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


  • R. Knoll
  • L. Bonaguro
  • J.C. Dos Santos
  • S. Warnat-Herresthal
  • M.C.P. Jacobs-Cleophas
  • E. Blümel
  • N. Reusch
  • A. Horne
  • M. Herbert
  • M. Nuesch-Germano
  • T. Otten
  • W.A. van der Heijden
  • L. van de Wijer
  • A.K. Shalek
  • K. Händler
  • M. Becker
  • M.D. Beyer
  • M.G. Netea
  • L.A.B. Joosten
  • A.J.A.M. van der Ven
  • J.L. Schultze
  • A.C. Aschenbrenner


  • Frontiers in Immunology


  • Front Immunol 14: 1275136


  • 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.