Aids Treatments Seek to Eradicate Virus, Restore Immunity
DURHAM, N.C. -- Duke University researchers and physicians
are set to launch a multi-pronged attack against HIV, the virus
that causes AIDS, and will employ clinical strategies never
Using a $4 million grant from the National Institutes of
Health, two sets of experiments will be conducted that aim to
annihilate HIV from infected patients as much as possible, and
to then rebuild their immune system.
During the process, Duke researchers hope to increase
science's understanding of how the virus reacts to both drug
treatments and novel forms of reconstituting protective
"We are pushing the envelope of what is known and what can
be imagined in effective therapy," said Dani Bolognesi,
director of the Duke Center for AIDS Research, and an expert on
the virus. "While we can't predict HIV will be totally
eliminated from patients, we hope to be able to help them keep
the virus under control while restoring their health."
Bolognesi has assembled a team of basic scientists and
physicians from across the medical center campus to treat
The four-year grant is known as a Strategic Program for
Innovative Research on AIDS Therapy (SPIRAT), and involves two
The first protocol will enroll 24 patients who are
HIV-positive, and who agree to be treated and followed for more
than two years. All the patients will receive a potent mixture
of anti-viral drugs that includes AZT, 3TC, and ritonavir. AZT
and 3TC are nucleoside analogues, which interrupt a step in the
virus's life cycle when its genetic material is inserted in a
host cell's gene. Ritonavir, a protease inhibitor that received
FDA approval earlier this year, kills HIV by crippling an
enzyme crucial to its survival, a mechanism different from
other anti-viral compounds.
The three drugs are expected to reduce the "viral load" or
the amount of HIV in patients' bodies, by 99 percent, said Dr.
John Bartlett, who heads Duke's Infectious Diseases Clinic.
"But what we need to do is eliminate that last 1 percent of the
virus, which is hiding, and to understand why it eventually
becomes resistant to drug therapy."
HIV is found in three "compartments" in the body, Bartlett
said. The largest is the lymphoid tissue, such as nodes, liver
and spleen. The others are plasma and peripheral blood
While clinical trials are underway at other centers to test
the effects of such a combination of drugs, the Duke trial goes
several steps farther, in trying two different experimental
protocols aimed at restoring the patients' damaged immune
systems. Protocol 1
Protocol 1 features three different "arms." One is simply a
long-term test of the three drugs on eight patients, with no
In the second and the third arms, 16 patients on drug
therapy will undergo experimental restoration of their immune
systems in the hope that new immunity will fight off or control
the remaining 1 percent of virus.
The second arm will attempt to restore a complete immune
system in eight patients. Five weeks after beginning drug
therapy, these patients will receive a transplant of thymus
tissue taken from infants, an innovative therapy that has not
been tried in this way before (see accompanying backgrounder),
according to immunologist Dr. Louise Markert, head of the
General Clinical Research Center. The thymus tissue swatches
will be implanted into the patients' arm or leg muscles and
their progress in restoring a working immune system will be
closely monitored for two years.
"The thymus makes and educates a wide range of immune cells
to fight specific infections," Markert said. "As HIV damages
the thymus, the patient's immune system can respond to fewer
and fewer types of infection.
"Under cover of these potent anti-retroviral compounds, we
hope to reconstitute a new immune system from healthy thymic
tissue in patients whose own thymus has been destroyed or
crippled," she said. "By keeping the viral load extremely low,
the drugs may protect the thymus and allow it to produce new
The third arm of protocol 1 is a novel effort to boost the
immune system of eight patients by giving them massive doses of
immune cells during their combination drug therapy, according
to cellular immunologist Kent Weinhold.
Cytotoxic lymph cells (CTLs), also known as killer T-cells,
are immune system cells that attempt to attack HIV when it
invades the body, but the virus overwhelms this immune
response. Weinhold will extract these T-cells from patients,
and will expose them in a laboratory to a pox virus that
expresses an inert segment of HIV's genome. This exposed viral
particle will both stimulate the CTLs to rapidly multiply, as
if expanding its troops, and will also prime these CTLs to
readily recognize the virus.
Two to three weeks after their immune cells are extracted,
the patients will receive up to 1,000 times as many of these
cells back again. In all, patients will be infused three times
with massive doses of killer T-cells over a six-month
"We hope that these doses of CTLs will impact that hidden 1
percent reservoir of virus that drugs may not touch," Weinhold
said. "I don't think it's realistic to say that we can wipe the
disease out, but by boosting the health and ability of the
immune system to fight, we may be able to convert AIDS into a
chronic disease that doesn't progress." Protocol 2
For some patients, AIDS is double jeopardy. Not only is
their depleted immune system unable to fight infections, they
also are vulnerable to secondary diseases such as cancer. It's
fairly common for AIDS patients to develop lymphoma, a cancer
of the lymph tissue, which they frequently do not survive.
The team of Duke physicians and researchers is ready to take
an uncommon approach to saving these patients. They say their
approach is extreme, and potentially toxic, "but these patients
need the most aggressive of therapies, which has not been
available before now," said oncologist Dr. Clay Smith.
Smith said he hopes not only to save these patients, but to
answer some fundamental questions about the viability of bone
marrow transplantation in AIDS therapy.
The team plans to treat about a dozen HIV-infected patients
with lymphoma -- patients for whom traditional chemotherapy has
failed, and no other treatment is possible. These patients will
receive the same blitzkrieg concoction of medications as
patients in the first protocol, followed by high-dose
chemotherapy and radiation. These two steps should reduce the
HIV "viral load" to virtually nil, at the same time destroying
the cancer. "We want to kill the cells that house the virus as
well as the cancer," said Smith.
Then, to restore a healthy immune system, Smith will give
the patients a transplantation of blood stem cells. Another
alternative researchers are investigating is to use banked
umbilical cord blood stem cells, and that technological advance
would make the therapy cheaper and more available.
Progress in fighting the virus, as well as producing
immunity, will be closely compared between both protocols and
within the three arms of the first protocol.
"The testing to to be performed will be the most
comprehensive virologic assessment possible at this present
time," said virologist Michael Greenberg. "We will have a
detailed picture of what is happening to the virus and to
immunity in these patients, and their response to the different
Working with Dr. George Shaw, a researcher from the
University of Alabama, Greenberg will measure the levels of
virus that exists in the plasma, blood cells, and tissue before
and during the therapies.