Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection

To study human immunodeficiency virus (HIV)-specific cellular immunity in v ivo, we transferred syngeneic lymphocytes after ex vivo expansion and trans duction with a chimeric receptor gene (CD4/CD3-zeta) between identical twin s discordant for HIV infection. Single and multiple infusions of 10(10) gen etically modified CD8(+) T cells resulted in peak fractions in the circulat ion of approximately 10(4) to 10(5) modified cells/10(6) mononuclear cells at 24 to 48 hours, followed by 2- to 3-log declines by 8 weeks. In an effor t to provide longer high-level persistence of the transferred cells and pos sibly enhance anti-HIV activity, we administered a second series of infusio ns in which both CD4(+) and CD8(+) T cells were engineered to express the c himeric receptor and were costimulated ex vivo with beads coated with anti- CDS and anti-CD28. Sustained fractions of approximately 10(3) to 10(4) modi fied cells/10(6) total CD4(+) or CD8(+) cells persisted for at least 1 year . Assessment of in vivo trafficking of the transferred cells by lymphoid ti ssue biopsies revealed the presence of modified cells in proportions equiva lent to or below those in the circulation. The cell infusions were well tol erated and were not associated with substantive Immunologic or virologic ch anges. Thus, adoptive transfer of genetically modified HIV-antigen-specific T cells was safe. Sustained survival in the circulation was achieved when modified CD4(+) and CD8(+) T cells were infused together after ex vivo cost imulation, indicating the important role played by antigen-specific CD4(+) T cells in providing "help" to cytotoxic effecters. (C) 2000 by The America n Society of Hematology.