Chromatin accessibility of human monocyte-derived dendritic cells in response to infection with HIV-1

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 three deidentified human donors and infected with a single cycle HIV-1 reporter virus (HIV-1-GFP) in the presence of Vpx. Mock conditions were treated only with Vpx. Cells were sorted by flow cytometry at the indicated times and according to the indicated conditions (GFP +/- or CD86 high/low) and immediately processed for an assay of transposase-accessible chromatin (ATAC-seq).