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

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 re...

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Veröffentlicht in:PLoS pathogens 2013-09, Vol.9 (9), p.e1003587-e1003587
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1003587