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


Hauber, I; Hofmann-Sieber, H; Chemnitz, J; Dubrau, D; Chusainow, J; Stucka, R; Hartjen, P; Schambach, A; Ziegler, P; Hackmann, K; Schröck, E; Schumacher, U; Lindner, C; Grundhoff, A; Baum, C; Manz, M G; Buchholz, F; Hauber, J (2013). Highly significant antiviral activity of HIV-1 LTR-specific tre-recombinase in humanized mice. PLoS Pathogens, 9(9):e1003587.

Abstract

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.

Abstract

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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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:9 September 2013
Deposited On:18 Nov 2013 09:35
Last Modified:09 Aug 2017 13:05
Publisher:Public Library of Science (PLoS)
ISSN:1553-7366
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1371/journal.ppat.1003587
PubMed ID:24086129

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