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 Glavaš, Iart Luca Shytaj, Sheetal Sreeram, Carlotta Penzo, Nadine Tibroni, Yoelvis García‐Mesa, Konstantin Leskov, O. Fackler, Kristian Vlahoviček, Jonathan Karn, Bojana Lucic, Carl Herrmann, Marina Lušić
Abstract
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.