EXPERIMENTAL GENE-THERAPY - THE TRANSFER OF TAT-INDUCIBLE INTERFERON GENES PROTECTS HUMAN-CELLS AGAINST HIV-1 CHALLENGE IN-VITRO AND IN-VIVO IN SEVERE COMBINED IMMUNODEFICIENT MICE

Objectives: To evaluate in vitro and in vivo a strategy for gene thera py for AIDS based on the transfer of interferon (IFN)-alpha, -beta and -gamma genes to human cells. Design: Human U937 promonocytic cells we re stably transfected with Tat-inducible IFN expression vectors confer ring an antiviral state against infection with HIV. Methods: Transfect ed cells were either infected by HIV-1 in vitro or transplanted into s evere combined immunodeficient (SCID) mice for an HIV challenge in viv o. Results: U937 cell lines stably carrying IFN transgenes under the p ositive 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 in fection. HIV-1 proteins were found to be specifically trapped within t he genetically modified cells. In contrast, all IFN-U937 cells permitt ed full HIV-2 replication. Transfected cells injected into SCID mice a nd challenged against HIV-1 were strongly resistant to infection when cells were transduced with IFN-alpha or IFN-beta genes. However, IFN-g amma-transfected cells permitted HIV-1 infection in vivo despite the i nduction of a high level of IFN-gamma secretion. The quantity of provi ral DNA was 10(5)-fold lower in IFN-alpha- or IFN-beta-transfected U93 7 cells collected from these SCID mice than that in non-transfected ce lls. Conclusions: Our results substantiated the validity of a strategy , based on the transfer of HIV-1-inducible IFN-alpha or IFN-beta genes , to confer antiviral resistance to human cells.