Pathogenic Mechanisms in HIV Treatment Associated Hepatotoxicity: Role of Phosphodiesterase-4 and Endoplasmic Reticulum Stress

Highly Active Antiretroviral Therapy (HAART) has led to major increases in the life expectancy of HIV patients; however, there are significant side effects including lipodystrophy and hepatotoxicity. HIV protease inhibitors (HIV-PIs) are the major components of HAART and have been successfully used in the treatment of HIV-1 infection. The present study examined the potential mechanisms underlying HIV-PI induced liver toxicity, with a particular emphasis on endoplasmic reticulum (ER) stress and the pathogenic role of phosphodiesterase 4 (PDE4) family of enzymes. The data obtained from these studies demonstrated that the clinically relevant combinatorial treatment of HIV-PIs (Ritonavir+Lopinavir) led to a significant loss of hepatocyte survival. Notably, inhibition of PDE4 by rolipram markedly attenuated hepatotocyte cell death. The data also demonstrate that HIV-PIs triggered ER stress with activation of transcription factors ATF-3 and ATF-4, and the pro-apoptotic protein CHOP. Moreover, exposure to HIV-PIs up-regulated the hepatocyte death-inducing ligand, FasL. These effects were markedly decreased by PDE4 inhibition, indicating its pathogenic role. Overall, these studies demonstrated the critical role of PDE4 enzymes in the development of HIV-PI induced ER stress and hepatocyte apoptosis, and consequent liver injury. Notably, these studies also suggest that the HIV-PI induced pathogenic expression of PDE4 is a relevant therapeutic target and PDE4 inhibitors may provide significant treatment options in HIV patients