Reshaping of the Dendritic Cell Chromatin Landscape and Interferon Pathways during HIV Infection

Cell Host Microbe. 2018 Mar 14;23(3):366-381.e9. doi: 10.1016/j.chom.2018.01.012.

Abstract

Myeloid dendritic cells (DCs) have the innate capacity to sense pathogens and orchestrate immune responses. However, DCs do not mount efficient immune responses to HIV-1, primarily due to restriction of virus reverse transcription, which prevents accumulation of viral cDNA and limits its detection through the cGAS-STING pathway. By allowing reverse transcription to proceed, we find that DCs detect HIV-1 in distinct phases, before and after virus integration. Blocking integration suppresses, but does not abolish, activation of the transcription factor IRF3, downstream interferon (IFN) responses, and DC maturation. Consistent with two stages of detection, HIV-1 "primes" chromatin accessibility of innate immune genes before and after integration. Once primed, robust IFN responses can be unmasked by agonists of the innate adaptor protein, MyD88, through a process that requires cGAS, STING, IRF3, and nuclear factor κB. Thus, HIV-1 replication increases material available for sensing, and discrete inflammatory inputs tune cGAS signaling to drive DC maturation.

Keywords: DNA sensing; HIV integration; HIV-1; IRF3; STING; cGAS; chromatin modification; dendritic cell; innate immunity; type I interferon.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Chromatin / metabolism*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Female
  • HEK293 Cells
  • HIV Infections / metabolism
  • HIV-1 / immunology*
  • HIV-1 / pathogenicity
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / metabolism
  • Interferons / metabolism*
  • Male
  • Membrane Proteins / metabolism
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Nucleotidyltransferases / metabolism
  • Reverse Transcription
  • Signal Transduction
  • THP-1 Cells
  • Virus Integration
  • Virus Replication

Substances

  • Chromatin
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • MYD88 protein, human
  • Membrane Proteins
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • STING protein, human
  • Interferons
  • MB21D1 protein, human
  • Nucleotidyltransferases