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

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?/??c?/? 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.

SUBMITTER: Hauber I

PROVIDER: S-EPMC3784474 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Hauber Ilona I Hofmann-Sieber Helga H Chemnitz Jan J Dubrau Danilo D Chusainow Janet J Stucka Rolf R Hartjen Philip P Schambach Axel A Ziegler Patrick P Hackmann Karl K Schröck Evelin E Schumacher Udo U Lindner Christoph C Grundhoff Adam A Baum Christopher C Manz Markus G MG Buchholz Frank F Hauber Joachim J

PLoS pathogens 20130926 9

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 ...[more]

PMID: 24086129

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Project description:A major barrier in the use of humanized mice as models of HIV-1 (HIV) infection is the inadequate generation of virus-specific antibody responses. Humanized DRAGA (hDRAGA) mice generate antigen-specific class switched antibodies to several pathogens, but whether they do so in HIV infection and the extent to which their secondary lymphoid tissues (sLT) support germinal center responses is unknown. hDRAGA mice were evaluated for their ability to support HIV replication, generate virus-specific antibody responses, develop splenocyte subsets, and organize sLT architecture. hDRAGA mice supported persistent HIV replication and developed modest levels of gp41-specific human IgM and IgG. Spleens from uninfected and HIV infected hDRAGA mice contained differentiated B and CD4+ T cell subsets including germinal center (GC) B cells and T follicular helper cells (TFH); relative expansions of TFH and CD8+ T cells, but not GC B cells, occurred in HIV-infected hDRAGA mice compared to uninfected animals. Immunofluorescent staining of spleen and mesenteric lymph node sections demonstrated atypical morphology. Most CD4+ and CD8+ T cells resided within CD20hi areas. CD20hi areas lacked canonical germinal centers, as defined by staining for IgD-Ki67+cells. No human follicular dendritic cells (FDC) were detected. Mouse FDC were distributed broadly throughout both CD20hi and CD20lo regions of sLT. HIV RNA particles were detected by in situ hybridization within CD20+ areas and some co-localized with mouse FDC. Viral RNA+ cells were more concentrated within CD20hi compared to CD20lo areas of sLT, but differences were diminished in spleen and eliminated in mesenteric lymph nodes when adjusted for CD4+ cell frequency. Thus, hDRAGA mice recapitulated multiple aspects of HIV pathogenesis including HIV replication, relative expansions in TFH and CD8+ T cells, and modest HIV-specific antibody production. Nevertheless, classical germinal center morphology in sLT was not observed, which may account for the inefficient expansion of GC B cells and generation of low titer human antibody responses to HIV-1 in this model.

Dataset Information

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

Publications

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

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