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

Abstract

The human immunodeficiency virus (HIV-1) trans-activator (Tat) protein is an important viral protein that is known to contribute to the acquired immunodeficiency syndrome (AIDS) pathogenesis via cytokine dysregulation. In this study, we recognized that c-Myc regulated primary blood derived macrophage (PBMac) immune response induced by HIV-1 Tat. Treatment of PBMac with HIV-1 Tat was able to upregulate c-Myc expression in a time dependent manner. We subsequently delineated that HIV-1 Tat regulated c-Myc expression and function through the activation of dsRNA-activated protein kinase (PKR), ERK1/2 and p38 mitogen-activated protein kinase (MAPK). By knocking down the expression of c-Myc with gene specific small-interfering RNA (siRNA), we demonstrated that c-Myc may be critical for the expression of the pro-inflammatory cytokines TNF-α 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. In summary, 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 AIDS patients.