Combinatorial signals from CD28 differentially regulate human immunodeficiency virus transcription in T cells

Malini Natarajan, Avery August, Andrew J. Henderson

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Activation through the T-cell receptor and the costimulatory receptor CD28 supports efficient HIV transcription as well as reactivation of latent provirus. To characterize critical signals associated with CD28 that regulate HIV-1 transcription, we generated a library of chimeric CD28 receptors that harbored different combinations of key tyrosine residues in the cytoplasmic tail, Tyr-173, Tyr-188, Tyr-191, and Tyr-200.Wefound that Tyr-191 and Tyr-200 induce HIV-1 transcription via the activation of NF-κB and its recruitment to the HIV-long terminal repeat. Tyr-188 modifies positive and negative signals associated with CD28. Importantly, signaling through Tyr-188, Tyr-191, and Tyr-200 is required to overcome the inhibition posed by Tyr-173. CD28 also regulates P-TEFb activity, which is necessary for HIV-1 transcription processivity, by limiting the release of P-TEFb from the HEXIM1-7SK inhibitory complex in response to T-cell receptor signaling. Our studies reveal that CD28 regulates HIV-1 provirus transcription through a complex interplay of positive and negative signals that may be manipulated to control HIV-1 transcription and replication.

Original languageEnglish (US)
Pages (from-to)17338-17347
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number23
DOIs
StatePublished - Jun 4 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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