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Efficient entry inhibition of human and nonhuman primate immunodeficiency virus by cell surface-expressed gp41-derived peptides

Gene Therapy volume 15, pages 1210–1222 (2008)Cite this article

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, β7-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.

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Acknowledgements

This work was supported by the German Government grant: BMBF TreatID and by the National Institute of Health grants AI060354, AI061797, CA73473 and RR00168.

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Authors and Affiliations

  1. Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    R C Zahn, M D Rett & J E Schmitz

  2. Applied Virology and Gene Therapy, Georg-Speyer-Haus, Frankfurt, Germany

    R C Zahn, F G Hermann & D von Laer

  3. Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    E-Y Kim & S M Wolinsky

  4. New England Primate Research Center, Harvard Medical School, Southborough, MA, USA

    R P Johnson

  5. Department of Pathology and Laboratory Medicine, Emory School of Medicine, Atlanta, GA, USA

    F Villinger

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  1. R C Zahn
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Zahn, R., Hermann, F., Kim, EY. et al. Efficient entry inhibition of human and nonhuman primate immunodeficiency virus by cell surface-expressed gp41-derived peptides. Gene Ther 15, 1210–1222 (2008). https://doi.org/10.1038/gt.2008.73

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