Scientists at the National Institute of Allergy and Infectious Diseases (NIAID) have reported their first findings from a novel study to determine whether virus-fighting immune cells can be genetically altered to boost the immune system's response to HIV infection. "This innovative approach provides further groundwork for future efforts to treat HIV by manipulating the immune system," says NIAID Director Anthony S. Fauci, M.D.
The NIAID scientists studied 30 sets of identical twins in which one twin was infected with HIV and the other was uninfected. HIV-fighting T-cells were taken from the healthy twin and genetically altered to produce an extra receptor that helps the cells recognize HIV-infected cells. The engineered cells were then infused into the HIV-infected twin, with the goal of augmenting or restoring the T-cells' ability to fight the virus.
In a paper to be presented by principal investigator Robert E. Walker, M.D., at the 12th World AIDS Conference in Geneva, Switzerland, the scientists report that transfer of genetically altered T-cells into 30 HIV-infected twins was safe and well-tolerated. Trying different combinations of T-cells, they learned that a mix of genetically bolstered CD4+ and CD8+ T-cells proved to be the most long-lived. The cells not only persisted at high levels in the bloodstream for at least 100 days after infusion, but also proliferated. "Although these results are preliminary, they're encouraging enough for us to take the next steps in studying this approach," says Dr. Walker.
The research is a collaboration with Cell Geneses, Inc., of Foster City, Calif. Cell Geneses scientists developed the methods for transferring the receptor-producing genes into T-cells, while NIAID scientists are conducting the Phase I/II clinical trial of the experimental treatment at the NIH Clinical Center in Bethesda, Md. Cell Geneses is conducting additional work to examine this approach in the more practical setting of autologous infusions in patients undergoing treatment with highly active antiretroviral therapy. The patients are being treated with their own cells, which have been genetically modified in the same way.
In a related paper in the July 1998 issue of Nature Medicine, Dr. Walker and NIAID colleagues report that genetically marked but unaltered CD4+T-cells, infused into six HIV-infected twins, persisted in the blood for an extended period of time (4 to 18 weeks) after transfer. "This was an unexpected finding," Dr. Walker says. "Transferred cells were assumed to be short-lived. The fact that they live for weeks to months provides a rational basis for transfusing genetically altered cells to fight HIV infection."
To trace the infused cells, Dr. Walker and colleagues injected them with a marker gene called neomycin phosphotransferase. They used this gene because it has a track record for safety, having been used in many cancer and other clinical trials. Their results also showed that in the HIV-infected twins, new supplies of CD4+ T-cells were coming mainly from division of mature T-cells rather than from stem cells, the precursors of all immune system cells. Thus, once T-cells with certain specificities are lost to HIV infection, they may be difficult to replace. According to Dr. Walker, this finding suggests that "adoptive transfer of T-cells may prove to be a feasible approach to combating the virus."
References: R. Walker, et al. T cell survival in HIV-infected adults: peripheral expansion of pre-existing mature T cells is a major means of CD4+ T cell regeneration. Nature Medicine 4:852-856 (1998).
Press releases, fact sheets and other NIAID-related materials are available on the Internet via the NIAID home page at http://www.niaid.nih.gov, http://www.niaid.nih.gov. The home page for the 12th World AIDS Conference is http://www.aids98.ch.