HIV-1 activation of innate immunity depends strongly on the intracellular level of TREX1 and sensing of incomplete reverse transcription products

Swati Kumar, James H. Morrison, David Dingli, Eric M Poeschla

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

TREX1 has been reported to degrade cytosolic immune-stimulatory DNA, including viral DNA generated during HIV-1 infection; but the dynamic range of its capacity to suppress innate immune stimulation is unknown, and its full role in the viral life cycle remains unclear. A main purpose of our study was to determine how the intracellular level of TREX1 affects HIV-1 activation and avoidance of innate immunity. Using stable overexpression and CRISPR-mediated gene disruption, we engineered a range of TREX1 levels in human THP-1 monocytes. Increasing the level of TREX1 dramatically suppressed HIV-1 induction of interferon-stimulated genes (ISGs). Productive infection and integrated proviruses were equal or increased. Knocking out TREX1 impaired viral infectivity, increased early viral cDNA, and caused 10-fold or greater increases in HIV-1 ISG induction. Knockout of cyclic GMP-AMP synthase (cGAS) abrogated all ISG induction. Moreover, cGAS knockout produced no increase in single-cycle infection, establishing that HIV-1 DNA-triggered signaling is not rapid enough to impair the initial ISG-triggering infection cycle. Disruption of the HIV-1 capsid by PF74 also induced ISGs, and this was TREX1 level dependent, required reverse transcriptase catalysis, and was eliminated by cGAS gene knockout. Thus, the intracellular level of TREX1 pivotally modulates innate immune induction by HIV-1. Partial HIV-1 genomes are the TREX1 target and are sensed by cGAS. The nearly complete lack of innate immune induction despite equal or increased viral integration observed when the TREX1 protein level is experimentally elevated indicates that integration-competent genomes are shielded from cytosolic sensoreffectors during uncoating and transit to the nucleus.

Original languageEnglish (US)
Article numbere00001-18
JournalJournal of Virology
Volume92
Issue number16
DOIs
StatePublished - Aug 1 2018

Keywords

  • Capsid
  • CGAS
  • HIV-1
  • Innate immunity
  • PF74
  • Reverse transcription
  • TREX1

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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