Highly significant antiviral activity of HIV-1 LTR-specific tre-recombinase in humanized mice

Hauber, Ilona; Hofmann-Sieber, Helga; Chemnitz, Jan; Dubrau, Danilo; Chusainow, Janet; Stucka, Rolf; Hartjen, Philip; Schambach, Axel; Ziegler, Patrick; Hackmann, Karl; Schröck, Evelin; Schumacher, Udo; Lindner, Christoph; Grundhoff, Adam; Baum, Christopher; Manz, Markus G.; Buchholz, Frank; Hauber, Joachim

doi:10.1371/journal.ppat.1003587

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Journal article

Highly significant antiviral activity of HIV-1 LTR-specific tre-recombinase in humanized mice

Hauber, Ilona Heinrich Pette Institute – Leibniz Institute for Experimental Virology, Hamburg, Germany
Hofmann-Sieber, Helga Heinrich Pette Institute – Leibniz Institute for Experimental Virology, Hamburg, Germany
Chemnitz, Jan Heinrich Pette Institute – Leibniz Institute for Experimental Virology, Hamburg, Germany
Dubrau, Danilo Heinrich Pette Institute – Leibniz Institute for Experimental Virology, Hamburg, Germany
Chusainow, Janet Department of Medical Systems Biology, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Stucka, Rolf Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University Munich, Munich, Germany
Hartjen, Philip Heinrich Pette Institute – Leibniz Institute for Experimental Virology, Hamburg, Germany - Infectious Diseases Unit, I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Schambach, Axel Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany - Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America
Ziegler, Patrick Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Klinik für Onkologie, Hämatologie und Stammzelltransplantation, RWTH Aachen University, Aachen, Germany
Hackmann, Karl Institute for Clinical Genetics, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Schröck, Evelin Institute for Clinical Genetics, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Schumacher, Udo Institute for Anatomy and Experimental Morphology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Lindner, Christoph Department of Gynecology, Day Kimball Healthcare Hospital, Hamburg, Germany
Grundhoff, Adam Heinrich Pette Institute – Leibniz Institute for Experimental Virology, Hamburg, Germany
Baum, Christopher Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
Manz, Markus G. Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - University Hospital Zürich, Division of Hematology, Zürich, Switzerland
Buchholz, Frank Department of Medical Systems Biology, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Hauber, Joachim Heinrich Pette Institute – Leibniz Institute for Experimental Virology, Hamburg, Germany

26.09.2013

Published in:

Plos pathogens. - 2013, vol. 9, no. 9, p. e1003587

English Stable integration of HIV proviral DNA into host cell chromosomes, a hallmark and essential feature of the retroviral life cycle, establishes the infection permanently. Current antiretroviral combination drug therapy cannot cure HIV infection. However, expressing an engineered HIV-1 long terminal repeat (LTR) site-specific recombinase (Tre), shown to excise integrated proviral DNA in vitro, may provide a novel and highly promising antiviral strategy. We report here the conditional expression of Tre-recombinase from an advanced lentiviral self-inactivation (SIN) vector in HIV-infected cells. We demonstrate faithful transgene expression, resulting in accurate provirus excision in the absence of cytopathic effects. Moreover, pronounced Tre-mediated antiviral effects are demonstrated in vivo, particularly in humanized Rag2−/−γc−/− mice engrafted with either Tre-transduced primary CD4+ T cells, or Tre-transduced CD34+ hematopoietic stem and progenitor cells (HSC). Taken together, our data support the use of Tre-recombinase in novel therapy strategies aiming to provide a cure for HIV.

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