Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2.
Eradication of HIV-1 by the "kick and kill" strategy requires reactivation of latent virus to cause death of infected cells by either HIV-induced or immune-mediated apoptosis. To date this strategy has been unsuccessful, possibly due to insufficient cell death in reactivated cells to effec...
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2020-10-01
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Online Access: | https://doi.org/10.1371/journal.ppat.1008906 |
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doaj-43ec5f6e91a24ab2bbc1bd2c4e5d59c02021-08-12T04:31:37ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742020-10-011610e100890610.1371/journal.ppat.1008906Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2.Andrea J FrenchSekar NatesampillaiAshton KrogmanCristina CorreiaKevin L PetersonAlecia AltoAswath P ChandrasekarAnisha MisraYing LiScott H KaufmannAndrew D BadleyNathan W CumminsEradication of HIV-1 by the "kick and kill" strategy requires reactivation of latent virus to cause death of infected cells by either HIV-induced or immune-mediated apoptosis. To date this strategy has been unsuccessful, possibly due to insufficient cell death in reactivated cells to effectively reduce HIV-1 reservoir size. As a possible cause for this cell death resistance, we examined whether leading latency reversal agents (LRAs) affected apoptosis sensitivity of CD4 T cells. Multiple LRAs of different classes inhibited apoptosis in CD4 T cells. Protein kinase C (PKC) agonists bryostatin-1 and prostratin induced phosphorylation and enhanced neutralizing capability of the anti-apoptotic protein BCL2 in a PKC-dependent manner, leading to resistance to apoptosis induced by both intrinsic and extrinsic death stimuli. Furthermore, HIV-1 producing CD4 T cells expressed more BCL2 than uninfected cells, both in vivo and after ex vivo reactivation. Therefore, activation of BCL2 likely contributes to HIV-1 persistence after latency reversal with PKC agonists. The effects of LRAs on apoptosis sensitivity should be considered in designing HIV cure strategies predicated upon the "kick and kill" paradigm.https://doi.org/10.1371/journal.ppat.1008906 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrea J French Sekar Natesampillai Ashton Krogman Cristina Correia Kevin L Peterson Alecia Alto Aswath P Chandrasekar Anisha Misra Ying Li Scott H Kaufmann Andrew D Badley Nathan W Cummins |
spellingShingle |
Andrea J French Sekar Natesampillai Ashton Krogman Cristina Correia Kevin L Peterson Alecia Alto Aswath P Chandrasekar Anisha Misra Ying Li Scott H Kaufmann Andrew D Badley Nathan W Cummins Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2. PLoS Pathogens |
author_facet |
Andrea J French Sekar Natesampillai Ashton Krogman Cristina Correia Kevin L Peterson Alecia Alto Aswath P Chandrasekar Anisha Misra Ying Li Scott H Kaufmann Andrew D Badley Nathan W Cummins |
author_sort |
Andrea J French |
title |
Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2. |
title_short |
Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2. |
title_full |
Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2. |
title_fullStr |
Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2. |
title_full_unstemmed |
Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2. |
title_sort |
reactivating latent hiv with pkc agonists induces resistance to apoptosis and is associated with phosphorylation and activation of bcl2. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2020-10-01 |
description |
Eradication of HIV-1 by the "kick and kill" strategy requires reactivation of latent virus to cause death of infected cells by either HIV-induced or immune-mediated apoptosis. To date this strategy has been unsuccessful, possibly due to insufficient cell death in reactivated cells to effectively reduce HIV-1 reservoir size. As a possible cause for this cell death resistance, we examined whether leading latency reversal agents (LRAs) affected apoptosis sensitivity of CD4 T cells. Multiple LRAs of different classes inhibited apoptosis in CD4 T cells. Protein kinase C (PKC) agonists bryostatin-1 and prostratin induced phosphorylation and enhanced neutralizing capability of the anti-apoptotic protein BCL2 in a PKC-dependent manner, leading to resistance to apoptosis induced by both intrinsic and extrinsic death stimuli. Furthermore, HIV-1 producing CD4 T cells expressed more BCL2 than uninfected cells, both in vivo and after ex vivo reactivation. Therefore, activation of BCL2 likely contributes to HIV-1 persistence after latency reversal with PKC agonists. The effects of LRAs on apoptosis sensitivity should be considered in designing HIV cure strategies predicated upon the "kick and kill" paradigm. |
url |
https://doi.org/10.1371/journal.ppat.1008906 |
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