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

R. T. Mitsuyasu, P. A. Anton, S. G. Deeks, D. T. Scadden, E. Connick, M. T. Downs, A. Roberts, M. R. Bakker, C. H. June, S. Jalali, A. A. Lin, R. Pennathur-Das, K. M. Hege

Research output: Contribution to journalArticlepeer-review

311 Scopus citations

Abstract

We have genetically engineered CD4+ and CD8+ T cells with human immunodeficiency virus (HIV) specificity by inserting a gene, CD4ζ, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (ζ) 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 1010 autologous CD4ζ-modified CD4+ and CD8+ T cells administered with (n = 11) or without (n = 13) interleukin-2 (IL-2). Subjects had CD4 counts greater than 50/μL 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. CD4ζ 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 14 days, suggesting compartmental antiviral activity of CD4ζ T Cells. CD4+ counts increased by 73/μL 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.

Original languageEnglish (US)
Pages (from-to)785-793
Number of pages9
JournalBlood
Volume96
Issue number3
DOIs
StatePublished - Aug 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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