Increasing procaspase 8 expression using repurposed drugs to induce HIV infected cell death in ex vivo patient cells

Rahul Sampath, Nathan W Cummins, Sekar Natesampillai, Gary D. Bren, Thomas D. Chung, Jason Baker, Keith Henry, Amélie Pagliuzza, Andrew David Badley

Research output: Contribution to journalArticle

Abstract

HIV persists because a reservoir of latently infected CD4 T cells do not express viral proteins and are indistinguishable from uninfected cells. One approach to HIV cure suggests that reactivating HIV will activate cytotoxic pathways; yet when tested in vivo, reactivating cells do not die sufficiently to reduce cell-associated HIV DNA levels. We recently showed that following reactivation from latency, HIV infected cells generate the HIV specific cytotoxic protein Casp8p41 which is produced by HIV protease cleaving procaspase 8. However, cell death is prevented, possibly due to low procaspase 8 expression. Here, we tested whether increasing procaspase 8 levels in CD4 T cells will produce more Casp8p41 following HIV reactivation, causing more reactivated cells to die. Screening 1277 FDA approved drugs identified 168 that increased procaspase 8 expression by at least 1.7-fold. Of these 30 were tested for anti-HIV effects in an acute HIVIIIb infection model, and 9 drugs at physiologic relevant levels significantly reduced cell-associated HIV DNA. Primary CD4 T cells from ART suppressed HIV patients were treated with one of these 9 drugs and reactivated with αCD3/αCD28. Four drugs significantly increased Casp8p41 levels following HIV reactivation, and decreased total cell associated HIV DNA levels (flurbiprofen: p = 0.014; doxycycline: p = 0.044; indomethacin: p = 0.025; bezafibrate: P = 0.018) without effecting the viability of uninfected cells. Thus procaspase 8 levels can be increased pharmacologically and, in the context of HIV reactivation, increase Casp8p41 causing death of reactivating cells and decreased HIV DNA levels. Future studies will be required to define the clinical utility of this or similar approaches.

Original languageEnglish (US)
Article numbere0179327
JournalPLoS One
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Drug Repositioning
Caspase 8
Cell death
cell death
Cell Death
HIV
T-cells
drugs
Pharmaceutical Preparations
DNA
cells
T-lymphocytes
Cells
Bezafibrate
HIV Protease
Flurbiprofen
Doxycycline
Viral Proteins
Indomethacin
doxycycline

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Increasing procaspase 8 expression using repurposed drugs to induce HIV infected cell death in ex vivo patient cells. / Sampath, Rahul; Cummins, Nathan W; Natesampillai, Sekar; Bren, Gary D.; Chung, Thomas D.; Baker, Jason; Henry, Keith; Pagliuzza, Amélie; Badley, Andrew David.

In: PLoS One, Vol. 12, No. 6, e0179327, 01.06.2017.

Research output: Contribution to journalArticle

Sampath, Rahul ; Cummins, Nathan W ; Natesampillai, Sekar ; Bren, Gary D. ; Chung, Thomas D. ; Baker, Jason ; Henry, Keith ; Pagliuzza, Amélie ; Badley, Andrew David. / Increasing procaspase 8 expression using repurposed drugs to induce HIV infected cell death in ex vivo patient cells. In: PLoS One. 2017 ; Vol. 12, No. 6.
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