Harnessing HIV for therapy, basic research and biotechnology

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First described about a decade ago, lentiviral vectors (‘lentivectors’) have emerged as potent and versatile tools of gene transfer for basic and applied research and offer exciting perspectives for the field of gene therapy. In the clinic, HIV-based vectors are showing particular promise for delivering therapeutic genes to hematopoietic stem cells (HSCs) and terminally differentiated targets in the central nervous system (CNS). Their flexible design facilitates the accommodation of sophisticated elements of control for the precise tuning of transgene expression. The delivery of small interfering RNAs (siRNAs) and genomic or cDNA libraries and the creation of transgenic animals are the most recent and exciting applications of HIV-based vectors that will help to tackle fundamental issues across wide areas of biology.

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The basics of lentivector-mediated gene delivery

Like their gammaretrovirus-based predecessors, such as those based on murine leukemia virus (MLV), lentiviral vectors integrate their cargo into the chromosomes of target cells without transferring virus-derived coding sequences. Unlike MLV vectors, however, lentivectors can mediate this process in nondividing cells, which is a great asset for many experimental and clinical situations. A detailed description of currently available lentivector designs is beyond the scope of this review and can

The most promising therapeutic targets of lentivectors

Lentivectors can govern the efficient delivery, integration and long-term expression of transgenes into nondividing cells both in vitro and in vivo. As such, they represent attractive tools for most potential targets of gene therapy, whether the targets are early precursors or terminally differentiated cells (Box 1). So far, however, this expectation has been essentially fulfilled only in the CNS, the hematopoietic system and, to a lesser extent, in the liver, and more work is necessary to

Vector targeting

Minimizing host immune responses and avoiding the potentially toxic, off-target effects of transgene expression are important concerns. Vector targeting via modification of the virion envelope is in its infancy; however, restriction can be achieved at the transcriptional level by incorporating tissue-specific promoters and enhancers into lentivectors. This feature is particularly important when vectors are used to transduce tissues or organs by in vivo administration. In this delivery route,

Future perspectives

In less than a decade, lentivectors have become gene-delivery vehicles that are most actively exploited in many areas of basic and applied research. In gene therapy, numerous studies have confirmed that lentivectors can effect robust and highly efficient gene transfer into organs and tissues that are out of reach for many other gene-delivery systems. Although there is no ‘ideal’ vector that can function in all applications, the relatively large capacity of lentivectors and their integration

Acknowledgements

Research in our laboratory is supported by the Swiss National Science Foundation, the European Union and the Institut Clayton de la Recherche M.W. thanks Jola Szulc for helpful discussions and critical reading of the manuscript. We apologize to those whose work could not be cited owing to space considerations.

References (61)

  • D. Trono

    Lentiviral Vectors

    (2002)
  • E.M. Poeschla

    Efficient transduction of nondividing human cells by feline immunodeficiency virus lentiviral vectors

    Nat. Med.

    (1998)
  • S.M. White

    Lentivirus vectors using human and simian immunodeficiency virus elements

    J. Virol.

    (1999)
  • J.C. Olsen

    Gene transfer vectors derived from equine infectious anemia virus

    Gene Ther.

    (1998)
  • M. Stremlau

    The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys

    Nature

    (2004)
  • L. Naldini

    In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector

    Science

    (1996)
  • J.H. Kordower

    Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease

    Science

    (2000)
  • N.D. Mazarakis

    Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery

    Hum. Mol. Genet.

    (2001)
  • M. Azzouz

    VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model

    Nature

    (2004)
  • C. Lo Bianco

    α-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • E. Regulier

    Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant huntingtin in rat striatum

    Hum. Mol. Genet.

    (2003)
  • L.P. de Almeida

    Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length

    J. Neurosci.

    (2002)
  • W. Chen

    Lentiviral vector transduction of hematopoietic stem cells that mediate long-term reconstitution of lethally irradiated mice

    Stem Cells

    (2000)
  • Y. Hanazono

    Gene transfer into nonhuman primate hematopoietic stem cells: implications for gene therapy

    Stem Cells

    (2001)
  • P.A. Horn

    Lentivirus-mediated gene transfer into hematopoietic repopulating cells in baboons

    Gene Ther.

    (2002)
  • H. Miyoshi

    Transduction of human CD34+ cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors

    Science

    (1999)
  • T. Kafri

    Sustained expression of genes delivered directly into liver and muscle by lentiviral vectors

    Nat. Genet.

    (1997)
  • Y. Kang

    In vivo gene transfer using a nonprimate lentiviral vector pseudotyped with Ross River virus glycoproteins

    J. Virol.

    (2002)
  • F. Park

    Efficient lentiviral transduction of liver requires cell cycling in vivo

    Nat. Genet.

    (2000)
  • K. Ohashi

    Role of hepatocyte direct hyperplasia in lentivirus-mediated liver transduction in vivo

    Hum. Gene Ther.

    (2002)
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