The next generation of therapy to treat HIV, and perhaps eventually to cure it, is likely to involve changing the genes in your body. A small study in just six patients discussed in Boston at the 18th Conference on Retroviruses and Opportunistic Infections opened the door to those possibilities.
The clinical trial by San Francisco HIV physician Jay Lalezari took CD4 T-cells from each patient; knocked out a section of DNA that codes for the CCR5 cell receptor; grew those mutated cells to large numbers; and then put 30 million of them back into the patient. It used zinc finger technology developed by the Bay Area biotech company Sangamo to create the genetic deletion.
The primary goal of a phase 1 trial is safety, and this procedure passed with flying colors. The bonus was that it also appeared to robustly increase the number of CD4 cells in the patients. And there is no sign that HIV is able to infect them.
Lalezari said there was "a significant engraftment and expansion of the cells and a three-fold increase over what would have been predicted." Those changes seem to be lasting as 67 percent of the CD4 cells sampled in the blood three months later carried the modified DNA. It is "probably as good as we could have hoped for in this population."
The data is preliminary and the study is ongoing, with a multitude of questions that must be answered. They include: How long are the modified CD4 cells going to last? Do they have the same antimicrobial activity as unmodified cells? And, will they reappear as quickly as before?
Patient perspective
Matt Sharp is one of the six patients in the trial. The San Francisco resident and long time AIDS treatment activist was diagnosed with HIV in 1988. He said that he has been on "pretty much every drug," often as functional monotherapy, and has developed some degree of resistance to many of them.
About four years ago he was able to put together a new combination of drugs that for the first time suppressed his virus below the level of detection. The problem was that his T-cell count never rebounded above the mid-200 range.
When Lalezari mentioned the study he was putting together, Sharp initially was hesitant. "I've done some pretty wild things but I didn't think that was for me," he said. He slowly came around and entered the study last summer; receiving the modified CD4 cells back into his body in early September.
The first blood work came back a few weeks later showing "an immediate doubling of T-cells to about 550 ... I hadn't seen my numbers in this range in 20 years," he said. His blood work has fluctuated between 450 and 600 over the last six months.
Some of the patients in the trial eventually will interrupt their highly active antiretroviral treatment regimen at some point to see if the virus has been cleared from their body, or more reasonably, the extent to which their new CD4 cells alone might be able to control the infection.
Sharp is not one of them. He is concerned with "the fragile situation" of his immune system and first wants to see data on how others do when they interrupt treatment. If the data looks promising enough, he might consider trying it himself.
He remembers the early enthusiasm about how administering the cytokine IL-2, a signaling molecule produced by the immune system, increased a patient's CD4 count. But subsequent research showed the increased numbers to be hollow; many of the additional cells lacked full functionality, they simply did not perform their protective immune tasks very well.
While the zinc finger-modified CD4 cells seem to retain functionality in the lab, there is not yet any data in humans to back that up. Nor is there a sense as to how long the treatment might last or whether subsequent rounds are possible or advisable.
While Sharp is excited by the possibilities of where this line of research might lead, including perhaps to a cure for HIV, he knows that will all take time, and there are likely to be stumbles along the way.