title: HIV-1 trans-activator protein dysregulates IFN-γ signaling and contributes to the suppression of autophagy induction.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, China.
authors.forename: James C B
authors.initials: JC
authors.lastname: Li
authors.forename: Kin-yi
authors.initials: KY
authors.lastname: Au
authors.forename: Jun-wei
authors.initials: JW
authors.lastname: Fang
authors.forename: Howard C H
authors.initials: HC
authors.lastname: Yim
authors.forename: Kin-hung
authors.initials: KH
authors.lastname: Chow
authors.forename: Pak-leung
authors.initials: PL
authors.lastname: Ho
authors.forename: Allan S Y
authors.initials: AS
authors.lastname: Lau
mesh_terms: D001343:Autophagy / Q000235:genetics / Q000276:immunology; D015153:Blotting, Western; D002478:Cells, Cultured; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015533:Transcriptional Activation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*
chemical_list: D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma