Discovery of a small molecule agonist of phosphatidylinositol 3-kinase p110α that reactivates latent HIV-1.
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.
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Geneviève
G
Doyon
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Michele D
MD
Sobolewski
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Kelly
K
Huber
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Deborah
D
McMahon
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
John W
JW
Mellors
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Nicolas
N
Sluis-Cremer
D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D055808:Drug Discovery; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D015398:Signal Transduction; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency; D000077337:Vorinostat
C000591894:1,2,9,10-tetramethoxy-7H-dibenzo(de,g)quinolin-7-one; D019380:Anti-HIV Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015363:Quinolones; D000077337:Vorinostat; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt