1. ¹Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
2. ²Applied Virology and Gene Therapy, Georg-Speyer-Haus, Frankfurt, Germany
3. ³Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
4. ⁴New England Primate Research Center, Harvard Medical School, Southborough, MA, USA
5. ⁵Department of Pathology and Laboratory Medicine, Emory School of Medicine, Atlanta, GA, USA

Correspondence: Dr JE Schmitz, Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Research East 213D, 41 Avenue Louis Pasteur, Boston, MA 02115, USA. E-mail: jschmitz@bidmc.harvard.edu

Received 10 December 2007; Revised 9 March 2008; Accepted 11 March 2008; Published online 1 May 2008.

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, 7-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.