Document Type

Article

Journal Title

International Journal of Molecular Sciences

Publication Date

2026

Volume

27

Abstract

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 β-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

MeSH Headings

Animals, Oxazines, Piperazines, Tenofovir, Heterocyclic Compounds, 3-Ring, Mice, Pyridones, HIV Infections, HIV-1, Emtricitabine, Electrocardiography, Long QT Syndrome, Humans, Anti-HIV Agents, Disease Models, Animal, Mice, Inbred NOD, Female, Male

ISSN

1422-0067

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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