Highly significant antiviral activity of HIV-1 LTR-specific tre-recombinase in humanized mice
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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.
In: PLOS PATHOG, Vol. 9, No. 9, 01.01.2013, p. e1003587.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Highly significant antiviral activity of HIV-1 LTR-specific tre-recombinase in humanized mice
AU - Hauber, Ilona
AU - Hofmann-Sieber, Helga
AU - Chemnitz, Jan
AU - Dubrau, Danilo
AU - Chusainow, Janet
AU - Stucka, Rolf
AU - Hartjen, Philip
AU - Schambach, Axel
AU - Ziegler, Patrick
AU - Hackmann, Karl
AU - Schröck, Evelin
AU - Schumacher, Udo
AU - Lindner, Christoph
AU - Grundhoff, Adam
AU - Baum, Christopher
AU - Manz, Markus G
AU - Buchholz, Frank
AU - Hauber, Joachim
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
AB - 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.
KW - Animals
KW - Genetic Therapy
KW - Genetic Vectors
KW - HIV Infections
KW - HIV Long Terminal Repeat
KW - HIV-1
KW - Humans
KW - Integrases
KW - Mice
KW - Mice, Knockout
KW - Proviruses
KW - Transduction, Genetic
KW - Transplantation Chimera
KW - Virus Integration
U2 - 10.1371/journal.ppat.1003587
DO - 10.1371/journal.ppat.1003587
M3 - SCORING: Journal article
C2 - 24086129
VL - 9
SP - e1003587
JO - PLOS PATHOG
JF - PLOS PATHOG
SN - 1553-7366
IS - 9
ER -