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A Comprehensive Map of the Monocyte-Derived Dendritic Cell Transcriptional Network Engaged upon Innate Sensing of HIV.

Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Center for Infectious Disease Research, Seattle, WA 98109, USA. Electronic address: jarrod.johnson@biochem.utah.edu. Flatiron Institute, Center for Computational Biology, Simons Foundation, New York, NY 10010, USA. Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, 75005 Paris, France. Center for Infectious Disease Research, Seattle, WA 98109, USA. Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, INSERM UMR 1163, ATIP-Avenir Team, Université de Paris, 24 Boulevard du Montparnasse, 75015 Paris, France. Center for Infectious Disease Research, Seattle, WA 98109, USA; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. 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. Flatiron Institute, Center for Computational Biology, Simons Foundation, New York, NY 10010, USA; Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10003, USA; Center for Data Science, New York University, New York, NY 10011, USA. Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, INSERM UMR 1163, ATIP-Avenir Team, Université de Paris, 24 Boulevard du Montparnasse, 75015 Paris, France; The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address: mickael.menager@institutimagine.org.

Cell reports. 2020;(3):914-931.e9
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Abstract

Transcriptional programming of the innate immune response is pivotal for host protection. However, the transcriptional mechanisms that link pathogen sensing with innate activation remain poorly understood. During HIV-1 infection, human dendritic cells (DCs) can detect the virus through an innate sensing pathway, leading to antiviral interferon and DC maturation. Here, we develop an iterative experimental and computational approach to map the HIV-1 innate response circuitry in monocyte-derived DCs (MDDCs). By integrating genome-wide chromatin accessibility with expression kinetics, we infer a gene regulatory network that links 542 transcription factors with 21,862 target genes. We observe that an interferon response is required, yet insufficient, to drive MDDC maturation and identify PRDM1 and RARA as essential regulators of the interferon response and MDDC maturation, respectively. Our work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting complexity and cooperativity in the regulatory circuit controlling the response to infection.