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Discovery of a small molecule agonist of phosphatidylinositol 3-kinase p110α that reactivates latent HIV-1

Doyon, G and Sobolewski, MD and Huber, K and McMahon, D and Mellors, JW and Sluis-Cremer, N (2014) Discovery of a small molecule agonist of phosphatidylinositol 3-kinase p110α that reactivates latent HIV-1. PLoS ONE, 9 (1).

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Abstract

Combination antiretroviral therapy (cART) can effectively suppress HIV-1 replication, but the latent viral reservoir in resting memory CD4+ T cells is impervious to cART and represents a major barrier to curing HIV-1 infection. Reactivation of latent HIV-1 represents a possible strategy for elimination of this reservoir. In this study we describe the discovery of 1,2,9,10-tetramethoxy-7H-dibenzo[de,g]quinolin-7-one (57704) which reactivates latent HIV-1 in several cell-line models of latency (J89GFP, U1 and ACH-2). 57704 also increased HIV-1 expression in 3 of 4 CD8+-depleted blood mononuclear cell preparations isolated from HIV-1-infected individuals on suppressive cART. In contrast, vorinostat increased HIV-1 expression in only 1 of the 4 donors tested. Importantly, 57704 does not induce global T cell activation. Mechanistic studies revealed that 57704 reactivates latent HIV-1 via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. 57704 was found to be an agonist of PI3K with specificity to the p110a isoform, but not the p110β, δ or γ isoforms. Taken together, our work suggests that 57704 could serve as a scaffold for the development of more potent activators of latent HIV-1. Furthermore, it highlights the involvement of the PI3K/Akt pathway in the maintenance of HIV-1 latency. © 2014 Doyon et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Doyon, G
Sobolewski, MDmis135@pitt.eduMIS135
Huber, K
McMahon, Dmcmahond@pitt.eduMCMAHOND
Mellors, JWjwm1@pitt.eduJWM1
Sluis-Cremer, Nnps2@pitt.eduNPS2
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorDash, ChandravanuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 29 January 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 1
DOI or Unique Handle: 10.1371/journal.pone.0084964
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Date Deposited: 17 Jun 2014 14:51
Last Modified: 04 Feb 2019 15:56
URI: http://d-scholarship.pitt.edu/id/eprint/21891

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