Frontiers in immunology · 2023
Identification of drug candidates targeting monocyte reprogramming in people living with HIV.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.
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.