Journal of virology 2018 04 11() pii 10.1128/JVI.00037-18
HIV protease is known to cause cell death which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41 which directly binds Bak with nanomolar affinity causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2 possibly explaining why these cells do not die when they reactivate HIV. Here we determine that the Casp8p41:Bcl2 complex is polyubiquitinated and degraded by the proteasome. Ixazomib, a proteasome inhibitor in clinical use, blocks this pathway – increasing the abundance of Casp8p41 and causing more cells to die in a Casp8p41 dependent manner. The Casp8p41 pathway of cell death is unique to HIV infected cells, yet is blocked by Bcl2. Once bound by Bcl2, Casp8p41 is polyubiquitinated and degraded by the proteasome. Proteasome inhibition blocks degradation of Casp8p41, increasing Casp8p41 levels and causing more HIV infected cell to die.