       Document 0967
 DOCN  M9620967
 TI    Genetic modification of human peripheral blood lymphocytes with a
       transdominant negative form of Rev: safety and toxicity.
 DT    9602
 AU    Fox BA; Woffendin C; Yang ZY; San H; Ranga U; Gordon D; Osterholzer J;
       Nabel GJ; Howard Hughes Medical Institute, University of Michigan
       Medical; Center, Ann Arbor 48109-0650, USA.
 SO    Hum Gene Ther. 1995 Aug;6(8):997-1004. Unique Identifier : AIDSLINE
       MED/96022631
 AB    A transdominant mutant form of the rev gene, M10, confers resistance to
       infection by the human immunodeficiency virus (HIV) in vitro and is
       currently under investigation as a potential intervention in acquired
       immunodeficiency syndrome (AIDS). In this report, we examine three
       issues relevant to the safety of autologous transfer of human T cells
       genetically modified with Rev M10. First, the potential for malignant
       transformation was assessed in vitro using interleukin-2 (IL-2)
       dependence and fibroblast transformation assays, and tumorigenicity was
       evaluated in severe combined immunodeficient (SCID) mice. Possible
       toxicity was evaluated by pathologic analysis following adoptive
       transfer of genetically modified human T cells into SCID mice. Second,
       methods were developed that permit T cell activation required for gene
       transfer but do not allow replication of endogenous HIV. Third, T cell
       function was evaluated in peripheral blood lymphocytes (PBL) of
       HIV-seropositive donors transduced with Rev M10 and compared to a
       negative control mutant, delta Rev M10. By all criteria, no oncogenicity
       or toxicity was observed. Human T cells transduced with these vectors
       did not grow in the absence of IL-2 in vitro, and no tumors were
       observed following transplantation of genetically modified human cells
       into recipient SCID mice. Histopathological analysis of heart, lung,
       liver, spleen, and kidney of animals 1-21 weeks following adoptive
       transfer of gene-modified human T cells revealed no significant
       abnormalities. Additionally, no differences were observed in the pattern
       of cytokine secretion in enriched human PBL expressing Rev M10 compared
       to delta Rev M10.2+
 DE    Animal  Antiviral Agents/PHARMACOLOGY  Base Sequence  Cell Line  Cell
       Transformation, Neoplastic  Cytokines/BIOSYNTHESIS  Female  Fibroblasts
       *Gene Transfer  Genes, rev/*GENETICS  Genes, Dominant  *Genetic Vectors
       Gold/TOXICITY  Human  HIV-1/*GENETICS/PHYSIOLOGY  Immunotherapy,
       Adoptive  Interleukin-2/PHYSIOLOGY  Lymphocyte Transformation  Mice
       Mice, Inbred BALB C  Mice, SCID  Microspheres  Molecular Sequence Data
       Retroviridae/GENETICS  Reverse Transcriptase Inhibitors/PHARMACOLOGY
       Support, U.S. Gov't, P.H.S.
       T-Lymphocytes/*IMMUNOLOGY/METABOLISM/TRANSPLANTATION  Virus
       Replication/DRUG EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

