Experimental gene therapy

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Abstract
Objectives: To evaluate in vitro and in vivo a strategy for gene therapy for AIDS based on the transfer of interferon (IFN)-α, β and -γ genes to human cells. Design: Human U937 promonocytic cells were stably transfected with Tat-inducible IFN expression vectors conferring an antiviral state against infection with HIV. Methods: Transfected cells were either infected by HIV-1 in vitro or transplanted into severe combined immunodeficient (SCID) mice for an HIV challenge in vivo. Results: U937 cell lines stably carrying IFN transgenes under the positive control of the HIV-1 Tat protein were highly resistant to HIV-1 replication in vitro. This antiviral resistance was associated with a strong induction of IFN synthesis immediately following the viral infection. HIV-1 proteins were found to be specifically trapped within the genetically modified cells. In contrast, all IFN-U937 cells permitted full HIV-2 replication. Transfected cells injected into SCID mice and challenged against HIV-1 were strongly resistant to infection when cells were transduced with IFN-α or IFN-β genes. However, IFN-γ-transfected cells permitted HIV-1 infection in vivo despite the induction of a high level of IFN-γ secretion. The quantity of proviral DNA was 105-fold lower in IFN-α- or IFN-β-transfected U937 cells collected from these SCID mice than that in non-transfected cells. Conclusions: Our results substantiated the validity of a strategy, based on the transfer of HIV-1-inducible IFN-α or IFN-β genes, to confer antiviral resistance to human cells.

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