Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2.

• Main Authors: 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
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2020-10-01
• Series: PLoS Pathogens
• Online Access: https://doi.org/10.1371/journal.ppat.1008906
• ISSN: 1553-7366; 1553-7374

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.