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Nuclear landscape of HIV-1 integration in microglia – unexplored HIV-1 reservoirs

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Applicant

Dr. Carl Herrmann

Ruprecht-Karls-Universität Heidelberg 
Institut für Pharmazie und Molekulare Biotechnologie (IPMB)  

www.hdsu.org

Dr. Marina Lusic, Ph.D.
Universitätsklinikum Heidelberg 
Department für Infektiologie 

Summary

The introduction of combinatorial antiretroviral therapy (cART) has significantly improved the management of HIV-1 infection as well as the health and life expectancy of HIV-1 infected individuals. While viral loads can be efficiently controlled by cART, transcriptionally silenced, but replication competent virus persists integrated into the host genome, creating long-lasting reservoirs in different anatomical sites throughout the body. These long-lived reservoirs in memory T cells, macrophages and brain microglia, are unreachable by current treatments and impede a functional HIV-1 cure . Where the virus is hidden in the human genome has functional consequences for the viral fate . Our previous work on T cells, major sanctuaries of latent HIV-1, has started exploring the link between 3D host genome organization and HIV-1 integration site selection. We showed that HIV-1 does not position its genome randomly but prefers the outer spatial shells, associated with the open chromatin domains underneath the nuclear pore complex (NPC) . More recently we discovered that HIV-1 commonly targets clusters of cell type specific genes with super-enhancer (SE) regulatory elements (Lucic et al doi: doi.org/10.1101/287896).   Whereas  several  studies report on the mechanisms of chromatin mediated transcriptional silencing of HIV-1 in microglia, almost nothing is known about the integration sites of the virus in these cells. Here we propose to study HIV-1 integration and latency in microglia through a genomics view-point and to investigate DNA features and chromatin factors that could contribute to integration and silencing events in HIV-1 life cycle. We propose to identify the integration sites of HIV-1, to define the chromatin signatures and to map the genome contacts with respect to the integrated viral genome. Lusic lab will focus on the cell biology and genomics of viral infection, while the Herrmann group will contribute to the project by analysing these complex genomics data and generating an overall picture of chromatin profiles and genomic contacts relevant for the virus in microglial cells. We will join forces with other members of the SPP proposal, and we will collaborate directly with Vassilis Roukos (IMB Mainz) and Irina Solovei (LMU Munich) to visualize HIV-1 and genomic regions where it integrates in microglia by fluorescence in situ hybridization (FISH) and high-throughput microscopy.