Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages

Kumar, A.; Caballero, R. E. H.; Dong, S. X. M.; Gajanayaka, N.; Ali, H.; Cassol, E.; Cameron, W.; Korneluk, R.; Tremblay, M.; Angel, J.

doi:10.1101/543017

bioRxiv · 10.1101/543017

Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages

Kumar, A.·Caballero, R. E. H.·Dong, S. X. M.·Gajanayaka, N.·Ali, H.·Cassol, E.·Cameron, W.·Korneluk, R.·Tremblay, M.·Angel, J.

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Abstract

Latent viral reservoirs of HIV-1 that persist despite antiretroviral therapy (ART) are major barriers for a successful cure. Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC)-mimetics (SM) specifically induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, and GFP-expressing HIV, chronically infected U1 cells, and ex-vivo derived MDMs from naive and ART-treated HIV patients. SM-induced cell death was found to be mediated by IAPs using IAP siRNAs, was independent of endogenously produced TNF and was attributed to the concomitant downregulation of IAP-1/2 and the receptor interacting protein kinase-1 degradation following HIV infection. Altogether, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.

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Kumar, A., Caballero, R. E. H., Dong, S. X. M., Gajanayaka, N., Ali, H., Cassol, E., Cameron, W., Korneluk, R., Tremblay, M., Angel, J.. 2019-02-06. Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages. https://doi.org/10.1101/543017

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