CD28 ligation in the absence of TCR promotes RelA/NF-kappaB recruitment and trans-activation of the HIV-1 LTR.
CD28 is one of the most important co-stimulatory receptors necessary for full T lymphocyte activation. CD28 can act as a TCR-independent signalling unit by delivering specific signals which may induce HIV transcription and replication. However, the mechanisms by which CD28 regulates HIV expression remain largely unknown. Here we show that the TCR-independent CD28 signals lead to the trans-activation of HIV-1 LTR in an NF-kappaB-dependent manner. In particular, we found that CD28 engagement by B7 induces the specific recruitment of RelA/NF-kappaB subunit to the HIV-1 LTR promoter both in vitro and in ex vivo infected cells. The results obtained by mutating specific tyrosine residues within the CD28 cytoplasmic tail as well as by using LY294002 inhibitory drug evidenced that the recruitment and activation of the phosphatidylinositol 3-kinase/Akt signalling pathway is crucial in mediating CD28-induced HIV transcription through RelA/NF-kappaB.
Annibaldi
Alessandro
A
Department of Cellular and Developmental Biology, Sapienza University of Rome, Rome, Italy.
Sajeva
Angela
A
Muscolini
Michela
M
Ciccosanti
Fabiola
F
Corazzari
Marco
M
Piacentini
Mauro
M
Tuosto
Loretta
L
D019943:Amino Acid Substitution; D018122:B7-1 Antigen / Q000494:pharmacology; D018106:CD28 Antigens / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D015967:Gene Expression Regulation, Viral; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D007976:Leupeptins / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D018122:B7-1 Antigen; D018106:CD28 Antigens; D002867:Chromones; D004791:Enzyme Inhibitors; D007976:Leupeptins; D009025:Morpholines; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; C498143:RELA protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde