Genomic profiling of HIV-1 integration in microglia cells links viral integration to the topologically associated domains
Mona Rheinberger,
Ana Luisa Costa,
Martin Kampmann,
Dunja Glavas,
Iart Luca Shytaj,
Sheetal Sreeram,
Carlotta Penzo,
Nadine Tibroni,
Yoelvis Garcia-Mesa,
Konstantin Leskov,
Oliver T. Fackler,
Kristian Vlahovicek,
Jonathan Karn,
Bojana Lucic,
Carl Herrmann,
Marina Lusic
Affiliations
Mona Rheinberger
Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), 69120 Heidelberg, Germany
Ana Luisa Costa
Health Data Science Unit, Medical Faculty University Heidelberg and BioQuant, 69120 Heidelberg, Germany
Martin Kampmann
Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany
Dunja Glavas
Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
Iart Luca Shytaj
Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), 69120 Heidelberg, Germany
Sheetal Sreeram
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA
Carlotta Penzo
Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany
Nadine Tibroni
Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany
Yoelvis Garcia-Mesa
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA
Konstantin Leskov
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA
Oliver T. Fackler
Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), 69120 Heidelberg, Germany
Kristian Vlahovicek
Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
Jonathan Karn
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA
Bojana Lucic
Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), 69120 Heidelberg, Germany; Corresponding author
Carl Herrmann
Health Data Science Unit, Medical Faculty University Heidelberg and BioQuant, 69120 Heidelberg, Germany; Corresponding author
Marina Lusic
Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), 69120 Heidelberg, Germany; Corresponding author
Summary: HIV-1 encounters the hierarchically organized host chromatin to stably integrate and persist in anatomically distinct latent reservoirs. The contribution of genome organization in HIV-1 infection has been largely understudied across different HIV-1 targets. Here, we determine HIV-1 integration sites (ISs), associate them with chromatin and expression signatures at different genomic scales in a microglia cell model, and profile them together with the primary T cell reservoir. HIV-1 insertions into introns of actively transcribed genes with IS hotspots in genic and super-enhancers, characteristic of blood cells, are maintained in the microglia cell model. Genome organization analysis reveals dynamic CCCTC-binding factor (CTCF) clusters in cells with active and repressed HIV-1 transcription, whereas CTCF removal impairs viral integration. We identify CTCF-enriched topologically associated domain (TAD) boundaries with signatures of transcriptionally active chromatin as HIV-1 integration determinants in microglia and CD4+ T cells, highlighting the importance of host genome organization in HIV-1 infection.
