Combinatorial signals from CD28 differentially regulate human immunodeficiency virus transcription in T cells.
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. We found that Tyr-191 and Tyr-200 induce HIV-1 transcription via the activation of NF-kappaB 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.
Natarajan
Malini
M
Intercollege Graduate Degree Program in Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
August
Avery
A
Henderson
Andrew J
AJ
D018106:CD28 Antigens / Q000378:metabolism / Q000502:physiology*; D016827:CD8 Antigens / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006678:HIV / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D014158:Transcription, Genetic; D014443:Tyrosine / Q000737:chemistry
D018106:CD28 Antigens; D016827:CD8 Antigens; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D014443:Tyrosine