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, William K Henry, Amélie Pagliuzza, Andrew D. Badley

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 2017

Bibliographical note

Funding Information:
This publication was made possible by CTSA Grant Number KL2 TR000136 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH); grant numbers R01 AI110173 and R01 AI120698 from the National Institute of Allergy and Infectious Diseases; and by funding from the Division of Infectious Diseases, Mayo Clinic Rochester and the Minneapolis Medical Research Foundation (MMRF). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NIH, Mayo Clinic or University of Minnesota. The authors would like to thank the participants who donated blood for the purposes of the above experiments and the clinicians who referred them to our study. Authors thank Sanford Burnham Prebys Medical Discovery Institute (SBP) for the gift of microtiter plates pre-spotted (50 nL) with the Prestwick Chemical Library as prepared by Fu-Yue Zeng, Ph.D. of the Conrad Prebys Center for Chemical Genomics at SBP using their Echo 555 acoustic droplet ejector (Labcyte, Sunnyvale, CA).

Publisher Copyright:
© 2017 Sampath et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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