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- Title
Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2.
- Authors
French, Andrea J.; Natesampillai, Sekar; Krogman, Ashton; Correia, Cristina; Peterson, Kevin L.; Alto, Alecia; Chandrasekar, Aswath P.; Misra, Anisha; Li, Ying; Kaufmann, Scott H.; Badley, Andrew D.; Cummins, Nathan W.
- Abstract
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. Author summary: The major barrier to an HIV cure is the latent viral reservoir. We questioned why some drugs that reactivate latent HIV fail to reduce the viral reservoir size. We show that some HIV latency reversal agents, particularly PKC agonists such as bryostatin-1, activate the anti-apoptotic BCL2 protein in CD4 T cells. This unintended biologic effect inhibits apoptosis and, thereby, may promote HIV persistence despite viral reactivation. It is therefore important to screen potential latency reversal agents for off-target effects that might promote survival of HIV infected cells.
- Subjects
PROTEIN kinase C; APOPTOSIS; CELL death; CD4 antigen; VIRUS reactivation; KAPOSI'S sarcoma-associated herpesvirus; HIV
- Publication
PLoS Pathogens, 2020, Vol 16, Issue 10, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1008906