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HIV provides tools for gene therapy.

The potential of gene therapy as a treatment for AIDS received a boost on two continents this week. In the United States, experts advising the National Institutes of Health (NlH) gave the nod to two preliminary trials involving the transfer of genes into AIDS patients. Meanwhile, in Berlin, at the Ninth International Conference on AIDS, other scientists described progress in their efforts to treat AIDS and other diseases by harnessing HIV's ability to infect nondividing cells.

Two of 13 gene therapy protocols approved by the NIH Recombinant DNA Advisory Committee target HIV infection. One uses genes to boost the immune response, while the second "is really an antiviral strategy," says Gary J. Nabel of the University of Michigan Medical Center in Ann Arbor.

The first protocol will assess the safety of transferring DNA that will cause the recipients' cells to make HIV proteins-in particular, a viral envelope protein. These proteins should help activate the body's immune response and slow the progression of disease, says Steven J. Mento of Viagene, Inc., in San Diego. For the study, Jeffrey E. Galpin of the University of Southern California in Los Angeles and Dennis A. Casciato at the University o! California, Los Angeles, will inject a disabled mouse virus once a month for three months into five people infected with HIV who are not sick. The mouse virus contains the genes for the HIV proteins. Five more people will get injections that lack this virus and the genes.

The researchers will then monitor the number of killer T cells, a kind of immune system cell, in each volunteer but will not know which patients received the genes until the study is finished. If the transferred genes increase the number of T cells without causing severe side effects or other safety problems, five additional participants will receive a higher dose of the genes.

The second gene therapy trial will involve a dozen AIDS patients now receive ing the anti-HIV agent AZT (zidovudine) Nabel and his colleagues will separate and grow T cells from each patient" blood. The researchers will genetically. alter some cells to produce a mutated form of an HIV protein called rev. This aberrant protein inhibits viral replication and should prolong the life of altered cells, Nabel explains. Other cells will receive an inactivated form of the same gene, so they will make no rev protein The scientists will then return the cells to each participant and compare the survival of the two groups of cells to asses rev's protective effects.

Neither Nabel nor other scientists developing anti-AIDS gene therapy expect this approach to cure the disease. "But it could be a valuable tool," says Nabel. "It gives us an independent way of attacking the disease."

Most gene therapists transfer genes using disabled mouse retroviruses. However, these viruses work only in actively dividing cells, explains Mario Stevenson, a virologist at the University o! Nebraska Medical Center in Omaha. At that time, the cell's nuclear membrane breaks down, so the virus' genetic material can join the cell's own DNA.

But HIV sneaks through the intact nuclear membrane of cells that are not dividing, using the cells' energy to do so, reports Michael Bukrinsky of the Picower Institute for Medical Research in Manhassett, N.Y While working with Stevenson in Nebraska, Bukrinsky and his colleagues found that one HIV protein contains a five-amino-acid sequence that enables it to bind to a chaperone protein inside the cells it infects. At the Berlin meeting, Bukrinsky described how that chaperone then actively transports the guts of the virus into a nucleus.

Knowing that amino acid sequence helps pave the way for creating new gene transporters, says Michael Emerman, a virologist at the Fred Hutchinson Cancer Research Center in Seattle. He and his colleagues are now trying to splice the gene that specifies this sequence into the genetic material of mouse viruses used in gene therapy, "We can then use existing [transfer] technology and have it work in nondividing cells," says Stevenson.

They have yet to figure out how much HIV genetic material they need to insert and how to add it without disrupting the mouse virus' genome. But once they do, they hope the new hybrid virus will surpass existing gene transfer mechanisms. "Ours would be able to target more cells," says Emerman.

"The use of gene therapy to deal with AIDS will accelerate the state of the art to the point where gene therapy will be much more easily applied to other diseases," Stevenson predicts.
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Title Annotation:gene therapy research
Author:Pennesi, Elizabeth
Publication:Science News
Date:Jun 12, 1993
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