Despite the use of Highly active antiretroviral therapy (HAART), neuronal cell death remains a problem that is frequently found in the brains of HIV-1-infected patients. HAART has successfully prevented many of the former end-stage complications of AIDS, however, with increased survival times, the prevalence of minor HIV-associated cognitive impairment appears to be rising among AIDS patients. Further, HIV encephalitis (HIVE) is still prevalent in treated patients as well as attenuated forms of HIVE and CNS opportunistic disorders. HIV-associated cognitive impairment correlates with the increased presence in the CNS of activated, though not necessarily HIV-1- infected, microglia and CNS macrophages. This suggests that indirect mechanisms of neuronal injury and loss/death occur in HIV/AIDS as a basis for dementia since neurons are not themselves productively infected by HIV-1. Recent evidence indicates that the p53 tumor suppressor protein and its related family member, p73, play an essential role in regulating neuronal loss/apoptosis. The mechanisms involved in induction of p53 or p73 which lead to dendritic retraction and neuronal loss are not fully elucidated. Increased levels of p53 were observed in the neurons of AIDS patients, which may be connected to the occurrence of HIV-1-associated dementia (HAD) in those patients. Similar to p53 activation in neurons, p53 activation in microglia and astrocytes may also contribute to alterations in the physiology of these cells that eventually result in a neurotoxic environment and neuronal loss. Importantly, for p53 to be functional and stable, activated p73 is required. Based on this finding, we have studied the relationship between p73 and Tat, and have demonstrated the ability of HIV-1 in general and of Tat in particular, to induce the endogenous levels of p73. P73 induction prevents acetylation of Tat on lysine 28 through their direct physical interaction, which also inhibits Tat's apoptotic activity. The association of Tat with p73 also reduces Tat-activation of the HIV- 1 LTR, and prevents p73 from causing cell death in astrocytes. These data suggest a basis for the restricted replication of HIV-1 in astrocytes. We also investigated the interplay between Tat and p73 in neuronal cells. Surprisingly, Tat was unable to promote neuronal death in the absence of either p73 or p53, suggesting a strong link between Tat, p73, p53 and neuronal cell death. Hence, we now propose to study the mechanism(s) whereby Tat induces p73. This will include analysis of control of the p73 promoter and of p73 protein turnover. We will also examine whether induction of p73 by Tat leads to activation of p53 and induction of neuronal cell death. The outcome from the proposed studies should provide new information regarding mechanisms of neuronal loss in AIDS patients and suggest possible new therapeutic approaches.
This proposal focuses on the relationship between the HIV-1 regulatory protein, Tat, and cellular factors. The results of these studies will highlight the pathways used by Tat to cause damage to neurons and lead to new avenues for the development of safe and effective therapeutic approaches to inhibit neurodegeneration seen in AIDS patients.
| Wang, Ying; Santerre, Maryline; Tempera, Italo et al. (2017) HIV-1 Vpr disrupts mitochondria axonal transport and accelerates neuronal aging. Neuropharmacology 117:364-375 |
| Bagashev, Asen; Mukerjee, Ruma; Santerre, Maryline et al. (2014) Involvement of miR-196a in HIV-associated neurocognitive disorders. Apoptosis 19:1202-14 |
| Del Carpio-Cano, Fabiola E; Dela Cadena, Raul A; Sawaya, Bassel E (2013) HIV and Bone Disease: A Perspective of the Role of microRNAs in Bone Biology upon HIV Infection. J Osteoporos 2013:571418 |
| Chang, J Robert; Ghafouri, Mohammad; Mukerjee, Ruma et al. (2012) Role of p53 in neurodegenerative diseases. Neurodegener Dis 9:68-80 |
| Mukerjee, Ruma; Chang, J Robert; Del Valle, Luis et al. (2011) Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders. J Biol Chem 286:34976-85 |
| Deshmane, Satish L; Mukerjee, Ruma; Fan, Shongshan et al. (2011) High-performance capillary electrophoresis for determining HIV-1 Tat protein in neurons. PLoS One 6:e16148 |
| Chang, J Robert; Mukerjee, Ruma; Bagashev, Asen et al. (2011) HIV-1 Tat protein promotes neuronal dysfunction through disruption of microRNAs. J Biol Chem 286:41125-34 |
| Mukerjee, Ruma; Claudio, Pier Paolo; Chang, J Robert et al. (2010) Transcriptional regulation of HIV-1 gene expression by p53. Cell Cycle 9:4569-78 |
| Cherrier, T; Suzanne, S; Redel, L et al. (2009) p21(WAF1) gene promoter is epigenetically silenced by CTIP2 and SUV39H1. Oncogene 28:3380-9 |
| Deshmane, Satish L; Kremlev, Sergey; Amini, Shohreh et al. (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 29:313-26 |
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