Important note: Information in this article was accurate in 2000. The state of the art may have changed since the publication date.
Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences.
Nat Genet. 2000 Jun;25(2):217-22. Unique Identifier : AIDSLINE MED/20296629 Follenzi A; Ailles LE; Bakovic S; Geuna M; Naldini L; Laboratorie for Gene Transfer and Therapy, IRCC, Institute for; Cancer Research and Treatment, University of Torino Medical; School, Candiolo (Torino), Italy.
Abstract:
Gene-transfer vectors based on lentiviruses are distinguished by their ability to transduce non-dividing cells. The HIV-1 proteins Matrix, Vpr and Integrase have been implicated in the nuclear import of the viral genome in non-dividing cells. Here we show that a sequence within pol is also required in cis. It contains structural elements previously associated with the progress of reverse transcription in target cells. We restored these elements in cis within late-generation lentiviral vectors. The new vector transduced to a much higher efficiency several types of human primary cells, when both growing and growth-arrested, including haematopoietic stem cells assayed by long-term repopulation of NOD/SCID mice. On in vivo administration into SCID mice, the vector induced higher plasma levels of human clotting factor IX (F.IX) than non-modified vector. Our results indicate that nuclear translocation of the genome is a rate-limiting step in lentiviral infection of both dividing and non-dividing cells, and that it depends on protein and nucleic acid sequence determinants. Full rescue of this step in lentivirus-based vectors improves performance for gene-therapy applications.
Keywords: JOURNAL ARTICLE Animal Base Sequence Cell Division Cell Nucleus/*GENETICS/METABOLISM/VIROLOGY Cells, Cultured Endothelium, Vascular/CYTOLOGY/METABOLISM Factor IX/ANALYSIS/GENETICS Fibroblasts/CYTOLOGY/METABOLISM Gene Products, pol/*GENETICS/PHYSIOLOGY *Gene Transfer Genes, Viral/GENETICS/PHYSIOLOGY Genetic Vectors/*GENETICS Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells/CYTOLOGY/METABOLISM Human HIV-1/*GENETICS/PHYSIOLOGY Lymphocytes/CYTOLOGY/METABOLISM Macrophages/CYTOLOGY/METABOLISM Mice Mice, SCID Molecular Sequence Data RNA, Viral/GENETICS/METABOLISM Support, Non-U.S. Gov't Transduction, Genetic/*GENETICS Virus Integration
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Important note: Information in this article was accurate in 2000. The state of the art may have changed since the publication date.
