title: Efficient entry inhibition of human and nonhuman primate immunodeficiency virus by cell surface-expressed gp41-derived peptides.
abstract: Membrane-anchored C-peptides (for example, maC46) derived from human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41 effectively inhibit HIV-1 entry in cell lines and primary human CD4+ cells in vitro. Here we evaluated this gene therapy approach in animal models of AIDS. We adapted the HIV gp41-derived maC46 vector construct for use in rhesus monkeys. Simian immunodeficiency virus (SIV and SHIV) sequence-adapted maC46 peptides, and the original HIV-1-derived maC46 expressed on the surface of established cell lines blocked entry of HIV-1, SIVmac251 and SHIV89.6P. Furthermore, primary rhesus monkey CD4+ T cells expressing HIV sequence-based maC46 peptides were also protected from SIV entry. Depletion of CD8+ T cells from PBMCs enhanced the yield of maC46-transduced CD4+ T cells. Supplementation with interleukin-2 (IL-2) increased transduction efficiency, whereas IL-7 and/or IL-15 provided no additional benefit. Phenotypic analysis showed that maC46-transduced and expanded cells were predominantly central memory CD4+ T cells that expressed low levels of CCR5 and slightly elevated levels of CD62L, beta7-integrin and CXCR4. These findings show that maC46-based cell surface-expressed peptides can efficiently inhibit primate immunodeficiency virus infection, and therefore serve as the basis for evaluation of this gene therapy approach in an animal model for AIDS.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Zahn
authors.forename: F G
authors.initials: FG
authors.lastname: Hermann
authors.forename: E-Y
authors.initials: EY
authors.lastname: Kim
authors.forename: M D
authors.initials: MD
authors.lastname: Rett
authors.forename: S M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: R P
authors.initials: RP
authors.lastname: Johnson
authors.forename: F
authors.initials: F
authors.lastname: Villinger
authors.forename: D
authors.initials: D
authors.lastname: von Laer
authors.forename: J E
authors.initials: JE
authors.lastname: Schmitz
mesh_terms: D016915:AIDS Vaccines; D000163:Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D030541:Databases, Genetic; D005818:Genetic Engineering; D015700:HIV Envelope Protein gp41 / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D008253:Macaca mulatta; D023421:Models, Animal; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D016097:Simian Acquired Immunodeficiency Syndrome; D015302:Simian Immunodeficiency Virus; D014161:Transduction, Genetic / Q000379:methods; D016662:Virus Integration
chemical_list: D016915:AIDS Vaccines; C515020:C46 HIV-1 fusion inhibitory peptide; D015700:HIV Envelope Protein gp41; D011993:Recombinant Fusion Proteins