Prime, shock, and kill: Priming CD4 T cells from HIV patients with a BCL-2 antagonist before HIV reactivation reduces HIV reservoir size

Nathan W. Cummins, Amy M. Sainski, Haiming Dai, Sekar Natesampillai, Yuan Ping Pang, Gary D. Bren, Maria Cristina Miranda De Araujo Correia, Rahul Sampath, Stacey A. Rizza, Daniel O'Brien, Joseph D. Yao, Scott H. Kaufmann, Andrew D. Badley

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Understanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling HIV cure efforts. HIV killing of CD4 T cells that replicate HIV can involve HIV protease-mediated cleavage of procaspase 8 to generate a fragment (Casp8p41) that directly binds and activates the mitochondrial proapoptotic protein BAK. Here, we demonstrate that Casp8p41 also binds with nanomolar affinity to the antiapoptotic protein Bcl-2, which sequesters Casp8p41 and prevents apoptosis. Further, we show that central memory CD4 T cells (TCM) from HIV-infected individuals have heightened expression of BCL-2 relative to procaspase 8, possibly explaining the persistence of HIV-infected TCM despite generation of Casp8p41. Consistent with this hypothesis, the selective BCL-2 antagonist venetoclax induced minimal killing of uninfected CD4 T cells but markedly increased the death of CD4 T cells and diminished cell-associated HIV DNA when CD4 T cells from antiretroviral therapy (ART)- suppressed HIV patients were induced with αCD3/αCD28 to reactivate HIV ex vivo. Thus, priming CD4 T cells from ART suppressed HIV patients with a BCL-2 antagonist, followed by HIV reactivation, achieves reductions in cell-associated HIV DNA, whereas HIV reactivation alone does not.

Original languageEnglish (US)
Pages (from-to)4032-4048
Number of pages17
JournalJournal of virology
Volume90
Issue number8
DOIs
StatePublished - Apr 1 2016

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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