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Posted: 18 Aug 2011
30 years in 30 weeks, 1996

At the 11th International Conference on AIDS in Vancouver in July of 1996, the results of the first trials of triple-combination therapy were announced, showing dramatic improvement in patients’ health. Combination therapy, also called HAART (highly active antiretroviral therapy) became the gold standard of treatment in the following years. Meanwhile, as described in the commentary by Dr. Didier Trono, in a very different area of research, involving gene therapy of hereditary and chronic diseases the major advance, somewhat unexpectedly, came from research on HIV and AIDS.

In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector.
Science. 1996 Apr 12;272(5259):263-7.
Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D.

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Commentary by Dr. Didier Trono

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Dr. Didier Trono
The AIDS epidemic was raging in the early 90’s, as the revolution to be brought about by highly active antiretroviral therapies was yet to come. On a different medical front, the field of gene therapy was vexingly stalled by its ineffectiveness at introducing therapeutic genes into cells in order to cure, as had once been promised, disorders such as hemophilia, Parkinson disease, muscular dystrophy and even AIDS itself. The problem was that in most cases the cells needing correction, whether they were hematopoietic stem cells, liver cells, muscle cells or neurons, rarely underwent division, hence kept their chromosomes, the obligatory targets of the therapeutic manipulation, hidden in their nucleus. And gene delivery systems in use at the time could not traverse the barrier surrounding this sanctuary, the so-called nuclear envelope.

As AIDS researchers, we felt that we might have a clue on how to proceed: why didn’t we simply follow the path so demonstratively indicated by HIV, which as other members of the lentivirus family had mastered the art of penetrating the nucleus of non-dividing cells such as primary macrophages? And rather than trying to transfer the HIV components possibly responsible for this property to the then “en vogue” gene delivery systems, why didn’t we develop a vector directly from HIV itself? This would require extreme care in inactivating all of the virus’ ability to replicate and cause disease, but at the time our understanding of HIV molecular biology was already such that we knew pretty well what to do. Teaming up with our Salk colleagues, we thus embarked in the development of HIV-derived lentiviral vectors, an endeavor greatly facilitated by our years-long experience studying this virus. We performed a proof-of-principle study described in the April 12 1996 issue of Science, which demonstrated that HIV-derived vectors can stably integrate a genetic cargo into the genome of non-dividing cells, including neurons of a rat brain. This paper, which to this date has been cited more than two thousand times in the scientific literature, was significant not only because it removed a stumbling block for gene therapy, but also because it provided researchers with a tool that would prove capable of doing marvels for the study of the most fundamental biological processes. Today, thousands of laboratories worldwide make use of lentiviral vectors in their experiments, covering almost every area of biomedical research from stem cells to cognition and from cancer to AIDS. But it is in the clinics that the most spectacular impact was to be made: in 2009 hematopoietic stem cell gene therapy with an HIV-derived vector was successfully used to treat two patients with adrenoleukodystrophy, a deadly brain demyelinating disease, and today clinical trials are under way that use lentiviral vectors for the genetic treatment of a range of lympho-hematopoietic and neurological diseases, with great hopes of obtaining similar successes.

An incommensurable reward for the small group of scientists who, deaf to the criticisms of the many who said that it was a foolish enterprise, decided one day that they ought to be able to turn a deadly foe into a therapeutic wonder.

About the author: Dr. Didier Trono is the Professor of virology and genetics at the School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Switzerland.     

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