Transcriptomic responses of human monocyte-derived dendritic cells to HIV and other innate stimuli

Transcriptional programming of the innate immune response is pivotal for host protection. The transcriptional mechanisms that link pathogen sensing with innate activation remain poorly understood. During infection with HIV-1, human dendritic cells (DCs) can detect the virus through an innate sensing pathway leading to antiviral type I interferon and DC maturation. Here, we have developed an iterative experimental and computational approach to map the innate response circuitry during HIV-1 infection. By integrating genome-wide chromatin accessibility with expression kinetics, we have inferred a gene regulatory network that links 542 transcription factors (TFs) with 21,862 target genes. Through genetic perturbation and drug treatments we identify PRDM1 and RARA as essential regulators of the interferon response and DC maturation, respectively. This work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting the complexity and cooperativity in the regulatory circuit controlling the DC response to HIV-1 infection. Overall design: DCs were derived from the peripheral blood from seven deidentified human donors and infected with HIV or stimulated with innate immune agonists. Conditions include infection with HIV-1-GFP in the presence or absence of Vpx, infection with wild type HIV-1, HIV-2, mutated HIV-2 capsid, or stimulation with LPS ( 100ng/ml), polyIC (10ug/ml) , cGAMP, recombinant IFN, R848, and polydCdG. Bulk RNA-Seq was performed on cells at 0, 2, 6, 24, and 48 hours after infection or stimulation as indicated. For some samples, cells were sorted by flow cytometry prior to sequencing based on GFP or CD86 expression as indicated.