Unmasking two stages of interferon signaling in dendritic cells infected with HIV-1

• Published in: The Journal of immunology (1950) 2016-05, Vol.196 (1_Supplement), p.61-61.8
• Main Authors: Johnson, Jarrod S, Lucas, Sasha, Skelton, Stephanie, Nazitto, Rodolfo, Amon, Lynn, Littman, Dan R, Aderem, Alan
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.196.Supp.61.8

Myeloid dendritic cells (DCs) have the innate capacity to sense pathogens and mount counteroffensive responses, which include the production of type I and type III interferons (IFN). In the case of HIV-1 infection, DCs can internalize and present viral antigens, but the majority of DCs are not productively infected due to restriction at the level of reverse transcription. Consequently, DCs do not efficiently ‘sense’ HIV-1, fail to produce IFN, do not mature, and cannot program appropriate adaptive immune responses. To improve our understanding of how IFN and cell maturation are regulated in monocyte-derived DCs, we have used systems analyses to study how DCs respond to HIV-1 after removing the block to reverse transcription with the lentiviral protein Vpx. We have profiled changes in open chromatin during infection using an assay for transposase-accessible chromatin (ATAC-seq), and have tracked the kinetics of gene expression in parallel. Using antiretroviral drugs and virus mutants to separate stages of the life cycle, we have determined that at least two signals cooperate to drive innate immune responses during HIV-1 infection: the first coming from the cytoplasmic sensor, cGAS, which is known to recognize reverse transcribed HIV cDNA, and the second from an unrelated pathway engaged after virus integration. Moreover, by interrogating infection in combination with a battery of classic innate agonists we have found that HIV-1 primes DCs to produce IFN, even in the presence of certain antiretroviral drugs. Our studies demonstrate that robust IFN production in response to HIV-1 infection depends on the coordinated action of distinct transcription factors and illuminate key pathways that regulate innate immunity in myeloid cells.