The effect of HIV-1 regulatory proteins on cellular genes: derepression of the IL-2 promoter by Tat.
In HIV-infected individuals dysregulation of the immune system is characterized by severe disorders of the cytokine network. Increase secretion of IL-2, the major T cell growth and differentiation cytokine, may play a decisive role in sensitization of T cells for activation induced apoptosis and indirect death of activated T cells through augmented virus replication. We investigated the cause of enhanced IL-2 secretion and found that the HIV Tat induces this effect. We demonstrate that increased IL-2 secretion is due to Tat-enhanced IL-2 promoter activation. Tat derepresses and activates the distal AP-1 site (position -185 to -177) in the IL-2 promoter. In nonstimulated T cells a repressor complex containing NF-IL6, JunB, c-Fos and Fra-1 is formed on the AP-1(IL-2/d) site and represses IL-2 promoter activity. After T cell activation, a heterodimeric activator containing p65 and c-Jun binds to the AP-1(IL-2/d) site. HIV Tat enhances activation of NF-kappaB and consequently, activates the AP-1(IL-2/d) site. Our data provide evidence for a novel mechanism by which HIV Tat dysregulates IL-2 production and therefore may contribute to the HIV-1 infection in a way yet to be clarified.
Ehret
A
A
Tumorimmunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Li-Weber
M
M
Frank
R
R
Krammer
P H
PH
D001665:Binding Sites; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000502:physiology*; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D012097:Repressor Proteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D007376:Interleukin-2; D012333:RNA, Messenger; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D054322:tat Gene Products, Human Immunodeficiency Virus