Genetically modified HIV shows early promise as a gene therapy viral vector

A new type of gene therapy, based on a genetically modified version of HIV, has been successfully used in humans for the first time with “encouraging” results, according to research published this week in the online edition of the Proceedings of the National Academy of Sciences. This small proof-of-concept study suggests that gene therapy utilising genetically modified HIV as a viral vector, could be used to fight not just HIV, but other diseases as well, and “hint[s] at something more,” says lead investigator, Dr Carl June, of the University of Pennsylvania School of Medicine.

The aim of gene therapy is to modify the genetic material of living cells for therapeutic purposes. Most current research is investigating the potential for gene therapy in treating inherited genetic disorders, and researchers hope that it may be possible to correct genetic abnormalities that can cause diseases previously regarded as untreatable.

Although HIV infection is not an inherited genetic disorder, it could be viewed as an acquired genetic disorder since it inserts its own genetic material into human DNA. Consequently, gene therapy can be used to target the HIV genes in infected cells in a similar manner to the way in which they target 'faulty' human genes in inherited genetic disorders.

Researchers at the University of Pennsylvania School of Medicine used a cell culture system that allows for an individual's own CD4 T cells to be taken from their body and expanded. They then combined these CD4 cells with a modified version of HIV, called VRX496 – which contains an antisense sequence that prevents HIV from being able to make copies of itself by preventing translation of the full-length HIV envelope gene – and the modified CD4 cells were then reinfused back into the individuals.

Lead author, Dr Bruce Levine, describes VRX496 as “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," he explains. "Essentially, the vector puts a wrench in the HIV replication process.”

The primary endpoints of the study were safety-focused, and looked for adverse events, and viral load and CD4 count changes. The investigators also wanted to find evidence that the genetically modified HIV was not replicating. Secondary endpoints included discovering how long the genetically modified CD4 cells persisted, as well as the individual's immune function.

This phase I study involved five highly treatment-experienced HIV-positive volunteers. All had been on failing antiretroviral therapy prior to enrolment and four decided to remain on therapy during the nine-month study period.

All participants were male – three were Caucasian, two were African-American – and they had received an average of seven previous anti-HIV drugs. All had viral loads at baseline above 20,000 copies/ml and CD4 counts ranged between 220 and 316 cells/mm³.

The first participant was infused in July 2003, and the last participant received his infusion in September 2004. Each of the five participants received one infusion of their own gene-modified CD4 cells. The target dose was 10 billion cells, representing between 2-10% of the total number in an average person.

Viral load remained stable or decreased during the study, and one individual showed a sustained decrease in viral load. CD4 cell counts remained steady or increased in four of the five individuals.

Additionally, immune function that was specific to HIV improved in four of the five participants. The investigators also found no evidence that the genetically modified HIV was replicating, but did find that the genetically modified CD4 cells persisted for longer than a year in two of the five individuals. "That's significant,” notes Dr Levine, “showing that these cells just don't die inside the patient.”

The investigators also noted that the infusions were well tolerated, with “no serious adverse events that were judged as possibly, likely, or related to the VRX496 cells.” All five individuals will be followed for 15 years, however, since it is possible that adverse events may take years to appear.

Overall, the study results are significant, say the researchers, because it is the first demonstration of safety in humans for a lentiviral vector (of which HIV is an example) for any disease. Additionally, they add, VRX496 produced encouraging results in some patients where other treatments have failed.

"The goal of this phase I trial was safety and feasibility and the results established that," notes Dr June. "But the results also hint at something much more. Gene therapy has long been discussed as an alternative treatment to HIV. The results from this phase I trial are encouraging – particularly since these are late-stage patients – and demonstrate that gene therapy has the potential to treat HIV and other serious human diseases.”

However, cautions Dr Levine, "just because this has produced encouraging results in one or two patients doesn't mean it will work for everyone. We have much more work to do."

A second trial involving six successive infusions in HIV-positive individuals on successful antiretroviral therapy is now recruiting. This will include a planned treatment interruption in order to test the effect of the gene therapy's ability to control HIV.

Although the specific process and targets used in this study is unique, a variety of other HIV-focused gene therapies are currently being studied, including several that are further ahead in their development. These include Johnson & Johnson's OZ1 (previously known as RRz2) – which has already advanced into a Phase II study with 74 participants – Cell Genesys' T-cell modifier, and Enzo Biochem's HGTV43, which also delivers antiretroviral antisense.