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1.
Vaccine ; 30(15): 2499-509, 2012 Mar 28.
Article in English | MEDLINE | ID: mdl-22342915

ABSTRACT

Despite being at the origin of one of the world's most devastating public health concerns, the Human Immunodeficiency Virus (HIV) has properties that can be harnessed for therapeutic purposes. Indeed, the ability of HIV to efficiently deliver its genome into the nuclear compartment makes it an ideal vector for gene delivery into target cells. The design of so-called HIV-derived vectors, or more generally lentiviral vectors (LVs), consists in keeping only the parts of the virus that ensure efficient nuclear delivery while entirely removing all coding sequences that contribute towards the replication and pathogenesis of the virus: as a result, the vector genome is composed of less than 10% of the original virus genome and exclusively cis-active sequences. Proteins required for the formation of the lentivector particles and for the early steps of viral replication (including Gag- and Pol-derived proteins) are provided in trans. HIV-derived vectors are thus non-replicative virus shells that deliver genes of interest into target cells with high efficiency. Undoubtedly, there is a hopeful twist of fate in our fight against AIDS, which consists in using these vectors to achieve gene therapy and vaccination against HIV itself. This review summarises the current generation of LVs with a special focus on vaccine applications against AIDS. Preclinical data are very encouraging and efforts are ongoing to optimise these vectors, to increase their safety and improve their immunogenicity.


Subject(s)
Genetic Vectors , HIV Infections/therapy , HIV-1/genetics , AIDS Vaccines/genetics , AIDS Vaccines/therapeutic use , Animals , Genetic Therapy , HIV Infections/prevention & control , Humans , Lentivirus/genetics
2.
Hum Gene Ther ; 18(9): 811-20, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17824830

ABSTRACT

Lentiviral vectors are efficiently pseudotyped with RD114-TR, a chimeric envelope glycoprotein made of the extracellular and transmembrane domains of the feline leukemia virus RD114 and the cytoplasmic tail of the murine leukemia virus amphotropic envelope. RD114-TR-pseudotyped vectors may be concentrated by centrifugation, are resistant to complement inactivation, and are suitable for both ex vivo and in vivo gene therapy applications. We analyzed RD114-TR-pseudotyped, HIV-1-derived lentiviral vectors for their ability to transduce human cord blood, bone marrow, and peripheral blood mobilized CD34(+) hematopoietic stem/progenitor cells. Transduction efficiency was analyzed in CD34(+) cells in liquid culture, in CD34(+) clonogenic progenitors in semisolid culture, and in CD34(+) repopulating stem cells after xenotransplantation in NOD-SCID mice. Compared with a standard VSV-G-based packaging system, RD114-TR-pseudotyped particles transduced hematopoietic stem/progenitor cells at lower multiplicity of infection, with lower toxicity and less pseudo-transduction at comparable vector copy number per genome. Potential changes in the CD34(+) cell transcription profile and phenotype on transduction with RD114-TR-pseudotyped vectors was comparatively investigated by microarray analysis. Our study shows that the biology of repopulating hematopoietic stem cells and their progeny is not affected by transduction with RD114-TR-pseudotyped lentiviral vectors. RD114-TR is compatible with the development of lentiviral stable packaging cell lines, and may become the envelope of choice for clinical studies aiming at safe and efficient genetic modification of human hematopoietic stem cells.


Subject(s)
Genetic Vectors , Hematopoietic Stem Cells/physiology , Lentivirus/genetics , Signal Transduction , Viral Envelope Proteins/genetics , Animals , Antigens, CD34/blood , Antigens, CD34/immunology , Antigens, CD34/metabolism , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Cells, Cultured , Colony-Forming Units Assay , Fetal Blood/cytology , Fetal Blood/metabolism , Gene Expression Profiling , Green Fluorescent Proteins/metabolism , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/metabolism , Humans , Immunodeficiency Virus, Feline/chemistry , Leukemia Virus, Murine/genetics , Lymphocytes/immunology , Lymphocytes/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Oligonucleotide Array Sequence Analysis , Transplantation, Heterologous
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