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NIH Scientists Report Promising Gene Therapy in AIDS Animal Model

February 1998

BETHESDA, Md. - Scientists at the National Institutes of Health (NIH) and Johns Hopkins University School of Medicine have demonstrated for the first time in a non-human primate that gene therapy works against viruses that destroy the immune system. Their work, which is being published in the February, 1998 issue of Nature Medicine, may eventually benefit patients infected with HIV, the virus that causes AIDS.

The researchers tested their potential anti-HIV gene therapy in rhesus monkeys using the best available animal model of HIV: simian immunodeficiency virus (SIV), which causes an AIDS-like disease in monkeys.

Both HIV and SIV infect CD4 cells, the helper cells of the immune system. In order to successfully reproduce in infected cells, both viruses also require two regulatory proteins, known as Tat and Rev. The researchers gene therapy is designed to attack the RNA molecule that SIV uses to make the essential Tat and Rev proteins. The Tat and Rev RNA is attacked using an antisense RNA that is a mirror-image (or complementary) copy to the SIV Tat/Rev RNA. This antisense RNA binds to the SIV RNA and makes it a double-stranded RNA. Many viruses contain double stranded RNAs and cells have developed mechanisms for destroying these double-stranded RNAs. The antisense molecule works against SIV mainly by degrading SIV RNA, but it also halts translation - the ability of RNA to make the vital Tat and Rev proteins.

The researchers removed CD4 cells from three monkeys and used a gene-transfer retrovirus to engineer the cells to resist SIV by inserting the antisense Tat/Rev gene into them. They returned the engineered cells to the monkeys, and then infected the three, along with three control monkeys, with SIV.

All six monkeys became infected, but the three that had received antisense gene therapy displayed evidence of only limited SIV replication and less disease progression than the control monkeys. The treated monkeys had significantly fewer viruses in both their blood and their lymph nodes, no decrease in number of CD4 cells, and little disruption of the structure of their lymph nodes.

The study was a collaboration among the laboratories of Dr. Richard A. Morgan and Dr. Bruce A. Bunnell at the Clinical Gene Therapy Branch of the National Human Genome Research Institute (NHGRI), Dr. Robert E. Donahue at the Hematology Branch of the National Heart, Lung and Blood Institute (NHLBI), and Dr. Janice E. Clements at the Division of Comparative Medicine at Johns Hopkins University School of Medicine.

"We've actually been able to show that in the best animal model for HIV infection, you can indeed stop viruses from replicating, and that can result in sustained CD4 cell counts," said corresponding author Richard A. Morgan, who heads the Gene Transfer Technology Section at NHGRI. "If you can maintain a number of CD4 cells that have normal function, if you're producing less virus, that may be of benefit to people infected with HIV long-term."

"This study demonstrates for the first time in a non-human primate animal model that an antisense vector has the potential to effectively reduce the pathogenicity of a virus infection, such as that associated with SIV," said lead author Robert E. Donahue, who directs a program evaluating gene transfer in non-human primates at NHLBI. "These findings reconfirm the importance of the use of animal models in evaluating such novel technologies as gene transfer. "

The NHGRI oversees the NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery.

Jeff Witherly
Phone: (301) 402-8564

Galen Perry
Phone: (301) 402-3035

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Last updated: September 01, 2006