Tumor suppressor protein p53-mediated induction of apoptosis and type-I interferon production in lentivirus-infected T cells

During the course of lentivirus infection, apoptosis plays a pivotal role in the depletion of CD4+ T cells characteristic of acquired immunodeficiency syndrome (AIDS). Accumulating evidence suggests that, besides being a tumor suppressor protein, 1253 induces lentivirus-induced T-cell apoptosis. To understand the mechanism, infection of quiescent CD4 + T cells of pig-tailed macaques with a highly pathogenic strain of simian immunodeficiency virus (SIV), SIV-PBj14, which replicates efficiently in resting primary T cells, was used. Early after infection, 1253 was upregulated specifically in SIVPBj 14-infected cells. However, infection by an integrase-defective (IN-) SIV-PBj14 failed to upregulate 1253. In addition, 1253 was activated through phosphorylation of Ser15, possibly in response to unrepaired integration intermediates that might be perceived by cellular components as DNA damage. This hypothesis was supported by augmented 1253 expression in infected cells treated with a DNA-repair enzyme inhibitor. A combination of drug treatments showed that activation of 1253 was dependent on ATR, the ataxia-telangiectasia-mutated (ATM) and Rad3-related protein. Furthermore, 1253 induced apoptosis of SIV-PBj14-infected cells through both intrinsic and extrinsic pathways.; In response to virus infection, interferon (IFN)-alpha/beta expression is induced and these proteins subsequently augment transcription of several antiviral genes, including that of p53. In SIV-PBj14-infected CD4+ T cells, activated p53 enhanced transcription of IFN-alpha/beta genes through interaction of p53 with IFN regulatory factor (IRF)-3, IRF-7, and p300/CBP at the promoter of IFN-alpha/beta genes. Moreover, p53 also triggered activation of nuclear factor kappa B (NF-kappaB), another regulator of IFN-alpha/beta transcription. Although IFN-alpha/beta can stimulate transcription of the p53 gene, these cytokines alone cannot stabilize and activate p53 efficiently. Virus infection was required for p53 activation via phosphorylation, carried out by ATM or one of its downstream kinases, at serine residues other than Ser15. IFN-gamma also enhances T-cell apoptosis via a p53-dependent pathway. The results described herein demonstrate that in primate lentivirus-infected cells, p53 functions as a key innate antiviral protein by inducing apoptosis and augmenting type-I IFN synthesis. These studies not only will help elucidate the role of p53 in lentiviral pathogenesis, but also suggest a potential therapeutic approach against AIDS and other retrovirus-induced diseases.