Intron-containing RNA from the HIV-1 provirus activates type I interferon and inflammatory cytokines

Nat Commun. 2018 Dec 13;9(1):5305. doi: 10.1038/s41467-018-07753-2.


HIV-1-infected people who take drugs that suppress viremia to undetectable levels are protected from developing AIDS. Nonetheless, HIV-1 establishes proviruses in long-lived CD4+ memory T cells, and perhaps other cell types, that preclude elimination of the virus even after years of continuous antiviral therapy. Here we show that the HIV-1 provirus activates innate immune signaling in isolated dendritic cells, macrophages, and CD4+ T cells. Immune activation requires transcription from the HIV-1 provirus and expression of CRM1-dependent, Rev-dependent, RRE-containing, unspliced HIV-1 RNA. If rev is provided in trans, all HIV-1 coding sequences are dispensable for activation except those cis-acting sequences required for replication or splicing. Our results indicate that the complex, post-transcriptional regulation intrinsic to HIV-1 RNA is detected by the innate immune system as a danger signal, and that drugs which disrupt HIV-1 transcription or HIV-1 RNA metabolism would add qualitative benefit to current antiviral drug regimens.

Publication types

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

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology*
  • Cell Line
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / virology
  • Gene Expression Regulation, Viral / genetics
  • HEK293 Cells
  • HIV-1 / genetics
  • HIV-1 / growth & development*
  • HIV-1 / immunology
  • Humans
  • Interferon Type I / metabolism
  • Macrophages / immunology
  • Proviruses / genetics
  • Proviruses / growth & development*
  • RNA Splicing / genetics
  • RNA, Viral / biosynthesis*
  • RNA, Viral / genetics
  • Virus Replication / drug effects*
  • rev Gene Products, Human Immunodeficiency Virus / genetics


  • Anti-HIV Agents
  • Cytokines
  • Interferon Type I
  • RNA, Viral
  • rev Gene Products, Human Immunodeficiency Virus
  • rev protein, Human Immunodeficiency Virus-1