Identification of drug candidates targeting monocyte reprogramming in people living with HIV.

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: Bulk and single-cell transcriptomics, flow cytometry, proteomics, chromatin landscape analysis by ATAC-seq as well as 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.

Copyright © 2023 Knoll, Bonaguro, dos Santos, Warnat-Herresthal, Jacobs-Cleophas, Blümel, Reusch, Horne, Herbert, Nuesch-Germano, Otten, van der Heijden, van de Wijer, Shalek, Händler, Becker, Beyer, Netea, Joosten, van der Ven, Schultze and Aschenbrenner.

PMID: 38077315