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 Rizza, Daniel O'Brien, Joseph D. Yao, Scott H Kaufmann, Andrew David Badley

Research output: Contribution to journalArticle

41 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

  • Immunology
  • Virology

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