The University Record, April 2, 1996

U-M researchers take giant step in battle against AIDS

Researchers at the University of Michigan Medical Center have, for the first time in a clinical setting, demonstrated that antiviral gene therapy can prolong T-cell survival in HIV-infected patients, with no harmful side effects.

Their research, published in the April 2 issue of the Proceedings of the National Academy of Sciences , represents a major step forward in the battle to prolong the period in which an individual tests positive for HIV but shows no symptoms of AIDS.

"This study suggests that gene transfer can be used to prolong T-cell survival and, ultimately, help to sustain the immune system in HIV-infected patients," says Gary J. Nabel, professor of internal medicine and biological chemistry at the Medical Center and investigator at the Howard Hughes Medical Institute.

In this pilot study, three patients who tested positive for HIV were infused with genetic material that was manipulated to produce a defective HIV protein called Rev M10, which has been shown in the lab to block the action of the Rev protein, which is essential to HIV replication.

"These results were obtained in a small number of HIV-infected patients," Nabel adds, "and additional studies will be needed to help define clinical efficacy and the optimal methods of T-cell gene transfer. Such studies are now in progress."

The goal of gene therapy is to disable the virus's ability to reproduce by introducing this new genetic material, making HIV unable to continue its rapid replication and thereby posing no threat to the genetically modified cells.

Two aspects of the study's clinical design were important: first, the gene transfer technique facilitated analysis of the survival of cells containing the antiviral gene compared to a negative control in the same patient, allowing informative conclusions to be drawn from a small trial.

Second, techniques were developed to introduce antiviral genes into cells derived from HIV-infected patients, avoid ing the need to obtain heterologous donor cells. This novel approach eliminates the need to obtain cells from healthy donors and will make it possible to treat most patients. This approach can also serve as a paradigm for the testing of other antiviral genes.

None of the patients participating in this phase-one study experienced any complications or adverse effects from the treatments. "These results indicate that this form of genetic treatment could safely be tested in a larger number of HIV patients," Nabel says.

Volunteers for the study had their blood drawn at University Hospital's General Clinical Research Center. The CD+4 T-cells in the sample were modified in the lab to make them more resistant to HIV replication. The gene was delivered with a nonviral vector, using gold microparticles to shoot the DNA into cells. The treated white blood cells were then reinfused into the patients, who underwent frequent monitoring for immune system function.

This study was performed in Nabel's laboratory at the Medical Center. Authors of the study include Clive Woffendin, assistant research scientist, internal medicine; Udaykumar Ranga, research fellow, internal medicine; Zhi-Yong Yang,research inves tigator, internal medicine; Ling Xu, research associate, internal medicine; and Nabel.