"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 Genesys, Inc., of Foster City,
Calif. Cell Genesys 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 Genesys 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."
NIAID is a component of the National Institutes of Health (NIH). NIAID
conducts and supports research to prevent, diagnose and treat illnesses
such as HIV disease and other sexually transmitted diseases,
tuberculosis, malaria, asthma and allergies. NIH is an agency of the
U.S. Department of Health and Human Services.
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. The home page for the 12th World AIDS
Conference is http://www.aids98.ch.
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).