p73 modulates HIV-1 Tat transcriptional and apoptotic activities in human astrocytes

Abstract

HIV-1 Tat is a potent transcriptional activator of the viral promoter with the ability to modulate a number of cellular regulatory circuits including apoptosis. Tat exerts its effects through interaction with viral as well as cellular proteins. Here, we studied the influence of p73, a protein that is implicated in apoptosis and cell cycle control, on Tat apoptotic function in the central nervous system. We recently demonstrated the ability of Tat to associate with p73, and that this association modulates Tat transcriptional activity (Amini et al., Mol Cell Biol 2005; 18: 8126-8138). We demonstrated that p73 interferes with Tat-mediated apoptosis by preventing the up-regulation of Bax and down-regulation of Bcl-2 proteins in astrocytes. Thus, the interplay between Tat and p73 may affect Tat contribution to apoptotic events in the brain, limiting its involvement in the neuropathology often observed in the brains of HIV-1 patients.

HIV-1 Tat Interacts with and Regulates the Localization and Processing of Amyloid Precursor Protein

“…Although Tat is a nuclear protein, a significant amount is found in the cytosol of human brain bizarre astrocytes, primary astrocyte cultures infected with HIV, U-87 MG glioblastoma cells [35], and astrocytes derived from the brains of AIDS encephalopathy patients [36], [37]. Consistent with these results, Tat was observed in both the nucleus and the cytosol of many transfected U-87 MG cells (Figure 2 B and C , Figure S2A ).…”

Activation of the Oxidative Stress Pathway by HIV-1 Vpr Leads to Induction of Hypoxia-inducible Factor 1α Expression

“…Sec-tions were processed for immunohistochemistry as described previously (36). A rabbit polyclonal anti-HIF-1␣ antibody was utilized as primary antibody.…”

Roles and functions of HIV-1 Tat protein in the CNS: an overview

“…Cell death cascade also appears to be activated as data suggest that the p53 family of proteins plays a suppressing role in HIV-1 Tat acetylation by P/CAF, a required interaction for activation of HIV-1 LTR promoter [65,66]. This appears to be mostly a defensive response to the HIV-1 infection, since it does not necessarily leads to astrocytes apoptosis.…”

“…Extracellular Tat is rapidly internalized by neurons and astrocytes and this may inhibit p53 ubiquitination leading to p53 accumulation. Also, p53 accumulates in microglia and astrocyte nuclei in a subset of AIDS patients without dementia, while increased neuronal p53 was only observed in HAD cases ([65,66] and references within). Tat perform these functions through its physical interaction with p53 protein [68].…”

“…Although, direct or indirect mechanisms, which lead to p53 activation in neurons in the context of HIV-1 remain unclear, it is highly likely that, like many other viruses, HIV-1 may stimulate p53 activation, which thereby alters the phenotype of uninfected microglia, and leads to neuronal loss. Note that p53 cannot induce apoptosis in response to DNA damage without p73 [66]. This illustrates that p73 is vital for p53-induced apoptosis and furthermore, that p73 is an important component of the tumor suppressor activity of p53.…”