Linked Life Data

21531716

Source:http://linkedlifedata.com/resource/pubmed/id/21531716

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
25
pubmed:dateCreated
2011-6-20
pubmed:abstractText
Deacetylation of histone proteins at the HIV type 1 (HIV-1) long terminal repeat (LTR) by histone deactylases (HDACs) can promote transcriptional repression and virus latency. As such, HDAC inhibitors (HDACI) could be used to deplete reservoirs of persistent, quiescent HIV-1 proviral infection. However, the development of HDACI to purge latent HIV-1 requires knowledge of the HDAC isoforms contributing to viral latency and the development of inhibitors specific to these isoforms. In this study, we identify the HDACs responsible for HIV-1 latency in Jurkat J89GFP cells using a chemical approach that correlates HDACI isoform specificity with their ability to reactivate latent HIV-1 expression. We demonstrate that potent inhibition or knockdown of HDAC1, an HDAC isoform reported to drive HIV-1 into latency, was not sufficient to de-repress the viral LTR. Instead, we found that inhibition of HDAC3 was necessary to activate latent HIV-1. Consistent with this finding, we identified HDAC3 at the HIV-1 LTR by chromatin immunoprecipitation. Interestingly, we show that valproic acid is a weak inhibitor of HDAC3 (IC(50) = 5.5 mm) relative to HDAC1 (IC(50) = 170 ?m). Because the total therapeutic concentration of valproic acid ranges from 275 to 700 ?m in adults, these data may explain why this inhibitor has no effect on the decay of latent HIV reservoirs in patients. Taken together, our study suggests an important role for HDAC3 in HIV-1 latency and, importantly, describes a chemical approach that can readily be used to identify the HDAC isoforms that contribute to HIV-1 latency in other cell types.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
24
pubmed:volume
286
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
22211-8
pubmed:meshHeading
pubmed-meshheading:21531716-Adult, pubmed-meshheading:21531716-HIV Long Terminal Repeat, pubmed-meshheading:21531716-HIV-1, pubmed-meshheading:21531716-Histone Deacetylase Inhibitors, pubmed-meshheading:21531716-Histone Deacetylases, pubmed-meshheading:21531716-Humans, pubmed-meshheading:21531716-Hydroxamic Acids, pubmed-meshheading:21531716-Jurkat Cells, pubmed-meshheading:21531716-Peptides, Cyclic, pubmed-meshheading:21531716-Phosphatidylinositol 3-Kinases, pubmed-meshheading:21531716-Protein Isoforms, pubmed-meshheading:21531716-Proto-Oncogene Proteins c-akt, pubmed-meshheading:21531716-Signal Transduction, pubmed-meshheading:21531716-Substrate Specificity, pubmed-meshheading:21531716-Valproic Acid, pubmed-meshheading:21531716-Virus Activation, pubmed-meshheading:21531716-Virus Latency
pubmed:year
2011
pubmed:articleTitle
Inhibitors of histone deacetylases: correlation between isoform specificity and reactivation of HIV type 1 (HIV-1) from latently infected cells.
pubmed:affiliation
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
pubmed:publicationType
Journal Article