Maintenance of the HIV reservoir is antagonized by selective BCL2 inhibition

Nathan W Cummins, Amy M. Sainski-Nguyen, Sekar Natesampillai, Fatma Aboulnasr, Scott H Kaufmann, Andrew David Badley

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Decay of the HIV reservoir is slowed over time in part by expansion of the pool of HIV-infected cells. This expansion reflects homeostatic proliferation of infected cells by interleukin-7 (IL-7) or antigenic stimulation, as well as new rounds of infection of susceptible target cells. As novel therapies are being developed to accelerate the decay of the latent HIV reservoir, it will be important to identify interventions that prevent expansion and/or repopulation of the latent HIV reservoir. Our previous studies showed that HIV protease cleaves the host protein procaspase 8 to generate Casp8p41, which can bind and activate Bak to induce apoptosis of infected cells. In circumstances where expression of the anti-apoptotic protein BCL2 is high, Casp8p41 instead binds BCL2, and cell death does not occur. This effect can be overcome by treating cells with the clinically approved BCL2 antagonist venetoclax, which prevents Casp8p41 from binding BCL2, thereby allowing Casp8p41 to bind Bak and kill the infected cell. Here we assess whether the events that maintain the HIV reservoir are also antagonized by venetoclax. Using the J-Lat 10.6 model of persistent infection, we demonstrate that proliferation and HIV expression are countered by the use of venetoclax, which causes preferential killing of the HIVexpressing cells. Similarly, during new rounds of infection of primary CD4 T cells, venetoclax causes selective killing of HIV-infected cells, resulting in decreased numbers of HIV DNA-containing cells.

Original languageEnglish (US)
Article numbere00012-17
JournalJournal of Virology
Volume91
Issue number11
DOIs
StatePublished - Jun 1 2017

Keywords

  • Antiapoptosis
  • Bcl-2 family
  • HIV
  • Reservoir

ASJC Scopus subject areas

  • Immunology
  • Virology

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