RIG-I-mediated antiviral signaling is inhibited in HIV-1 infection by a protease-mediated sequestration of RIG-I

J Virol. 2011 Feb;85(3):1224-36. doi: 10.1128/JVI.01635-10. Epub 2010 Nov 17.

Abstract

The rapid induction of type I interferon (IFN) is essential for establishing innate antiviral responses. During infection, cytoplasmic viral RNA is sensed by two DExD/H box RNA helicases, RIG-I and MDA5, ultimately driving IFN production. Here, we demonstrate that purified genomic RNA from HIV-1 induces a RIG-I-dependent type I IFN response. Both the dimeric and monomeric forms of HIV-1 were sensed by RIG-I, but not MDA5, with monomeric RNA, usually found in defective HIV-1 particles, acting as a better inducer of IFN than dimeric RNA. However, despite the presence of HIV-1 RNA in the de novo infection of monocyte-derived macrophages, HIV-1 replication did not lead to a substantial induction of IFN signaling. We demonstrate the existence of an evasion mechanism based on the inhibition of the RIG-I sensor through the action of the HIV-1 protease (PR). Indeed, the ectopic expression of PR resulted in the inhibition of IFN regulatory factor 3 (IRF-3) phosphorylation and decreased expression of IFN and interferon-stimulated genes. A downregulation of cytoplasmic RIG-I levels occurred in cells undergoing a single-cycle infection with wild-type provirus BH10 but not in cells transfected with a protease-deficient provirus, BH10-PR(-). Cellular fractionation and confocal microscopy studies revealed that RIG-I translocated from the cytosol to an insoluble fraction during the de novo HIV-1 infection of monocyte-derived macrophages, in the presence of PR. The loss of cytoplasmic RIG-I was prevented by the lysosomal inhibitor E64, suggesting that PR targets RIG-I to the lysosomes. This study reveals a novel PR-dependent mechanism employed by HIV-1 to counteract the early IFN response to viral RNA in infected cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / antagonists & inhibitors*
  • HIV Protease / metabolism*
  • HIV-1 / immunology*
  • HIV-1 / pathogenicity*
  • Humans
  • Immune Evasion*
  • Interferon Regulatory Factor-3 / antagonists & inhibitors
  • Interferons / antagonists & inhibitors*
  • Interferons / immunology
  • Macrophages / immunology
  • Macrophages / virology
  • Protein Binding
  • RNA, Viral / immunology
  • Receptors, Immunologic
  • Signal Transduction*

Substances

  • Interferon Regulatory Factor-3
  • RNA, Viral
  • Receptors, Immunologic
  • Interferons
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1
  • RIGI protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases