AUTHOR=Knoll Rainer , Bonaguro Lorenzo , dos Santos Jéssica C. , Warnat-Herresthal Stefanie , Jacobs-Cleophas Maartje C. P. , Blümel Edda , Reusch Nico , Horne Arik , Herbert Miriam , Nuesch-Germano Melanie , Otten Twan , van der Heijden Wouter A. , van de Wijer Lisa , Shalek Alex K. , Händler Kristian , Becker Matthias , Beyer Marc D. , Netea Mihai G. , Joosten Leo A. B. , van der Ven Andre J. A. M. , Schultze Joachim L. , Aschenbrenner Anna C. TITLE=Identification of drug candidates targeting monocyte reprogramming in people living with HIV JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1275136 DOI=10.3389/fimmu.2023.1275136 ISSN=1664-3224 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

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