A new approach in fight against HIV

HIV virus

The complex HIV virus replicates itself millions of times each day and undergoes thousands of mutations, producing a mob of different strains, and has an uncanny ability to evade and escape the human immune system.

James Riley, research associate professor of pathology and laboratory medicine at Penn, says HIV is able to “bend” away from the immune system. Even the slightest change in the virus, he says, can leave it unrecognizable to antibodies or T cells, which the immune system uses to fight disease.

As a result, T cell-based vaccines used often in the fight against HIV/AIDS have produced mixed results. Merck’s V520 vaccine, for instance, failed miserably in 2007.

But Adaptimmune, a company that uses T cell therapy to treat cancer and infectious diseases, announced in the November issue of the online journal Nature Medicine that it has made a breakthrough in T cell-based therapy. With the help of Penn researchers, the company has successfully engineered T cells capable of recognizing HIV-1 strains—the most common form of HIV—that long have evaded the immune system.

Co-senior author Riley, first author Angel Varela-Rohena, a Penn Ph.D. student, and co-author Carl June, director of translational research at Penn’s Abramson Family Cancer Research Institute, joined with colleagues in the United Kingdom to test the Adaptimmune findings to see how well the T cell engineering worked.

Adaptimmune augmented the affinity of T cells for antigens, which are substances that cause the human immune system to produce antibodies against it. CD8 cells, a type of T cell that binds to and kills infected cells, were transduced, or converted, in the study to have a high affinity for HIV. CD8 cells are similar to CD4 cells except they do not get infected by HIV.

Riley says the Adaptimmune approach is a promising strategy because in the normal course of infection, the CD8 cells that recognize HIV essentially get tired of fighting the disease and lose their function, becoming “exhausted T cells.”

“What this allows us to do is transduce cells,” Riley says. “Cells that weren’t normally HIV-specific beforehand, now they become HIV-specific. These cells are fresh. These are a new set of players to go onto the field, and so we’re hoping that will help them fight the virus better.”

Riley says they hope to begin testing the transduced cells relatively soon, possibly within the next year or so. For safety and ethical reasons, those with advanced HIV will be treated first. As is usually the case with HIV, Riley says it is likely that the virus will mutate and adapt and evade the engineered T cells, but they are hopeful that HIV will have to bend more than it would like to, thus resulting in a less fit virus, which may lead to a sustained lower viral load, the amount of the HIV virus in an infected person’s blood.

Riley says he believes the findings can teach researchers what they would like to have in a vaccine because they don’t yet understand what can protect against HIV. He also says they are very optimistic that this type of therapy will work even better in cancer studies because tumors can’t mutate as rapidly as HIV and the human immune system is missing a good T cell repertoire to fight cancer. In some respects, Riley says if this type of approach doesn’t work well—because they actually engineered the cell—it doesn’t speak well for the future of T cell-based vaccines.

In the future, Riley says he hopes to infuse T cells with two or three different specificities in order to attack the virus from different fronts. “Certainly, if HIV has taught us something, it’s taught us that you need to target multiple things at the same time,” he says. “If we can reach that point, then I think HIV would have to do quite a number of tricks to mutate out of that.”

Originally published on January 8, 2009