Increasing MG1-Mediated Death in HIV-Infected Cells with SMAC Mimetics

It was previously shown that interferon defects in latently HIV infected cells make them permissive to MG1 mediated killing. To increase effectiveness of MG1 therapy, we have combined MG1 with the SMAC mimetic birinapant to increase MG1 mediated killing in latently infected J1.1 cells. Increased cell death was observed compared to either treatment alone and was accompanied by increased caspase-3/7 and caspase-1 expression. However, cell death could not be blocked by the pan-caspase inhibitor ZVAD-fmk or the necroptosis inhibitor necrostatin1-s, alone or in combination, indicating that cell death does not occur via a single pathway. Furthermore, it was shown that SMAC mimetic treatment results in decreased transcription of genes that take part in the immune signalling pathway, which is likely one the ways how SMAC mimetic treament senstizes HIV infected cells to MG1 mediated death. 12 samples of J1.1 cells were analyzed using RNA-seq under 4 conditions containing 3 replicates each; untreated, infected with MG1_eGFP, infected with MG1_eGFP and treated with Birinapant, and treated with Birinipant only.