Anti-HIV or HIV-HCV/HBV co-infection drugs help people with HIV/AIDS live longer and healthier lives. However, the HIV medicines often cause side effects. Although most side effects from the HIV medicines are manageable, a few such as damages to the liver can be very serious and life threatening. To be worse, nearly half of the HIV infected patients abuse/consume alcohol or having a multiple drug-abuse problem, which not only impairs patients’ adherence to the anti-HIV therapy but also deteriorates antiviral-induced hepatotoxicity leading to greater morbidity and mortality. Hence molecular mechanisms and potential therapeutic targets underlying the hepatotoxicity are under intense investigations. Previous studies by us and others suggest that endoplasmic reticulum (ER) stress contributes to HIV protease inhibitors and/or alcohol abuse-induced hepatic cell death, steatohepatitis and cirrhosis in animal models and patients. However, therapies to ensure proper ER homeostasis such as applications of chemical chaperones, antioxidants, autophagy inducers, or selective enhancement of protective ER signaling pathways only yield partial effects in a variety of in vitro and in vivo model systems, which suggest that other more precise cellular targets are involved in the anti-HIV drugs and/or alcohol-induced hepatotoxicity. Our most recent studies reveal a strong effect of certain HIV protease inhibitors on the ER-Golgi trafficking and integrity of the Golgi apparatus, which occurs earlier than the ER stress response and results in increased cell death compared to the cell death induced by pharmaceutical ER stress inducing agents. Herein we hypothesize that the anti-HIV drugs target primarily at the Golgi apparatus and dysfunction of Golgi triggers other organelle stress response leading to liver disease development, which is deteriorated by alcohol-induced ER stress response. We propose to: (1) identify specific molecular components of the ER-Golgi traffic machineries that are affected by the anti-HIV drugs and/or alcohol; (2) investigate mechanisms that regulate the drug-induced Golgi stress response; (3) study how the Golgi stress mediates downstream hepatic injury; (4) evaluate cytoprotective effects of therapies targeting the Golgi stress. This project will provide a scientific basis for a better care for HIV/AIDS patients suffering from liver damages resulted from anti-HIV drugs and alcohol abuse.