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

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

Author information

1
Center for Infectious Disease Research, Seattle, WA 98109, USA. Electronic address: jarrod.johnson@biochem.utah.edu.
2
Center for Infectious Disease Research, Seattle, WA 98109, USA.
3
Center for Infectious Disease Research, Seattle, WA 98109, USA; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
4
Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.

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

PMID:
29544097
PMCID:
PMC6176724
[Available on 2019-03-14]
DOI:
10.1016/j.chom.2018.01.012
[Indexed for MEDLINE]

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