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Cell. 2015 Jun 4;161(6):1293-1305. doi: 10.1016/j.cell.2015.04.050.

PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1.

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Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, D-63225 Langen, Germany.
Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor, MI 48109.
Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029.
APHP, Hôpital Robert Debré, DHU PROTECT, Service de Neurologie Pédiatrique et Pathologie Métabolique, F-75019 Paris 2. Sorbonne Paris Cité, Université Paris Diderot, F-75010.
National Reference Center for Fragile X and Other XLID, Biobank NeuroBioTec, Hospices Civils de Lyon, Université de Lyon and CNRS UMR 5304 (L2C2), Bron, France.
Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029.
German Center for Infection Research (DZIF), Langen, Germany.
Contributed equally


Dendritic cells (DCs) play a critical role in the immune response to viral infection through the facilitation of cell-intrinsic antiviral activity and the activation of adaptive immunity. HIV-1 infection of DCs triggers an IRF3-dependent innate immune response, which requires the activity of cyclic GAMP synthase (cGAS). We report the results of a targeted RNAi screen utilizing primary human monocyte-derived DCs (MDDCs) to identify immune regulators that directly interface with HIV-1-encoded features to initiate this innate response. Polyglutamine binding protein 1 (PQBP1) emerged as a strong candidate through this analysis. We found that PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response. MDDCs derived from Renpenning syndrome patients, who harbor mutations in the PQBP1 locus, possess a severely attenuated innate immune response to HIV-1 challenge, underscoring the role of PQBP1 as a proximal innate sensor of a HIV-1 infection.

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