Prolonged survival and tissue trafficking following adoptive transfer of CD4ζ gene-modified autologous CD4+ and CD8+ T cells in human immunodeficiency virus-infected subjects

We have genetically engineered CD4(+) acid CD8(+) T cells with human immunodeficiency Virus (HIV) specificity by Inserting a gene, CD4 zeta, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (zeta) chain of the T-cell receptor (which mediates T-cell activation), Twenty-four HIV-positive subjects received a single infusion of 2 to 3 x 10(10) autologous CD4 zeta-modified CD4(+) and CD8+ T cells administered with (n = II) or without (n = 13) Interleukin-2 (IL-2), Subjects had CD4 counts greater than 50/mu L and viral loads of at least 1000 copies/ml at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks, CD4 zeta was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue-associated HIV RNA was observed for at least Iri days, suggesting compartmental antiviral activity of CD4 zeta T cells. CD4+ counts increased by 73/mu L at 8 weeks in the group receiving IL-2, There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function. (C) 2000 by The American Society of Hematology.