Highly significant antiviral activity of HIV-1 LTR-specific tre-recombinase in humanized mice.
Highly significant antiviral activity of HIV-1 LTR-specific tre-recombinase in humanized mice.
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DOI：
10.1371/journal.ppat.1003587
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Hauber J
中科院分区：
文献类型：
--
作者：
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 MG;Buchholz F;Hauber J
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. Current antiretroviral combination therapy can efficiently suppress virus replication, but cannot eliminate HIV. Therefore, no cure for HIV exists. A main hurdle for virus eradication is seen in the existence of resting cells that contain integrated replication-competent, but temporarily silenced, HIV genomes. Therefore, the most direct approach to eliminating virus reservoirs is to remove HIV genomes from infected cells. As previous studies suggested, this may be achievable by Tre-recombinase, an engineered enzyme that can excise integrated HIV from host cell chromosomes. The present work analyzes the expression of Tre-recombinase in human cells and demonstrates highly accurate Tre activity in complete absence of Tre-related cytopathic effects. Furthermore, in vivo analysis of Tre-recombinase demonstrates highly significant antiviral effects of Tre in HIV-infected humanized mice. The presented data suggest that Tre-recombinase might become a valuable component of a future therapy that aims at virus eradication.
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影响因子：
5.4
作者：
Chemnitz, Jan;Pieper, Dorothea;Hauber, Joachim
通讯作者：
Hauber, Joachim
影响因子：
4.8
作者：
Fries, Barbara;Heukeshoven, Jochen;Chemnitz, Jan
通讯作者：
Chemnitz, Jan
影响因子：
56.9
作者：
HWANG, SS;BOYLE, TJ;CULLEN, BR
通讯作者：
CULLEN, BR
影响因子：
6.7
作者：
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--
影响因子：
16.8
作者：
Durand CM;Blankson JN;Siliciano RF
通讯作者：
Siliciano RF