Efficient entry inhibition of human and nonhuman primate immunodeficiency virus by cell surface-expressed gp41-derived peptides.
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.
Zahn
R C
RC
Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Hermann
F G
FG
Kim
E-Y
EY
Rett
M D
MD
Wolinsky
S M
SM
Johnson
R P
RP
Villinger
F
F
von Laer
D
D
Schmitz
J E
JE
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
D016915:AIDS Vaccines; C515020:C46 HIV-1 fusion inhibitory peptide; D015700:HIV Envelope Protein gp41; D011993:Recombinant Fusion Proteins