Journal Article

Discovery of a Small Molecule Agonist of Phosphatidylinositol 3-Kinase p110α That Reactivates Latent HIV-1

Mellors, John W., McMahon, Deborah, Sobolewski, Michele D., Sluis-Cremer, Nicolas, Doyon, Geneviève, Huber, Kelly

2014

Overview

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 p110α 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 1-Phosphatidylinositol 3-kinase / Acquired immune deficiency syndrome / AIDS / AKT protein / Anti-HIV Agents - pharmacology / Antiretroviral agents / Antiretroviral therapy / Biology / CD4 antigen / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - enzymology / CD4-Positive T-Lymphocytes - virology / CD8 antigen / CD8-Positive T-Lymphocytes - virology / Cell activation / Cell culture / Cell Line / Class Ia Phosphatidylinositol 3-Kinase - genetics / Class Ia Phosphatidylinositol 3-Kinase - metabolism / Drug Discovery / Drug Therapy, Combination / Enzyme Activation - drug effects / Gene Expression / Heterocyclic Compounds, 4 or More Rings - pharmacology / Histone Deacetylase Inhibitors - pharmacology / HIV / HIV Infections - drug therapy / HIV Infections - enzymology / HIV Infections - virology / HIV-1 - drug effects / HIV-1 - physiology / Human immunodeficiency virus / Humans / Hydroxamic Acids - pharmacology / Immunological memory / Isoforms / Kinases / Latency / Lymphocyte Activation / Lymphocyte Depletion / Lymphocytes / Lymphocytes T / Medicine / Memory cells / Ovarian cancer / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Quinolones - pharmacology / Signal Transduction / Signaling / Virus Activation - drug effects / Virus Latency