The National Institute of Allergy and Infectious Diseases (NIAID) has launched a new program to accelerate the development of innovative therapies to fight HIV infection.
The new effort, called the Strategic Program for Innovative Research on AIDS Treatment (SPIRAT), supports six research teams, each containing three or more investigators from separate U.S. institutions and companies with related research interests.
NIAID has awarded a first-year total of $6.2 million to the institutions of the principal investigators of each team. The teams will receive funding for four years, with early studies in humans to commence, at the latest, by the third year of the awards.
The SPIRAT will enable scientists to explore such cutting-edge strategies as gene therapy, immune system restoration and DNA-based therapeutic vaccines, and to move these novel concepts from the laboratory into pilot clinical studies.
With the SPIRAT, we will promote the development of innovative ways to inhibit the replication of HIV and restore the immune responses of HIV-infected individuals," says Anthony S. Fauci, M.D., director of NIAID.
This effort is crucial because currently available anti-HIV drugs only partially and temporarily suppress replication of the virus, and their use is hampered by toxicity and drug resistance. Moreover, the SPIRAT will likely add to our understanding of the pathogenic mechanisms of HIV disease."
Adds John Y. Killen, M.D., director of the NIAID Division of AIDS (DAIDS), "The SPIRAT provides an important bridge between basic and clinical research and offers the potential for the development of effective, long-term treatments for HIV-infected people. The state-of-the-art strategies proposed by the research groups are conceptually exciting and scientifically well-grounded."
The principal investigators of the six SPIRAT teams and some of their research efforts are the following:
* Phillip Greenberg, M.D., of the Fred Hutchinson Cancer Research Center in Seattle, Wash., and his group will concentrate on ways to bolster the immune system cells that are essential to mount an effective immune response against HIV. They will pursue an adoptive immunotherapy strategy that first involves removal of immune system cells called CD8+ and CD4+ T cells from an HIV-infected person. The investigators then will genetically manipulate the cells to specifically target and fight HIV and/or to resist infection by the virus. In the laboratory, the cells are modified and grown in large quantities and later re-infused into the person from which they originally were removed.
* Judy Lieberman, M.D., Ph.D., of the New England Medical Center in Boston, Mass., will lead a team focusing on augmenting the immune system's capacity to eliminate HIV-infected cells. This adoptive immunotherapy strategy will use immune cells combined with cytokines, the protein messengers necessary for cell-to-cell communication. Expanding the number of CD4+ T cells is especially important in advanced AIDS, where substantial depletion of CD4+ T cells has occurred.
* Thomas Merigan, M.D., of Stanford University in Stanford, Calif., and his group will explore a similar adoptive immunotherapy technique using immune cells from donors without HIV infection that are then infused into their HIV-infected siblings. Investigators will use their knowledge of cells that stimulate other cells of the immune system to further induce HIV-specific immune responses in HIV-infected individuals. These approaches should broaden the capacity for immune restoration both by using non-self immune cells and by stimulating the patient's immune cells in the laboratory and in the HIV-infected patient.
* Gary Nabel, M.D., Ph.D., of the University of Michigan in Ann Arbor, and his team will investigate a gene therapy strategy in HIV-infected children. They will determine whether a defective gene from HIV can prevent the killing and depletion of CD4+ T cells. This group will use an altered form of the HIV rev gene. Normally, rev produces a protein (Rev) that allows transport of certain HIV genetic material within the infected cell from the nucleus to the cytoplasm, a critical step in viral replication. The altered Rev protein competes and interferes with functions of the normal protein inside an infected cell. This technique is already being tested in HIV-infected adults.
* Flossie Wong-Staal, Ph.D., of the University of California at San Diego, will head a group to study another type of gene therapy that uses an antiviral gene to produce ribozyme molecules designed specifically to cleave and inactivate a specific part of HIV's genetic material. The procedure, similar to that described above, involves removing T-cells from HIV-infected people and arming the cells with the ribozyme gene. Preliminary data from laboratory investigations by these scientists have shown that ribozymes confer long-term resistance to diverse strains of HIV.
* David Weiner, Ph.D., of the University of Pennsylvania in Philadelphia, and his team will explore the effectiveness of DNA-based therapeutic vaccines. The investigators will inject non-infectious HIV genes into the muscle tissue of HIV-infected people. The genes carry instructions for making HIV-specific proteins, a strategy that mimics many aspects of attenuated vaccines and can stimulate immune responses against the virus.
"By fostering strong interaction between basic and clinical investigators, the SPIRAT will allow scientists to pursue strategies to restore or maintain functional immune systems in people infected with HIV or to attack HIV replication directly on the macromolecular and cellular levels rather than by drug intervention, says Nava Sarver, Ph.D., coordinator of the SPIRAT and chief of the Targeted Drug Discovery Section of the Developmental Therapeutics Branch at DAIDS.
The SPIRAT will complement NIAID's National Cooperative Drug Discovery Groups for the Treatment of HIV (NCDDG). The NCDDG-HIV unites scientists in research efforts to discover and develop at the preclinical level new antiviral targets and strategies to fight HIV infection.
NIAID, a component of the National Institutes of Health (NIH), supports research on AIDS tuberculosis, allergies, immunology and infectious diseases. NIH is an agency of the U.S. Public Health Service, Department of Health and Human Services.