title: Genetic vaccination-induced immune responses to the human immunodeficiency virus protein Rev: emergence of the interleukin 2-producing helper T lymphocyte.
abstract: Rev M10 is a trans-dominant negative inhibitor of HIV replication. Hence, stable transduction of CD4+ T cells with Rev M10 represents a novel gene therapy aimed at inhibiting HIV replication within these cells, thereby slowing the progression of AIDS. However, the immune system may recognize Rev M10 as foreign and target transduced cells for elimination. In the current study, mice were genetically immunized with a plasmid encoding Rev M10, to (1) identify immune parameters that may be induced by Rev M10 gene transfer, (2) determine the impact of repeated introduction of the Rev M10-encoding plasmid on the immune response to the transgene product, and (3) determine if cotransfection with a plasmid encoding TGFbeta1 would suppress the response. Kinetic studies revealed that Rev-specific IL-2-producing helper T lymphocytes (HTLs) appeared following the second genetic immunization, peaked after the third, and persisted at peak levels for at least 6 weeks. Rev-specific HTLs were CD4+, and the development of these cells was ablated by cotransfection with TGFbeta1. Other cytokines were not readily detectable when immune splenocytes were restimulated with Rev in vitro, and Rev-specific IgG antibodies were not present in the sera of these mice. To our knowledge, this represents the first report that genetic immunization with Rev M10 induces an immune response that is dominated by IL-2-producing HTLs. Further, this study demonstrates the potential utility of introducing immunosuppressive genes as a means to control the immune response to foreign transgene products.
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109, USA.
authors.forename: S Y
authors.initials: SY
authors.lastname: Chan
authors.forename: M C
authors.initials: MC
authors.lastname: Louie
authors.forename: J R
authors.initials: JR
authors.lastname: Piccotti
authors.forename: G
authors.initials: G
authors.lastname: Iyer
authors.forename: X
authors.initials: X
authors.lastname: Ling
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Yang
authors.forename: G J
authors.initials: GJ
authors.lastname: Nabel
authors.forename: D K
authors.initials: DK
authors.lastname: Bishop
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015694:Gene Products, rev / Q000235:genetics* / Q000276:immunology*; D018014:Gene Transfer Techniques; D007074:Immunoglobulin G / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000235:genetics; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D019076:Transgenes; D014611:Vaccination
chemical_list: D016207:Cytokines; D015694:Gene Products, rev; D007074:Immunoglobulin G; D007376:Interleukin-2; D016212:Transforming Growth Factor beta