Low autocrine interferon beta production as a gene therapy approach for AIDS: Infusion of interferon beta-engineered lymphocytes in macaques chronically infected with SIVmac251

Wilfried Gay,Jérome Larghero,Dominique Dormont,Roger Le Grand,Franck Matheux,Sophie Peyramaure,Evelyne Lauret,Bertrand Boson,Edward De Maeyer,Véronique Rousseau

doi:10.1186/1742-4690-1-29

Abstract

BackgroundThe aim of this study was to evaluate gene therapy for AIDS based on the transduction of circulating lymphocytes with a retroviral vector giving low levels of constitutive macaque interferon β production in macaques chronically infected with a pathogenic isolate of SIVmac251.ResultsTwo groups of three animals infected for more than one year with a pathogenic primary isolate of SIVmac251 were included in this study. The macaques received three infusions of their own lymphocytes transduced ex vivo with the construct encoding macaque IFN-β (MaIFN-β or with a vector carrying a version of the MaIFN-β gene with a deletion preventing translation of the mRNA. Cellular or plasma viremia increased transiently following injection in most cases, regardless of the retroviral construct used. Transduced cells were detected only transiently after each infusion, among the peripheral blood mononuclear cells of all the animals, with copy numbers of 10 to 1000 per 106 peripheral mononuclear cells.ConclusionLong-term follow-up indicated that the transitory presence of such a small number of cells producing such small amounts of MaIFN-β did not prevent animals from the progressive decrease in CD4+ cell count typical of infection with simian immunodeficiency virus. These results reveal potential pitfalls for future developments of gene therapy strategies of HIV infection.

Highlights

The aim of this study was to evaluate gene therapy for AIDS based on the transduction of circulating lymphocytes with a retroviral vector giving low levels of constitutive macaque interferon β production in macaques chronically infected with a pathogenic isolate of SIVmac251
During HIV infection, the induction of type I IFN production has been shown to be impaired in T cells and macrophages, which are considered to be the major targets of the virus [13,14,15,16]
We have previously shown that peripheral blood lymphocytes (PBL) obtained from seronegative animals and transduced with a vector carrying the macaque IFN-β coding sequence placed under the control of a 0.6-kb fragment of the murine H2-Kb gene promoter develop greater resistance to SIVmac251 in vitro [23]

Summary

Introduction

The aim of this study was to evaluate gene therapy for AIDS based on the transduction of circulating lymphocytes with a retroviral vector giving low levels of constitutive macaque interferon β production in macaques chronically infected with a pathogenic isolate of SIVmac251. It has been suggested that the efficacy of type I IFNs for the treatment of HIV infection could be increased by developing a gene therapy strategy based on the modified production of IFN-β in genetically engineered lymphocytes [18] For this purpose, a retroviral vector derived from Moloney murine leukemia virus, in which the human IFN-β coding sequence has been placed under the control of a fragment of the murine H2-Kb gene promoter, has been used to ensure the continuous generation of low levels of IFN-β in transduced cells [10,19]. IFN-β production in PBL from HIV-infected donors increases Th1-type cytokine production, improves cytotoxic responses against cells expressing HIV proteins, and the proliferative response to recall antigens [10,12] These in vitro results have been confirmed in the SCID mouse model of HIV infection [20]. As the human-SCID mouse has a number of limitations as a model of AIDS, the efficacy and safety of this strategy should be evaluated in a more appropriate model, such as macaques infected with simian immunodeficiency virus (SIV)

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