Regulation of HIV-Tat induced cytokine expression and consequent opportunistic infection by the proto-oncogene c-Myc

Abstract

Human immunodeficiency virus (HIV) remains a major health problem around the globe, especially in 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-α and IL- 6. In this study, we recognised that c-Myc, a proto-oncogene known to regulate a wide range of cellular process, also regulated primary blood derived macrophage (PBMac) immune response induced by HIV-1 Tat. We first found that HIV-1 Tat could induce the expression of c-Myc.The function and expression of HIV- 1 Tat induced c-Myc was subsequently found to be regulated through the activation of the dsRNA-activated protein kinase (PKR), ERK1/2 and p38 mitogen-activated protein kinase (MAPK). Inhibition of c-Myc expression in turn demonstrated that c-Myc may be essential for the up-regulation of the pro-inflammatory cytokines TNF-α and IL-6 by HIV-1 Tat. Furthermore, c-Myc regulation of HIV-1 Tat induced cytokine expression consequently affected the intracellular survival of the opportunistic microbe, Mycobacteria avium intracellulare, in PBMac. Taken together, we demonstrated that c-Myc may play a significant role in the pathogenesis of AIDS, by mediating the dysregulation of cytokine expression induced by Tat and possibly accentuate opportunistic infection.