HIV TAT modulation of IFN-γ-induced expression of autophagy-associated genes in primary human blood macrophages

Abstract

Human immunodeficiency virus (HIV), the causative agent of AIDS, continues to be a major cause of morbidity and mortality worldwide. Immune defects in HIV patients are closely associated with intense cytokine dysregulation. HIV trans-activator protein, Tat, plays a critical role in HIV replication; and its induction of apoptosis, Type I programmed cell death, in CD4+ T cells contributes to immune defects. We recently showed that HIV Tat impairs the IFN-γ-receptor signaling pathway at the level of STAT1 phosphorylation due to SOCS-2 activation (Blood 2009). Since IFN-γ was found to induce autophagy, a cellular process proposed to be associated with intracellular killing of M. tuberculosis, we investigated whether HIV Tat can inhibit IFN-γ-induced signaling pathway leading to ultimate downregulation of the IFN-γ-induced autophagy in peripheral blood monocyte derived macrophages (PBMac). We demonstrated that IFN-γ can induce the expression of an autophagy-associated gene, microtubule-associated protein 1 light chain 3 (LC3 I and II) in a time- and dose-dependent manner in human macrophages. With pretreatment of the cells with HIV Tat, the IFN-γ-induced expression of the autophagy-associated gene was suppressed. Tat exerted its activities on IFN-γ-induced effects in a dose-dependent manner. We further showed that HIV Tat inhibition on IFN-γ-induced expression of the autophagy-associated gene was through the suppression of phosphorylated-STAT1 protein generation, by using a specific inhibitor for STAT1 activation. Detailed mechanisms underlying the effects of Tat on the modulation of autophagy-associated genes are in progress. Taken together, modulation of the expression of autophagy-associated genes by HIV Tat may affect mycobacterial survival. These results may have implications in understanding the rampant spread of mycobacterial infection in AIDS.