TY - JOUR
T1 - Noncanonical-NF-κB activation and DDX3 inhibition reduces the HIV-1 reservoir by elimination of latently infected cells ex-vivo
AU - Jansen, Jade
AU - Kroeze, Stefanie
AU - Man, Shirley
AU - Andreini, Matteo
AU - Bakker, Jan-Willem
AU - Zamperini, Claudio
AU - Tarditi, Alessia
AU - Kootstra, Neeltje A.
AU - Geijtenbeek, Teunis B. H.
N1 - Publisher Copyright: Copyright © 2023 Jansen et al.
PY - 2024/1/1
Y1 - 2024/1/1
N2 - Latency reversal and subsequent elimination of the human immunodeficiency virus-1 (HIV-1) reservoir using a combination of compounds with different mechanisms of action are considered a promising tool for HIV-1 cure. Here, we analyzed HIV-1 reservoir reduction by targeting the two host factors; inhibitor of apoptosis proteins (IAPs) and DEAD-box polypeptide 3 (DDX3) using a SMAC mimetic (SMACm) and DDX3 inhibitor (DDX3i), respectively. We observed that SMACm efficiently reactivated HIV-1 in a latency Jurkat model, which was further enhanced by DDX3 inhibition. Strikingly, this compound combination strongly decreased the proportion of latently as well as transcriptionally active infected cells in a T cell line model with a dual-reporter virus. To determine the efficacy of compounds to eradicate the HIV-1 reservoir in people living with HIV (PWH), a novel ex vivo HIV-1 reservoir reduction assay (HIVRRA) was developed. DDX3i and SMACm alone reduced the HIV-1 reservoir in peripheral blood mononuclear cells (PBMCs) from the majority of PWH, whereas notably, the SMACm/ DDX3i combination reduced the HIV-1 reservoir even further with 53%–90% in all PWH analyzed, while uninfected bystander cells were not affected. Our data highlight that IAPs as well as factors involved in HIV-1 replication like DDX3 are excellent targets for HIV-1 cure strategies. We show for the first time that the combination of SMACm and DDX3i reverses viral latency and specifically eliminates the HIV-1-infected cells in vitro and ex vivo.
AB - Latency reversal and subsequent elimination of the human immunodeficiency virus-1 (HIV-1) reservoir using a combination of compounds with different mechanisms of action are considered a promising tool for HIV-1 cure. Here, we analyzed HIV-1 reservoir reduction by targeting the two host factors; inhibitor of apoptosis proteins (IAPs) and DEAD-box polypeptide 3 (DDX3) using a SMAC mimetic (SMACm) and DDX3 inhibitor (DDX3i), respectively. We observed that SMACm efficiently reactivated HIV-1 in a latency Jurkat model, which was further enhanced by DDX3 inhibition. Strikingly, this compound combination strongly decreased the proportion of latently as well as transcriptionally active infected cells in a T cell line model with a dual-reporter virus. To determine the efficacy of compounds to eradicate the HIV-1 reservoir in people living with HIV (PWH), a novel ex vivo HIV-1 reservoir reduction assay (HIVRRA) was developed. DDX3i and SMACm alone reduced the HIV-1 reservoir in peripheral blood mononuclear cells (PBMCs) from the majority of PWH, whereas notably, the SMACm/ DDX3i combination reduced the HIV-1 reservoir even further with 53%–90% in all PWH analyzed, while uninfected bystander cells were not affected. Our data highlight that IAPs as well as factors involved in HIV-1 replication like DDX3 are excellent targets for HIV-1 cure strategies. We show for the first time that the combination of SMACm and DDX3i reverses viral latency and specifically eliminates the HIV-1-infected cells in vitro and ex vivo.
KW - DDX3
KW - HIV-1 reservoir
KW - IAP
KW - SMAC mimetics
KW - human immunodeficiency virus
KW - latency reversal
UR - http://www.scopus.com/inward/record.url?scp=85182501264&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/spectrum.03180-23
DO - https://doi.org/10.1128/spectrum.03180-23
M3 - Article
C2 - 38051053
SN - 2165-0497
VL - 12
JO - Microbiology spectrum
JF - Microbiology spectrum
IS - 1
ER -