Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages

Abstract 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 activat...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ramon Edwin Caballero, Simon Xin Min Dong, Niranjala Gajanayaka, Hamza Ali, Edana Cassol, William D. Cameron, Robert Korneluk, Michel J. Tremblay, Jonathan Angel, Ashok Kumar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e042e27adcd1469d86cdf4e6c7ba50c4
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e042e27adcd1469d86cdf4e6c7ba50c4
record_format	dspace
spelling	oai:doaj.org-article:e042e27adcd1469d86cdf4e6c7ba50c42021-11-28T12:18:41ZRole of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages10.1038/s41598-021-02146-w2045-2322https://doaj.org/article/e042e27adcd1469d86cdf4e6c7ba50c42021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02146-whttps://doaj.org/toc/2045-2322Abstract 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) induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, chronically infected U1 cells, and ex-vivo derived MDMs from HIV-infected individuals. To understand the mechanism governing SM-induced cell death, we show that SM-induced cell death of primary HIV-infected macrophages was independent of the acquisition of M1 phenotype following HIV infection of macrophages. Instead, SM-induced cell death was found to be mediated by IAPs as downregulation of IAPs by siRNAs induced cell death of HIV-infected macrophages. Moreover, HIV infection caused receptor interacting protein kinase-1 (RIPK1) degradation which in concert with IAP1/2 downregulation following SM treatment may result in apoptosis of macrophages. Altogether, our results show that SM selectively induce apoptosis in primary human macrophages infected in vitro with HIV possibly through RIPK1. Moreover, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.Ramon Edwin CaballeroSimon Xin Min DongNiranjala GajanayakaHamza AliEdana CassolWilliam D. CameronRobert KornelukMichel J. TremblayJonathan AngelAshok KumarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ramon Edwin Caballero Simon Xin Min Dong Niranjala Gajanayaka Hamza Ali Edana Cassol William D. Cameron Robert Korneluk Michel J. Tremblay Jonathan Angel Ashok Kumar Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages
description	Abstract 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) induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, chronically infected U1 cells, and ex-vivo derived MDMs from HIV-infected individuals. To understand the mechanism governing SM-induced cell death, we show that SM-induced cell death of primary HIV-infected macrophages was independent of the acquisition of M1 phenotype following HIV infection of macrophages. Instead, SM-induced cell death was found to be mediated by IAPs as downregulation of IAPs by siRNAs induced cell death of HIV-infected macrophages. Moreover, HIV infection caused receptor interacting protein kinase-1 (RIPK1) degradation which in concert with IAP1/2 downregulation following SM treatment may result in apoptosis of macrophages. Altogether, our results show that SM selectively induce apoptosis in primary human macrophages infected in vitro with HIV possibly through RIPK1. Moreover, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.
format	article
author	Ramon Edwin Caballero Simon Xin Min Dong Niranjala Gajanayaka Hamza Ali Edana Cassol William D. Cameron Robert Korneluk Michel J. Tremblay Jonathan Angel Ashok Kumar
author_facet	Ramon Edwin Caballero Simon Xin Min Dong Niranjala Gajanayaka Hamza Ali Edana Cassol William D. Cameron Robert Korneluk Michel J. Tremblay Jonathan Angel Ashok Kumar
author_sort	Ramon Edwin Caballero
title	Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages
title_short	Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages
title_full	Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages
title_fullStr	Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages
title_full_unstemmed	Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages
title_sort	role of ripk1 in smac mimetics-induced apoptosis in primary human hiv-infected macrophages
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e042e27adcd1469d86cdf4e6c7ba50c4
work_keys_str_mv	AT ramonedwincaballero roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages AT simonxinmindong roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages AT niranjalagajanayaka roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages AT hamzaali roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages AT edanacassol roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages AT williamdcameron roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages AT robertkorneluk roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages AT micheljtremblay roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages AT jonathanangel roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages AT ashokkumar roleofripk1insmacmimeticsinducedapoptosisinprimaryhumanhivinfectedmacrophages
_version_	1718408108432162816

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages

Ejemplares similares