A Reproducibility-Based Computational Framework Identifies An Inducible, Enhanced Antiviral Dendritic Cell State In HIV-1 Elite Controllers (TLR perturbation Bulk RNA-Seq)

Human immunity relies on the coordinated responses of many cellular subsets and functional states. Inter-individual variations in cellular composition and communication could thus potentially alter host protection. Here, we explore this hypothesis by applying single-cell RNA-Seq to examine viral responses among the dendritic cells (DCs) of three elite controllers (ECs) of HIV-1 infection. We discover a highly functional antiviral DC state in ECs whose fractional abundance after in vitro exposure to HIV-1 correlates with higher CD4+ T cell counts and lower HIV-1 viral loads, and that effectively primes polyfunctional T cell responses in vitro. We identify and validate select immunomodulators that increase the fractional abundance of this state in primary peripheral blood mononuclear cells (PBMCs) from healthy individuals in vitro. Overall design: Bulk RNA-seq profiling of TLR-perturbed cDCs and controls from a healthy donor for comparison with gene expression programs associated with cell-intrinsic HIV-1 immune recognition.

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Martin-Gayo E, Cole MB, Kolb KE, Ouyang Z, Cronin J, Kazer SW, Ordovas-Montanes J, Lichterfeld M, Walker BD, Yosef N, Shalek AK, Yu XG