2. Academic Validation
  3. Transcriptional behavior of the HIV-1 promoter in context of the BACH2 prominent proviral integration gene

Transcriptional behavior of the HIV-1 promoter in context of the BACH2 prominent proviral integration gene

  • Virus Res. 2021 Feb:293:198260. doi: 10.1016/j.virusres.2020.198260.
Martin V Hamann 1,  Philipp Ehmele 2,  Roxane Verdikt 3,  Julia K Bialek-Waldmann 4,  Sanamjeet Virdi 5,  Thomas Günther 5,  Carine Van Lint 6,  Adam Grundhoff 5,  Joachim Hauber 1,  Ulrike C Lange 7
Affiliations

Affiliations

  • 1 Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251 Hamburg, Germany; German Center for Infection Research (DZIF), Germany.
  • 2 Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251 Hamburg, Germany; Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
  • 3 Institute for Society and Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium.
  • 4 Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251 Hamburg, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany.
  • 5 Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251 Hamburg, Germany.
  • 6 Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium.
  • 7 Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251 Hamburg, Germany; German Center for Infection Research (DZIF), Germany; Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Electronic address: [email protected].
PMID: 33316352 DOI: 10.1016/j.virusres.2020.198260
Abstract

Chronic Infection with human immunodeficiency virus (HIV)-1 is characterized by accumulation of proviral sequences in the genome of target cells. Integration of viral DNA in patients on long-term antiretroviral therapy selectively persists at preferential loci, suggesting site-specific crosstalk of viral sequences and human genes. This crosstalk likely contributes to chronic HIV disease through modulation of host immune pathways and emergence of clonal infected cell populations. To systematically interrogate such effects, we undertook genome engineering to generate Jurkat cell models that replicate integration of HIV-1 long terminal repeat (LTR) sequences at the BTB and CNC Homolog 2 (BACH2) integration locus. This locus is a prominent HIV-1 integration gene in chronic Infection, found in 30 % of long-term treated patients with mapped proviral integrations. Using five clonal models carrying an LTR-driven reporter at different BACH2 intergenic regions, we here show that LTR transcriptional activity is repressed in BACH2 regions associated with proviral-DNA integrations in vivo but not in a control region. Our data indicates that this repression is in part epigenetically regulated, particularly through DNA methylation. Importantly, we demonstrate that transcriptional activity of the LTR is independent of BACH2 gene transcription and vice versa in our models. This suggests no transcriptional interference of endogenous and HIV-1 promoters. Taken together, our study provides first insights into how activity of HIV-1 LTR sequences is regulated at the BACH2 locus as prominent example for a recurrently-detected integration gene in chronic Infection. Given the importance of integration-site dependent virus/host crosstalk for chronic HIV disease, our findings for the BACH2 locus have potential implications for future therapeutic strategies.

Keywords

Bach2; Clonal expansion; HIV-1; Recurrent detected integration genes; Transcriptional interference.

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