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 immunity.
"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 volunteer patients.
The four-year grant is known as a Strategic Program for Innovative Research on AIDS Therapy (SPIRAT), and involves two protocols.
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 cells.
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 features three different "arms." One is simply a long-term test of the three drugs on eight patients, with no immune reconstitution.
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 T-cells."
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 period.
"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."
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 therapeutic modalities."
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.
In addition to the SPIRAT grant, of which there are nine in the country, the Duke University Medical Center is the recipient of a number of National Institutes of Health grants aimed at AIDS treatment and research. Duke has an adult AIDS clinical trial group, a pediatric clinical trial group, and a National Cooperative Vaccine Development Groups (NCVDG) grant to test novel AIDS preventive vaccines. Duke is also home to the Central Immunology Laboratory (CIL), the only NIH-funded laboratory that assesses the success of federally-funded AIDS vaccine trials going on around the country. Funding for the CIL, under the direction of Bolognesi, has just been renewed by the NIH for seven years.