This Project is directed at allowing pilot study of seven different regimens involving novel cell therapy. First, gp 160 pulsed allogeneic dendritic cells from sex and HLA matched HIV seronegative siblings will be used to enhance HIV specific immune responses in HIV seropositive individuals. These cells will be studied in three groups of 4 patients either alone or in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin-2 (IL-2). In addition, pooled clones of CD8+ or CD4+ envelope specific cytotoxic T lymphocytes (CTL) obtained from sex and HLA matched HIV seronegative siblings will also be administered to HIV seropositive individuals with or without concurrent use of IL-2. Thus, within these seven different groups of patients, a large number of specific cellular therapy strategies will be studied to see if one can administer immune cell types from HLA matched HIV seronegative siblings to HIV infected individuals after purification without or with expansion in numbers. The patients given cells will be studied for both specific immunologic enhancement, cell persistence, impact on viral load and side effects as well as the possible use of gene therapy to prevent HIV infection of the transferred cells. The donor cells will be tracked in the blood and potentially within lymph nodes and delayed hypersensitivity response lesions by use of measurement of variable tandom repeats in the genes. Finally, careful study of the impact of these cells on viral load will be pursued in each treated individual utilizing newly developed quantitative polymerase chain reaction (PCR) for plasma virion RNA and CD4 specific cellular proviral DNA. The work will be done as a collaboration between the pathology group at Stanford University Blood Bank (II), who have devised methods for primary sensitization of dendritic cells and expansion methodology for the CTLs using envelope derived peptides and the critical dendritic cell isolation methodology as well as the group at Activated Cell Therapy (III) who is committed to the management of large scale T cell expansion, together with the project (1) group at the Center for AIDS Research at Stanford. The latter group has extensive experience with lymphokine administration to man, quantitation of CTL responses and measurement of viral load during chemo and immunotherapy as well as studies on identification of viral HIV CTL epitopes and escape mutants from studies with therapeutic vaccines. As we believe our interaction represents a unique set of talents to actually bring cell purification and expansion of critical immune cells in HIV infection into the clinic and derive useful immunologic and molecular biologic data which can guide this important newly developing field.
