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

Publication date: 14 March 2018
Source:Cell Host & Microbe, Volume 23, Issue 3
Author(s): Jarrod S. Johnson, Sasha Y. Lucas, Lynn M. Amon, Stephanie Skelton, Rodolfo Nazitto, Sara Carbonetti, D. Noah Sather, Dan R. Littman, Alan Aderem
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.

Graphical abstract

Teaser

Parameters regulating the innate immune response to HIV-1 remain unclear. Johnson et al. elucidate how dendritic cells sense HIV-1 in two stages. They demonstrate that cGAS/STING signaling can be tuned through unrelated pathways to unmask interferon responses before and after HIV-1 integration.


http://ift.tt/2FByzdw