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

PLoS Pathog. 2013;9(9):e1003587. doi: 10.1371/journal.ppat.1003587. Epub 2013 Sep 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Genetic Therapy / methods*
  • Genetic Vectors
  • HIV Infections* / genetics
  • HIV Infections* / metabolism
  • HIV Infections* / therapy
  • HIV Long Terminal Repeat*
  • HIV-1 / genetics
  • HIV-1 / metabolism*
  • Humans
  • Integrases / genetics
  • Integrases / metabolism*
  • Mice
  • Mice, Knockout
  • Proviruses / genetics
  • Proviruses / metabolism*
  • Transduction, Genetic
  • Transplantation Chimera
  • Virus Integration / genetics

Substances

  • Integrases
  • Tre-Recombinase

Grant support

This work was financially supported by a grant of the Federal Ministry of Education and Research (GO-Bio FKZ 0315090). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.