HIV-1 trans-activator protein dysregulates IFN-γ signaling and contributes to the suppression of autophagy induction

Objective and design: HIV-1 transactivator protein, Tat, has been identified as an activator of HIV-1 replication. It also dysregulates cytokine production and apoptosis in T-cells. Of the various cell death processes, autophagy is a self-digestion and degradation mechanism that recycles the contents of the cytosol, including macromolecules and cellular organelles, resulting in self-repair and conservation for survival. Recent reports demonstrated that autophagosomes can be activated by interferon-gamma (IFN-gamma) to participate in immune defence by processing foreign antigens for the recognition and killing of intracellular pathogens. As we previously showed that HIV-1 Tat perturbs IFN-gamma signaling through the suppression of STAT1 phosphorylation and consequently inhibits major histocompatibility complex class-II antigen expression, we postulate that Tat plays a role in regulating autophagy. Methods: The role of STAT1 in IFN-gamma-induced autophagy in primary human blood macrophages was examined using a small molecule inhibitor or siRNA specific for STAT1. The effect of HIV-1 Tat on autophagy was investigated by pretreating the macrophages with HIV-1 Tat and followed by IFN-gamma stimulation. The expressions of autophagy-associated genes and their effects on engulfing mycobacteria were examined. Results: The activation of STAT1 resulted in IFN-gamma-induced LC3B protein expression and autophagosome formation. As postulated, HIV-1 Tat protein suppressed IFN-gamma-induced autophagy processes, including LC3B expression. Additionally, HIV-1 Tat restricted the capturing of mycobacteria by autophagosomes. Conclusion: HIV-1 Tat suppressed the induction of autophagy-associated genes and inhibited the formation of autophagosomes. Perturbation of such cellular processes by HIV-1 would impair the effective containment of invading pathogens, thereby providing a favorable environment for opportunistic microbes in HIV-infected individuals. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins