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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere1008906
JournalPLoS pathogens
Volume16
Issue number10
DOIs
StatePublished - Oct 19 2020

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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