The role of c-Myc in regulating HIV-1 Tat protein induced cytokine expression and consequent effects on opportunistic infection

Abstract

INTRODUCTION: Human immunodeficiency virus (HIV) remains a major health problem around the globe, especially in the third world countries where acquired immunodeficiency syndrome (AIDS) is highly prevalent and currently incurable. The HIV-1 trans-activator (Tat) protein is an important viral protein that is known to contribute to the AIDS pathogenesis via the dysregulation of cytokines such as TNF-a and IL-6. In this study, we recognized that the proto-oncogene c-Myc regulated primary blood derived macrophage (PBMac) immune response induced by HIV-1 Tat. METHODS: PBMac was treated with HIV-1 Tat for 4 to 24 h and measured the expression of c-Myc by Western blot. For the measurement of activation of kinases, we treated PBMac for the indicated time and western blot was performed. In order to knockdown c-Myc expression, c-Myc specific small-interfering RNA (siRNA) was added to PBMac for 48 h prior to subsequent treatments. Colony forming unit (CFU) assay was carried out to measure the intracellular mycobacterial survival. RESULTS: The results showed that c-Myc expression was upregulated in a time-dependant manner by HIV-1 Tat treatment. We further delineated that HIV-1 Tat induced c-Myc expression through the activation of dsRNA-activated protein kinase (PKR) and p38 mitogen-activated protein kinase (MAPK). HIV-1 Tat upregulated c-Myc expression would in turn activate PKR, ERK1/2 and p38 MAPK for the mediation of cytokine expression. By knocking down the expression of c-Myc with siRNA, we demonstrated that c-Myc may be critical for the expression of the pro-inflammatory cytokines TNF-a and IL-6. To further investigate the role of c-Myc in AIDS pathogenesis and its effects in the fight against the opportunistic microbes, Mycobacteria avium intracellulare, was used as a pathogen model. Our recent results demonstrated that HIV-1 Tat induced c-Myc to dysregulate cytokine expression, which affects the M. avium intracellular survival in PBMac. CONCLUSION: c-Myc may play a significant role in the pathogenesis of AIDS by regulating the cytokine expression by HIV-1 Tat and possibly further enhancing the infection of opportunistic pathogens in HIV infected patients. This project was supported in part by grants to A.S.Y.L. from the Hong Kong Research Grants Council (GRF program-HKU 769810 M) and the Hong Kong Research Fund for the Control of Infectious Diseases (Grant # 11100802).