Journal of virology 2016 11 23() pii JVI.01389-16
Despite the success in viral inhibition and CD4 T cell recovery by highly active antiretroviral treatment (HAART), HIV-1 is still not curable due to the persistence of HIV-1 reservoir during treatment. One patient with acute myeloid leukemia who received allogeneic hematopoietic stem cell transplantation from homozygous CCR5 Δ32 donor has had no detectable viremia for 9 years after HAART cessation. This case has inspired a field of HIV-1 cure research focusing on engineering HIV-1 resistance of permissive cells. Here, we employed a glycosyl-phosphatidylinositol (GPI)-scFv X5 approach to confer resistance of human primary CD4 T cells to HIV-1. We showed that primary CD4 T cells expressing the GPI-scFv X5 were resistant to CCR5 (R5)-, CXCR4 (X4)- and dual tropic- HIV-1 and had survival advantage compared to control cells ex vivo In a hu-PBL mouse study, GPI-scFv X5-transduced CD4 T cells were selected in peripheral blood and lymphoid tissues upon HIV-1 infection. Finally, GPI-scFv X5-transduced CD4 T cells, after co-transfused with HIV-infected cells, significantly reduced viral loads and viral RNA copies relative to CD4 cells in hu-PBL mice compared to mice with GPI-scFv AB65-transduced CD4 T cells. We conclude that GPI-scFv X5-modified CD4 T cells could potentially be used as genetic intervention against both R5- and X4-tropic HIV-1 infection.
Blocking HIV-1 virus entry is one of most promising approaches for therapy. Genetic disruption of the HIV-1 co-receptor CCR5 by nucleases in T cells is under 2 clinical trials and leads to reduced viremia in patients. However, emergence of viruses using CXCR4 co-receptor is a concern for therapies applying single co-receptor disruption. We here report that HIV-1 permissive CD4 T cells engineered with GPI-scFv X5 are resistant to R5-, X4- or dual tropic virus infection ex vivo In a pre-clinical study using hu-PBL mice, we show CD4 T cells were protected and GPI-scFv X5-transduced cells were selected in HIV-1 infected animals. Moreover, we show that GPI-scFv X5-transduced CD4 T cells exerted negative effect on virus replication in vivo We conclude that GPI-scFv X5-modified CD4 T cells could potentially be used as genetic intervention against both R5- and X4-tropic HIV-1 infection.