Although the development of effective antiviral drug combinations holds great promise for treatment of HIV-infected patients, most patients receiving therapy have already had destruction of large numbers of T lymphocytes. The ability of these patients to lead normal lives will depend on their body's ability to make new T lymphocytes to replace those destroyed by HIV. New T lymphocytes are normally made in the thymus. However, studies of both HIV and acquired immune deficiencies not due to HIV, such as those caused by chemotherapy or radiation therapy in cancer or bone marrow transplant patients, have shown that the thymus' ability to produce new T lymphocytes decreases dramatically during adolescence. The thymic microenvironment may also be inhibited or damaged by HIV infection, which would further decrease the ability of the thymus to reconstitute the mature T lymphocyte compartment. Therefore, methods to restore the thymic production of new T lymphocytes are a essential part of strategies to cure HIV-infected patients. Using mice receiving bone marrow transplants (BMT) as a model, we have shown that the immune defects can be successfully prevented by administration of interleukin-(IL-7). We have also corrected immune function, by introducing the IL-7 gene into marrow stromal cells of mice. The purpose of the studies described in this grant are to use IL-7 to stimulate the development of new T cells in patients receiving antiviral therapy for HIV infection. Basic studies of isolated stromal cells and T cells, studies will be used to develop an IL-7 treatment program to restore immune function in HIV-infected patients.
Aim 1 will be to determine whether the normal human IL-7-producing cell, like that of the mouse is an MHC Class II+ CD45- stromal cell.
In Aim 2, in vitro infection with an HIV reporter will be used to determine whether the IL-7 producing stromal cell can be infected by HIV or whether HIV inhibits IL-7 production.
In Aim 3, vectors to transduce the IL-7 gene into human stromal cells will be tested. Experiments in Aim 4 to determine whether IL-7 results in transactivation of the HIV LTR will provide important pre-clinical information about possible toxicity of IL-7 in HIV-infected patients. The goal of these studies is to develop an IL-7 gene therapy trial in the next 2 years.
|Weinberg, K; Blazar, B R; Wagner, J E et al. (2001) Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 97:1458-66|
|Chung, B; Barbara-Burnham, L; Barsky, L et al. (2001) Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation. Blood 98:1601-6|