At the Institut Pasteur , Pierre CHARNEAU's group in the Viral Oncology
Unit headed by Luc MONTAGNIER, has recently demonstrated the efficacy of
a new gene transfer system, derived from HIV, but with all the viral genes
removed. This new system was developed following the discovery of the mechanism
by which viral DNA penetrates the nucleus of targeted cells. This major
scientific advance, published in the American journal, Cell, opens up many
new possibilities for application, notably in the area of AIDS gene therapy,
but also for cancer and human genetic diseases.
Currently, the principal obstacle to the development of gene therapy is
the absence of sufficiently reliable and effective systems for the transfer
of therapeutic genes. Two major types of viral vector have already been
used in therapeutic trials in humans :
"Classical" retroviral vectors (derived from mice oncogenics retroviruses). These have the advantage of integrating the therapeutic gene into human DNA without the expression of viral genes, thereby preventing rejection by the patient's immune system. Their major disadvantage, however, is that they only transfer genes into dividing cells. This greatly limits their use because the cells targeted in gene therapy (e.g. blood cell precursors, neurons, muscle cells, liver cells) are mostly cells that divide rarely, if at all.
Adenoviral vectors (derived from adenovirus, a cold virus). These have the advantage of being able to transfer DNA into non-dividing cells. However, they have the disadvantage of expressing viral genes, such that the patient's immune system rapidly eliminates treated cells, which remain within the patient's body for no more than a few weeks. Thus, treatment is only effective in the short term.
The AIDS virus (HIV human immunodeficiency virus) when used as a gene transfer vector is a system that combines all the advantages and none of the disadvantages of these other vectors. It can transfer genes into cells that do not divide, without expressing viral genes and therefore without leading to rejection of the treated cells by the body
A key step in the transfer of genes into non-dividing cells is the passage of therapeutic DNA into the nuclei of these cells. Viruses from the HIV family (lentiviruses, such as the EAIV virus in horses, VISNA in sheep, CAEV in goats, SIV in monkeys, and FIV in cats) are the only retroviruses able to transfer their DNA across the nuclear membranes of the cells they infect. It is this unique feature that renders HIV and related viruses very promising candidates for use in gene therapy.
Fundamental research carried out over the course of several years by Pierre CHARNEAU's group, on the passage of viral DNA into the cell nucleus, has led to the discovery of an unusual biological mechanism. A DNA molecule is a filament, generally structured as a double helix. The DNA of the AIDS virus carries at its centre a small region of three strands, the triplex or DNA flap. This unusual DNA structure is required for the passage of the viral genome into the nucleus of the cell. Their understanding of this mechanism is enabling researchers at the Pasteur Institute to improve markedly the efficacy of HIV-derived vectors in the hope of designing a vector suitable for use in gene therapy in man.
Thus, the development of a triplex or DNA flap vector from HIV could lead to a spectacular turnaround of the current situation: the possible use of a derivative of a dangerous virus in human medicine, for gene therapy to treat illnesses such as AIDS, cancer and genetic diseases. Thus, the current principal viral enemy of humans may in the future help to protect against several different diseases.
"HIV-1 genome nuclear import is mediated by a central DNA flap ",
Cell, April, 14th, 2000
V. Zennou1, C. Petit1, D. Guetard1, U. Nehrbass2, L. Montagnier1, P. Charneau1
1 Unité d'Oncologie Virale
2 Unité de Biologie Cellulaire du Noyau
Contacts :
- Pierre CHARNEAU, Unité
d'Oncologie Virale
Tel : (33) 1 45 68 88 22
e-mail : charneau@pasteur.fr
- Press office
Tel : (33) 1 45 68 81 46
e-mail : presse@pasteur.fr