Identification of drug candidates targeting monocyte reprogramming in people living with HIV
Rainer Knoll, Lorenzo Bonaguro, Jéssica Cristina dos Santos, Stefanie Warnat‐Herresthal, Maartje Jacobs‐Cleophas, Edda Blümel, Nico Reusch, Arik Horne, Miriam Herbert, Melanie Nuesch-Germano, Twan Otten, Wouter A. van der Heijden, Lisa Van de Wijer, Alex K. Shalek, Kristian Händler, Matthias Becker, Marc Beyer, Mihai G. Netea, Leo A. B. Joosten, André van der Ven, Joachim L. Schultze, Anna C. Aschenbrenner
Abstract
Introduction: People living with HIV (PLHIV) are characterized by functional reprogramming of innate immune cells even after long-term antiretroviral therapy (ART). In order to assess technical feasibility of omics technologies for application to larger cohorts, we compared multiple omics data layers. Methods: drug stimulation were performed in a small number of blood samples derived from PLHIV and healthy controls from the 200-HIV cohort study. Results: Single-cell RNA-seq analysis revealed that most immune cells in peripheral blood of PLHIV are altered in their transcriptomes and that a specific functional monocyte state previously described in acute HIV infection is still existing in PLHIV while other monocyte cell states are only occurring acute infection. Further, a reverse transcriptome approach on a rather small number of PLHIV was sufficient to identify drug candidates for reversing the transcriptional phenotype of monocytes in PLHIV. Discussion: These scientific findings and technological advancements for clinical application of single-cell transcriptomics form the basis for the larger 2000-HIV multicenter cohort study on PLHIV, for which a combination of bulk and single-cell transcriptomics will be included as the leading technology to determine disease endotypes in PLHIV and to predict disease trajectories and outcomes.