HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2)
The incidence of sudden cardiac death (SCD) in people living with HIV infection (PLWH), especially those with inadequate viral suppression, is high and the reasons for this remain incompletely characterized. The timely opening and closing of type 2 ryanodine receptor (RyR2) is critical for ensuring...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/1/274 |
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| author | Fadhel A. Alomar Chengju Tian Sean R. Bidasee Zachary L. Venn Evan Schroder Nicholas Y. Palermo Mohammad AlShabeeb Benson J. Edagwa Jason J. Payne Keshore R. Bidasee |
| author_facet | Fadhel A. Alomar Chengju Tian Sean R. Bidasee Zachary L. Venn Evan Schroder Nicholas Y. Palermo Mohammad AlShabeeb Benson J. Edagwa Jason J. Payne Keshore R. Bidasee |
| author_sort | Fadhel A. Alomar |
| collection | DOAJ |
| description | The incidence of sudden cardiac death (SCD) in people living with HIV infection (PLWH), especially those with inadequate viral suppression, is high and the reasons for this remain incompletely characterized. The timely opening and closing of type 2 ryanodine receptor (RyR2) is critical for ensuring rhythmic cardiac contraction–relaxation cycles, and the disruption of these processes can elicit Ca<sup>2+</sup> waves, ventricular arrhythmias, and SCD. Herein, we show that the HIV protein Tat (HIV-Tat: 0–52 ng/mL) and therapeutic levels of the antiretroviral drugs atazanavir (ATV: 0–25,344 ng/mL), efavirenz (EFV: 0–11,376 ng/mL), and ritonavir (RTV: 0–25,956 ng/mL) bind to and modulate the opening and closing of RyR2. Abacavir (0–14,315 ng/mL), bictegravir (0–22,469 ng/mL), Rilpivirine (0–14,360 ng/mL), and tenofovir disoproxil fumarate (0–18,321 ng/mL) did not alter [<sup>3</sup>H]ryanodine binding to RyR2. Pretreating RyR2 with low HIV-Tat (14 ng/mL) potentiated the abilities of ATV and RTV to bind to open RyR2 and enhanced their ability to bind to EFV to close RyR2. In silico molecular docking using a Schrodinger Prime protein–protein docking algorithm identified three thermodynamically favored interacting sites for HIV-Tat on RyR2. The most favored site resides between amino acids (AA) 1702–1963; the second favored site resides between AA 467–1465, and the third site resides between AA 201–1816. Collectively, these new data show that HIV-Tat, ATV, EFV, and RTV can bind to and modulate the activity of RyR2 and that HIV-Tat can exacerbate the actions of ATV, EFV, and RTV on RyR2. Whether the modulation of RyR2 by these agents increases the risk of arrhythmias and SCD remains to be explored. |
| first_indexed | 2024-03-11T09:59:28Z |
| format | Article |
| id | doaj.art-04af2925358d4ca4a1d16f33c484498c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:59:28Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-04af2925358d4ca4a1d16f33c484498c2023-11-16T15:30:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124127410.3390/ijms24010274HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2)Fadhel A. Alomar0Chengju Tian1Sean R. Bidasee2Zachary L. Venn3Evan Schroder4Nicholas Y. Palermo5Mohammad AlShabeeb6Benson J. Edagwa7Jason J. Payne8Keshore R. Bidasee9Department of Pharmacology and Toxicology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi ArabiaDepartments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USADepartments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USADepartments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USADepartments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USAVice Chancellor for Research Cores, University of Nebraska Medical Center, Omaha, NE 68198, USAPopulation Health Research Section, King Abdullah International Medical Research Center, King Saudi bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi ArabiaDepartments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USADepartments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USAThe incidence of sudden cardiac death (SCD) in people living with HIV infection (PLWH), especially those with inadequate viral suppression, is high and the reasons for this remain incompletely characterized. The timely opening and closing of type 2 ryanodine receptor (RyR2) is critical for ensuring rhythmic cardiac contraction–relaxation cycles, and the disruption of these processes can elicit Ca<sup>2+</sup> waves, ventricular arrhythmias, and SCD. Herein, we show that the HIV protein Tat (HIV-Tat: 0–52 ng/mL) and therapeutic levels of the antiretroviral drugs atazanavir (ATV: 0–25,344 ng/mL), efavirenz (EFV: 0–11,376 ng/mL), and ritonavir (RTV: 0–25,956 ng/mL) bind to and modulate the opening and closing of RyR2. Abacavir (0–14,315 ng/mL), bictegravir (0–22,469 ng/mL), Rilpivirine (0–14,360 ng/mL), and tenofovir disoproxil fumarate (0–18,321 ng/mL) did not alter [<sup>3</sup>H]ryanodine binding to RyR2. Pretreating RyR2 with low HIV-Tat (14 ng/mL) potentiated the abilities of ATV and RTV to bind to open RyR2 and enhanced their ability to bind to EFV to close RyR2. In silico molecular docking using a Schrodinger Prime protein–protein docking algorithm identified three thermodynamically favored interacting sites for HIV-Tat on RyR2. The most favored site resides between amino acids (AA) 1702–1963; the second favored site resides between AA 467–1465, and the third site resides between AA 201–1816. Collectively, these new data show that HIV-Tat, ATV, EFV, and RTV can bind to and modulate the activity of RyR2 and that HIV-Tat can exacerbate the actions of ATV, EFV, and RTV on RyR2. Whether the modulation of RyR2 by these agents increases the risk of arrhythmias and SCD remains to be explored.https://www.mdpi.com/1422-0067/24/1/274sudden cardiac deathHIVHIV-Tatantiretroviral drugstype 2 ryanodine receptor (RyR2)[<sup>3</sup>H]ryanodine |
| spellingShingle | Fadhel A. Alomar Chengju Tian Sean R. Bidasee Zachary L. Venn Evan Schroder Nicholas Y. Palermo Mohammad AlShabeeb Benson J. Edagwa Jason J. Payne Keshore R. Bidasee HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2) International Journal of Molecular Sciences sudden cardiac death HIV HIV-Tat antiretroviral drugs type 2 ryanodine receptor (RyR2) [<sup>3</sup>H]ryanodine |
| title | HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2) |
| title_full | HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2) |
| title_fullStr | HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2) |
| title_full_unstemmed | HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2) |
| title_short | HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2) |
| title_sort | hiv tat exacerbates the actions of atazanavir efavirenz and ritonavir on cardiac ryanodine receptor ryr2 |
| topic | sudden cardiac death HIV HIV-Tat antiretroviral drugs type 2 ryanodine receptor (RyR2) [<sup>3</sup>H]ryanodine |
| url | https://www.mdpi.com/1422-0067/24/1/274 |
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