(AIDSmeds)—Researchers at the University of Pennsylvania School of Medicine have reported encouraging results from a small clinical trial of a gene therapy approach to treat HIV. The study, reported in an online edition of the Proceedings of the National Academy of Sciences, involved five patients given a single intravenous infusion of their own immune cells that had been modified using a therapeutic gene called antisense, in an attempt to make the cells resistant to HIV infection.

Humans have between 50,000 and 100,000 genes that regulate how cells behave in the body. That is, genes can either “turn on” or “turn off” virtually any function that a cell is capable of.

Researchers have learned a great deal about the genes responsible for certain cellular activities. This has set the stage for additional research into ways to alter patients’ genetic material to fight or prevent diseases.

Gene therapy involves introducing genetic material into a person’s cells to turn specific functions on or off. In the case of HIV, turning off certain CD4 cell (T4 cell) functions may help protect CD4 cells from becoming infected with HIV or from producing new virus. Alternatively, gene therapy might be used to turn on certain CD4 cell functions, potentially causing HIV-infected cells to self destruct or to begin producing HIV so that standard HIV medications can go to work.

Gene therapy is complicated, as a gene cannot be directly inserted into a person’s cell. It must be delivered to the cell using a vehicle, or “vector.” The vectors most commonly used in gene therapy are viruses, given that they have a unique ability to recognize certain cells and insert their DNA into the cells. In gene therapy – as well as vaccine research using this approach – developing a vector involves replacing the genes in the virus that cause disease with those that are intended to have the desired effect on cells.

The University of Pennsylvania study is the first to use HIV itself as a vector. VRX496, developed by VIRxSYS Corporation, involves HIV that has had its genetic material removed, leaving only its outer shell (envelope). The envelope is then fitted with therapeutic material called antisense.

The antisense molecule is the mirror image of the gene responsible for producing new envelopes for the virus. When the modified CD4 cells are given back to the patient, the antisense gene is permanently integrated into the cellular DNA. When the virus starts to replicate inside the host cell, the antisense gene prevents the production of the envelope gene, thereby shutting down HIV replication.

“The new vector is a lab-modified HIV that has been disabled to allow it to function as a Trojan horse, carrying a gene that prevents new infectious HIV from being produced,” explains Bruce Levine, MD, a lead researcher of the study. “Essentially, the vector puts a wrench in the HIV replication process.”

In a laboratory, the modified HIV is added to CD4 cells that have been removed from the patient’s blood (using a process called apheresis). Once “infection” with the antisense-loaded vector has been established, the modified CD4 cells are returned to the patient’s body by simple intravenous infusion.

“The goal of this phase I trial was safety and feasibility and the results established that,” says Carl June, MD, another of the study’s lead investigators. “But the results also hint at something much more.”

Each patient received one infusion of his or her own gene-modified CD4 cells. The target dose was 10 billion cells, which is about 2% to 10% of the number of CD4 cells in an average person. The CD4 cell count remained steady or increased in four patients after the infusions. Dr. Levine also notes that they were able to detect the gene-modified cells for months and beyond a year in one or two patients. “That’s significant,” Dr. Levine says. “[It shows] that these cells just don’t die inside the patient. The really interesting part of the study came when we saw a significant decrease in viral load in two patients, and in one patient, a very dramatic decrease.”

Dr. Levine remains cautious, however. “Just because this has produced encouraging results in one or two patients doesn’t mean it will work for everyone,” he says. “We have much more work to do.” The current study will follow the five patients for 15 years.

The researchers are also recruiting patients for a second study using the VRX496 vector in which patients will receive six infusions, not just one. The clinical trial is designed to evaluate the safety of multiple infusions and to test the effect of infusions on the patients’ ability to control HIV after stopping their standard HIV treatment. The hope, the researchers say, is that this treatment approach may ultimately allow patients to stay off HIV treatment for extended periods of time.