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

36 Citations (Scopus)

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

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antagonists
Shock
T-lymphocytes
HIV
T-Lymphocytes
therapeutics
DNA
cells
Caspase 8
Cell- and Tissue-Based Therapy
cytotoxicity
proteinases
apoptosis
death
HIV Protease
Mitochondrial Proteins
Apoptosis
pro-apoptotic proteins

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Prime, shock, and kill : Priming CD4 T cells from HIV patients with a BCL-2 antagonist before HIV reactivation reduces HIV reservoir size. / Cummins, Nathan W; Sainski, Amy M.; Dai, Haiming; Natesampillai, Sekar; Pang, Yuan-Ping; Bren, Gary D.; De Araujo Correia, Maria Cristina Miranda; Sampath, Rahul; Rizza, Stacey; O'Brien, Daniel; Yao, Joseph D.; Kaufmann, Scott H; Badley, Andrew David.

In: Journal of Virology, Vol. 90, No. 8, 01.04.2016, p. 4032-4048.

Research output: Contribution to journalArticle

Cummins, Nathan W ; Sainski, Amy M. ; Dai, Haiming ; Natesampillai, Sekar ; Pang, Yuan-Ping ; Bren, Gary D. ; De Araujo Correia, Maria Cristina Miranda ; Sampath, Rahul ; Rizza, Stacey ; O'Brien, Daniel ; Yao, Joseph D. ; Kaufmann, Scott H ; Badley, Andrew David. / Prime, shock, and kill : Priming CD4 T cells from HIV patients with a BCL-2 antagonist before HIV reactivation reduces HIV reservoir size. In: Journal of Virology. 2016 ; Vol. 90, No. 8. pp. 4032-4048.
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