg-PrkdcscidIl2rgtm1Wjl\/SzJ humanized mice (Hu-mice) treated with the WHO\/NIH-recommended antiretroviral regimen, dolutegravir (DTG, INSTI)\/tenofovir disoproxil fumarate (TDF, NRTIs)\/emtricitabine (FTC, NRTIs), can recapitulate abnormalities in the ECG and subclinical structural heart disease that serve as harbingers of SCD in middle-aged PWH. HIV-1-infected and uninfected Hu-mice served as controls. After one month of infection (HIV-1ADA), ECG intervals\/segments were significantly altered. ECG changes progressively worsened as the duration of untreated infection increased. Treating HIV-1-infected animals with the DTG\/TDF\/FTC for eight weeks, starting four weeks after infection, prevented worsening, but did not restore ECG intervals\/segments to those before infection. In hearts from DTG\/TDF\/FTC-treated animals, steady-state levels of the sarco-(endo) plasmic reticulum Ca2+ ATPase (SERCA2) were reduced by 35%. Steady-state levels of type 2 ryanodine receptor (RyR2) did not change, but its phosphorylation status at Ser2808 was 2-fold higher than that of uninfected controls, indicative of a gain-of-function. The density of perfused micro vessels and fibrosis in hearts of DTG\/TDF\/FTC-treated animals was not significantly different from that of HIV-1-infected and uninfected Hu-mice. These data show for the first time that HIV-1 infection is triggering abnormalities in the ECG of Hu-mice, and changes in ECG persisted with DTG\/TDF\/FTC treatment, independent of ischemia and\/or fibrosis. They also indicate that chronic DTG\/TDF\/FTC treatment did not worsen ECG changes, including the QT interval. Since phosphorylation of RyR2 at Ser2808 occurs via \u03b2-adrenergic activation of protein kinase A, these new data also suggest that chronic hyperadrenergic activity may be increasing the risk of SCD via Ca2+ leak through RyR2.<\/jats:p>","DOI":"10.3390\/ijms27010519","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T13:35:47Z","timestamp":1767620147000},"page":"519","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prolonged QT Interval in HIV-1 Infected Humanized Mice Treated Chronically with Dolutegravir\/Tenofovir Disoproxil Fumarate\/Emtricitabine"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6490-2463","authenticated-orcid":false,"given":"Ali","family":"Namvaran","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6858-1788","authenticated-orcid":false,"given":"Julian V.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahendran","family":"Ramasamy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1536-4379","authenticated-orcid":false,"given":"Kayla","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farzaneh","family":"Tavakkoli Ghazani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryan T.","family":"Hackfort","sequence":"additional","affiliation":[{"name":"Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prasanta K.","family":"Dash","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8276-4620","authenticated-orcid":false,"given":"Reagan E.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benson","family":"Edagwa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santhi","family":"Gorantla","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4165-8362","authenticated-orcid":false,"given":"Keshore R.","family":"Bidasee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Afzal, M., Agarwal, S., Elshaikh, R.H., Babker, A.M.A., Osman, E.A.I., Choudhary, R.K., Jaiswal, S., Zahir, F., Prabhakar, P.K., and Abbas, A.M. 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