Gene therapy with plasmids encoding IFN-β or IFN-α14 confers long-term resistance to HIV-1 in humanized mice

Because endogenous interferon type I (IFN-I) produced by HIV-1 infection might complicate the analysis of therapeutically administered IFN-I, we tested different humanized mouse models for induction of IFN-I during HIV-1 infection. While HIV-1 induced high levels of IFN-a in BLT mice, IFN-I was undetectable following infection in the Hu-PBL mouse model, in which only T cells expand. We therefore tested the effect of treatment with Pegylated IFN-2 (pegasys), in Hu-PBL mice. Pegasys prevented CD4 T cell depletion and reduced the viral load for 10 days, but the effect waned thereafter. We next expressed IFN-I subsets (IFN-alpha 2, -alpha 6, -alpha 8, -alpha 14, and -beta) in HuPBL mice by hydrodynamic injection of plasmids encoding them and 2 days later infected the mice with HIV-1. CD4 T cell depletion was prevented in all subtypes of IFN-I-expressing mice by day 10. However, at day 40 post-infection, protection was seen in IFN-beta- and IFN-alpha 14-expressing mice, but not the others. The viral load followed an inverse pattern and was highest in control mice and lowest in IFN-beta- and IFN-alpha 14-expressing mice until day 40 after infection. These results show that gene therapy with plasmids encoding IFN-beta and -alpha 14, but not the commonly used -alpha 2, confers long-term suppression of HIV-1 replication.