Recruitment of phosphatidylinositol 3-kinase to CD28 inhibits HIV transcription by a Tat-dependent mechanism.
Activation through the TCR and the costimulatory molecule CD28 influences the susceptibility of T cells to HIV-1 infection and regulates proviral gene expression. Signaling events initiated by CD28 that directly impact HIV-1 transcription have not been fully characterized. T cell lines expressing CD8alpha/28 chimeric receptors containing a mutation in tyrosine 173 to phenylalanine, which inhibits the recruitment of phosphatidylinositol 3-kinase (PI3K) to CD28, expressed higher levels of HIV-1 following T cell activation. Whereas constitutively active PI3K decreased provirus transcription, inhibiting endogenous PI3K with specific inhibitors or by overexpressing PTEN phosphatase enhanced HIV-1 expression. PI3K-dependent inhibition required the viral Tat protein and a trans activation response region element. Tat pull-down and coimmunoprecipitation experiments indicate that PI3K affects the formation of the Tat-associated kinase trans-activating complex. These studies demonstrate that PI3K negatively impacts HIV-1 transcription and that Tat activity is sensitive to T cell signaling events.
Cook
Julie A
JA
Graduate Program, Department of Biochemistry, Pennsylvania State University, University Park, PA 16802, USA.
August
Avery
A
Henderson
Andrew J
AJ
D000818:Animals; D000998:Antiviral Agents / Q000235:genetics / Q000502:physiology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011533:Proviruses / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D018106:CD28 Antigens; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus