The glial response to CNS HIV infection includes p53 activation and increased expression of p53 target genes.
HIV-associated dementia (HAD) is a chronic neuroinflammatory disease that remains an important clinical problem without available rational treatment. As HIV does not infect neurons, the pathogenesis of HAD is thought to be secondary to the impact of infected leukocytes, including parenchymal microglia, which can secrete inflammatory mediators and viral products that alter the function of surrounding uninfected cells. We previously reported that the transcription factor p53 accumulates in neurons, microglia, and astrocytes of HAD patients. We have also shown that microglia from p53-deficient mice fail to induce neurotoxicity in response to the HIV coat protein gp120 in a coculture system, supporting the hypothesis that p53 plays a pathogenic role in the chronic neuroinflammatory component of HIV-associated neurodegeneration. We analyzed the extent and cell type specificity of p53 accumulation in subcortical white matter of ten AIDS patients that had previously been shown to demonstrate white matter p53 accumulation. To determine if p53 activation functioned to alter gene expression in HAD, cortical tissue sections were also immunolabeled for the p53 target genes Bax and p21(WAF1). These studies reveal that microglia, astrocytes, and oligodendrocytes all demonstrate p53 activation in response to HIV infection. We observed immunoreactivity for both Bax and p21(WAF1) in neurons and glia from patients demonstrating elevated p53 immunoreactivity. Our findings demonstrate that widespread increased p53 expression is present in HAD. Activation of p53 mediated pathways in the glia of HAD patients may contribute to the neuroinflammatory processes that promote neurodegeneration by inhibiting glial proliferation and/or promoting glial cell dysfunction.
Department of Neurology, University of Washington, Seattle, WA, USA.
Suman
S
Jayadev
Bomy
B
Yun
Huy
H
Nguyen
Hideaki
H
Yokoo
Richard S
RS
Morrison
Gwenn A
GA
Garden
D015526:AIDS Dementia Complex / Q000235:genetics* / Q000378:metabolism* / Q000821:virology; D000328:Adult; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002494:Central Nervous System Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D018390:Gene Targeting; D006367:HeLa Cells; D006801:Humans; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008875:Middle Aged; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D016159:Tumor Suppressor Protein p53