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

AIDS. 2011 Jan 2;25(1):15-25. doi: 10.1097/QAD.0b013e328340fd61.


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-γ (IFN-γ) 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-γ 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-γ-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-γ stimulation. The expressions of autophagy-associated genes and their effects on engulfing mycobacteria were examined.

Results: The activation of STAT1 resulted in IFN-γ-induced LC3B protein expression and autophagosome formation. As postulated, HIV-1 Tat protein suppressed IFN-γ-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy* / genetics
  • Autophagy* / immunology
  • Blotting, Western
  • Cells, Cultured
  • HIV Infections / genetics
  • HIV Infections / metabolism*
  • HIV-1 / pathogenicity*
  • Humans
  • Interferon-gamma / metabolism*
  • Macrophages / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Transcriptional Activation
  • tat Gene Products, Human Immunodeficiency Virus / genetics
  • tat Gene Products, Human Immunodeficiency Virus / immunology*
  • tat Gene Products, Human Immunodeficiency Virus / pharmacology*


  • tat Gene Products, Human Immunodeficiency Virus
  • Interferon-gamma