Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells.
Human immunodeficiency virus (HIV) persists in a latent form in infected individuals treated effectively with highly active antiretroviral therapy (HAART). In part, these latent proviruses account for the rebound in viral replication observed after treatment interruption. A major therapeutic challenge is to purge this reservoir. In this study, we demonstrate that suberoylanilide hydroxamic acid (SAHA) reactivates HIV from latency in chronically infected cell lines and primary cells. Indeed, P-TEFb, a critical transcription cofactor for HIV, is released and then recruited to the viral promoter upon stimulation with SAHA. The phosphatidylinositol 3-kinase/Akt pathway is involved in the initiation of these events. Using flow cytometry-based single cell analysis of protein phosphorylation, we demonstrate that SAHA activates this pathway in several subpopulations of T cells, including memory T cells that are the major viral reservoir in peripheral blood. Importantly, SAHA activates HIV replication in peripheral blood mononuclear cells from individuals treated effectively with HAART. Thus SAHA, which is a Food and Drug Administration-approved drug, might be considered to accelerate the decay of the latent reservoir in HAART-treated infected humans.
Contreras
Xavier
X
Department of Medicine, University of California, San Francisco, California 94143, USA.
Schweneker
Marc
M
Chen
Ching-Shih
CS
McCune
Joseph M
JM
Deeks
Steven G
SG
Martin
Jeffrey
J
Peterlin
B Matija
BM
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D005260:Female; D006678:HIV / Q000276:immunology / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007156:Immunologic Memory / Q000276:immunology; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011533:Proviruses / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D017735:Virus Latency / Q000187:drug effects* / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects* / Q000276:immunology; D000077337:Vorinostat
D006877:Hydroxamic Acids; D000077337:Vorinostat; D019869:Phosphatidylinositol 3-Kinases; D042925:Positive Transcriptional Elongation Factor B; D051057:Proto-Oncogene Proteins c-akt