While reports of the experience of this single person sound very encouraging, it is far too early to know what is really happening, either in this individual or in the study overall. Some people already have a natural ability to maintain extremely low or undetectable levels of virus without therapy. Some already have an inherited genetic characteristic that makes it very difficult for HIV to infect their cells or reproduce and make new copies of the virus. It is unclear whether this person's good fortune is due to these or other factors or to the therapy used in the study. The study is "blinded," which means that neither the volunteers nor the researchers know who got the new gene or placebo. Results will be unblinded after all volunteers complete their course of therapy, which is expected to be in February 2007.
The concept of this study has been in development for close to 15 years. The basic goal is to stimulate the growth of a new immune system in a person with HIV -- one that is resistant to infection by HIV. This requires a source of cells that can grow in the patient and a way of altering them so they resist HIV infection. Gene therapy is one way of altering cells. A "gene" can be described as a set of instructions that tell a cell how to make a particular protein or group of proteins. Every cell in your body already contains a set of instructions that made it what it is and tells it what to do. Gene therapy attempts to insert a new gene with some additional instructions. The new gene must be delivered to cells in the body where it can begin to work.
In this study, the researchers chose to insert the new gene into adult stem cells. These cells exist in small numbers in the body and don't yet have a specific purpose. They have the ability to grow into many possible kinds of cells and thus make a good target for this experiment -- as one could theoretically repopulate an entire spectrum of gene-modified, protected cells from a single stem cell.
This phase II study compares stem cells modified with an anti-HIV gene to "placebo" or unmodified stem cells. Immune system cells containing the new anti-HIV gene can inhibit HIV at as many as five different steps in its reproduction cycle. The study includes 74 people with CD4+ cell counts above 300, who have been on stable and effective anti-HIV therapy for at least six months. Volunteers have stem cells (which reside in large numbers in the bone marrow) mobilized out of the bone marrow using a therapy called G-CSF (commonly known as Neupogen, which is normally used for treating low neutrophil counts, or neutropenia). Once the stem cells are encouraged to move out of the bone marrow, they are harvested through a somewhat elaborate blood draw (called pherisis). In a test tube environment, the cells will be modified with either the anti-HIV gene or a placebo. A harmless mouse virus that has had the anti-HIV gene inserted into it is used to infect the stem cells of half the patients, thus giving their stem cells the new anti-HIV gene. The modified cells are then re-infused into the patients. The other half of the patients simply gets their original, unmodified stem cells back.
Once back in the volunteer, these cells grow and differentiate (i.e. become other types of cells as they mature) over time, taking over for the cells that die as a result of HIV infection. Since these cells are now protected against HIV, they live on and in theory will become the dominant cells of the immune system. After a number of months, the volunteers are taken off anti-HIV therapy and closely followed to see what happens. The ideal response would be to see the volunteer continue to do well without therapy, hopefully remaining "undetectable" for HIV. This is what appears to be happening to the person in the article, but it is not possible yet to know if this is a result of the gene therapy or some other factor. (For more information on gene therapy, see the article "Gene Therapy for HIV" in PI Perspective #38.)
Many will be watching carefully when the study data are analyzed next spring. Everything about the study makes sense. It represents much of the best thinking of modern science, combining stem cells and gene therapy in a truly leading edge experiment. Certainly, much has yet to be determined about its practicality. Though some of the procedures involved are costly, the total costs will some day have to be compared to the cost of maintaining people on anti-HIV drugs for a lifetime. We salute the researchers in the US and Australia who are treating the patients, the scientists in Australia who developed the gene, and the volunteers themselves who have contributed a great deal of their time and hopes.
That said, though, it would be best to avoid speculation until the actual results are in hand. Little is ever gained by trying to guess what's happening in a blinded study. Is this new study a "breakthrough" in the making? No one knows. It is, at the least, a bold and welcome experiment in seeking ways to either rid the body of HIV or minimize any future need for therapy. Even if it doesn't succeed, it will almost certainly contribute important guidance for other similar studies.
Project Inform does not endorse or support specific studies, but we do, on occasion, provide contact information for studies of notable interest to the community like this one. Some sites for this study are fully enrolled, others are still recruiting in Los Angeles and San Francisco. Consider the risks and benefits before agreeing to participate in any study.
University of California Los Angeles (UCLA) CARE Center
Los Angeles, California, 90095-1793
Study Contact 310-206-6414
Ronald Mitsuyasu, MD, Principal Investigator
Stanford University, Department of Medicine
Division of Infectious Disease
Stanford, California, 94305-5107
Study Contact 650-723-2804
Thomas Merigan, MD, Principal Investigator
Andrew Zolopa, MD, Sub-Investigator
Michael Harbour, MD, Sub-Investigator
AIDS Healthcare Foundation Research Centre
Los Angeles, California, 90015
Study Contact 323-913-1033
Charles Farthing, MD, Sub-Investigator
Quest Clinical Research
San Francisco, California, 94115
Study Contact 415-353-0800
Jay Lalezari, MD, Sub-Investigator
Pacific Horizon Medical Group
San Francisco, California, 94115
Study Contact 415-292-5477 x480
Lorna Thornton, MD, Sub-Investigator