Hepatotoxic mechanisms of anti-HIV- and anti-COVID-19 drugs and substance use disorders

抗 HIV 和抗 COVID-19 药物和物质使用障碍的肝毒性机制

• 批准号: 10684434
• 负责人: CHENG JI
• 金额: $ 39.19万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684434
• 关键词: 2019-nCoV; AGFG1 gene; Acetals; Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Alcohol consumption; Alcohols; Animal Model; Anti-HIV Agents; Antiviral Agents; Blood alcohol level measurement; Buprenorphine; Butyric Acids; COVID-19; COVID-19 patient; COVID-19 vaccine; Caring; Cause of Death; Cell Death; Cells; Cellular Stress; Compensation; Coronavirus; Development; Dexamethasone; Digestion; Disease; Dose; Drug Use Disorder; Drug usage; Endopeptidases; Endoplasmic Reticulum; Enzymes; Event; Excision; Experimental Models; FDA approved; Family; Fatty Liver; Functional disorder; Genetic; Golgi Apparatus; HIV; HIV Infections; HIV vaccine; HIV/AIDS; Hepatic; Hepatocyte; Hepatotoxicity; Home; Homeostasis; Hospitalization; Human; Immune response; In Vitro; Individual; Injury; Life; Link; Liver; Liver diseases; Lopinavir; Malignant Neoplasms; Measures; Molecular; Molecular Chaperones; Monomeric GTP-Binding Proteins; Mus; Organelles; Oxidoreductase; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Proteins; Quality of life; Quarantine; Recovery; Regimen; Reporting; Risk; Ritonavir; Role; Signal Transduction; Steatohepatitis; Stress; Substance Use Disorder; Substance abuse problem; Tenofovir; Testing; Therapeutic; Time; Transaminases; Viral; Virus Diseases; Virus Replication; alcohol oxidase; alcohol use disorder; antiretroviral therapy; biological adaptation to stress; catalase; chronic alcohol ingestion; comorbidity; coronavirus disease; drug induced liver injury; efavirenz; endoplasmic reticulum stress; improved; in vivo; liver injury; molecular marker; molnupiravir; nanoparticle; next generation; nirmatrelvir; novel; pandemic disease; prophylactic; rab GTP-Binding Proteins; remdesivir; response; side effect; stress reduction; substance use; tauroursodeoxycholic acid; trafficking; transcriptome sequencing; vaccine development; viral pandemic

Virus infections such as HIV/AIDS and SARS-CoV-2/COVID-19 sicken hundreds of millions of people. The current multiple pandemics have caused unprecedented levels of stress and other life disruptions, which exacerbate substance use disorders, increasing side effects of antiviral drugs and interfering with recovery of individuals suffering from virus infections. Antivirals such as remdesivir, molnupiravir, ritonavir, nirmatrelvir, tenofovir, and darunavir are commonly used to inhibit replication or cell entry for HIV and SARS-CoV-2, thereby inhibiting viral infections. However, some antivirals such as ritonavir of current regimens, especially in combination with other drugs or substance alcohol use, often induced liver injuries causing serious complications. Recently, we have found that remdesivir, ritonavir, and alcohol induce cellular organelle stress, especially endoplasmic reticulum (ER) stress, which is well established not only to cause hepatic cell death but also to compromise immune response leading to a spectrum of liver diseases in a variety of animal models as well as in human patients. Most recently, we discovered with next-generation RNA sequencing that a host protease, RCE1 is a potential off- target of the antiviral drugs. The substrates of RCE1 are limited to a few Rab small GTPase proteins (Rab proteins) with a CaaX motif, which are consequently reduced in the presence of anti-HIV or anti- COVID-19 drugs and reduced much more in drug and alcohol combinations. Because the Rab proteins regulate ER-Golgi trafficking that is essential for cellular organellar homeostasis in the liver, we hypothesize that the antiviral drugs inhibit the host RCE-Rab proteins and induce organelle stress responses that leads to fatty liver injury, and alcohol consumption under stress conditions (e.g., suffering from COVID-19 or frequent quarantine) worsens the drug-induced liver complications. We propose to investigate the pathogenic mechanisms of the RCE-Rab pathway in the antiviral-induced organelle stress and explore pharmaceutical and genetic solutions to mitigate the antiviral drug-induced hepatic injury. Our specific aims are to: (1) validate the mechanistic link of the RCE-Rab pathway with anti-HIV drug and alcohol-induced organelle stress and liver injury, (2) verify whether emerging anti- coronavirus drugs and/or alcohol consumption inhibit the RCE-Rab pathway and induce organelle stress in the liver, (3) explore pharmaceutical and genetic solutions to mitigate the antiviral drug- induced liver injury via testing prophylactic effects of enhanced expression of Rab proteins that compensate the consequence of the antiviral-inhibited host protease, and testing effects of unique enzyme nano-particles that facilitate alcohol removal. Our long-term objectives are to unravel specific pathogenic mechanisms underlying side effects of antivirals so that to improve/modify current antiviral drugs for a better care of the AIDS patients suffering from HIV and SARS-CoV-2 virus infections.

艾滋病毒/艾滋病和SARS-CoV-2/COVID-19等病毒感染使数亿人患病。