Peter Gasper - US grants

The overall goal of this investigation is to determine whether marrow transplantation therapy combined with immunotherapy and/or antiviral chemotherapy can ultimately be used to successfully treat people with retrovirus-mediated diseases. It is proposed to perform bone marrow transplant (BMT) studies in a well established animal model of human retrovirus infection; feline leukemia virus (FeLV) infection of cats. Attempts to treat patients with acquired immune deficiency syndrome (AIDS) illustrate how difficult it is to unseat persistent retrovirus infections. History suggests that inactivation of cellular replication of virus will not eliminate disease mediated by retrovirus infection. As long as the viurs remains, the potential for neoplasia or aplasia will exist. To cure AIDS and the growing list of retrovirus-induced diseases it will be necessary to eliminate the cells which are providing a reservoir for the virus. In cats, as in people, retrovirus infections are hemolymphatic cell infections--FeLV replication occurs primarily in mitotically active myelopoietic cells, megakaryocytes and follicular lymphoblasts in lymphatic tissues. Our rationale for how BMT can be used to treat retroviral diseases is as follows: 1) If one could eliminate infected hemolymphatic cells, on would be eliminating the majority of the virus burden from the individual; 2) If one could transplant non-infected hemolymphatic stem cells into that individual, a source of retrovirus-free blood cells, tissue macrophages, and immunocompetent lymphocytes would be provided - thereby reconstituting the depleted immune system of the marrow recipient and providing the potential for permanent elimination of the virus. 3) Finally, one must pharmacologically or immunologically remove or inhibit residual retrovirus during the interval between elimination of pre-existing infected hemolymphatic cells and engraftment of new noninfected hemolymphatic stem cells. We have recently eliminated persistent FeLV infection from two cats by using FeLV immunized cats as donor for recipient cats which had well established infections. Based on this initial success, the Specific Aims have been design to confirm whether this technique will prove to be a dependable means to cure persistent retrovirus infections. The first transplants will be performed in cats with controlled parameters, namely an apathogenic virus in the recipients and employment of donor cats immunized against the exact same virus. The next step will be to perform transplants with more cytopathic strains of the virus, ultimately leading to attempting to treat FeLV-infected pet cats. Additional studies include interleukin 2 stimulation and expansion of immune donor lymphocytes and antiviral chemotherapeutic treatment of donor cats prior to transplanting their cell into persistently infected recipients.