Highly Significant Antiviral Activity of HIV-1 LTR-Specific Tre-Recombinase in Humanized Mice

PLoS Pathogens

Markus G. Manz¹  Janet Chusainow²  Karl Hackmann³  Rolf Stucka⁴  Philip Hartjen⁵  Helga Hofmann-Sieber⁵  Danilo Dubrau⁵  Frank Buchholz⁵  Ilona Hauber⁵  Jan Chemnitz⁵  Axel Schambach⁶  Christopher Baum⁷  Adam Grundhoff⁸  Christoph Lindner⁸  Evelin Schröck⁹  Joachim Hauber^1,10  Patrick Ziegler^1,10  Udo Schumacher^1,11 

[1] Department of Gynecology, Day Kimball Healthcare Hospital, Hamburg, Germany;Department of Medical Systems Biology, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany;Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America;Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University Munich, Munich, Germany;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;Institute for Anatomy and Experimental Morphology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute for Clinical Genetics, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany;Institute for Research in Biomedicine, Bellinzona, Switzerland;Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany;Klinik für Onkologie, Hämatologie und Stammzelltransplantation, RWTH Aachen University, Aachen, Germany

关键词: HIV-1;    T cells;    Polymerase chain reaction;    HIV;    Mouse models;    DNA recombination;    Mammalian genomics;    Cell staining;   

DOI  :  10.1371/journal.ppat.1003587

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY