Expression of caspase‐3 in brains from paediatric patients with HIV‐1 encephalitis

Abstract

Apoptosis of neurones, macrophages, and microglia occurs in the brains of paediatric patients with human immunodeficiency virus (HIV) type 1 encephalitis, which is often associated with pre-mortem neurological disease (progressive encephalopathy). We have previously reported that TUNEL-positive neurones in brain tissue from paediatric patients with HIV type 1 encephalitis and progressive encephalopathy are strikingly devoid of the pro-apoptotic gene product Bax, in marked contrast to brain-resident macrophages and microglia. Using immunocytochemical methods, the present study demonstrate that neurones in patients with HIV type 1 encephalitis and progressive encephalopathy, as well as macrophages and microglia, but not astrocytes, overexpress caspase-3, a pro-apoptotic enzyme that is proteolytically activated downstream of Bax-Bcl-2 dysregulation. Co-localization of neuronal cytoplasmic caspase-3 and nuclear TUNEL staining, a marker for fragmented DNA, was also infrequently observed in brain tissue from patients with HIV type 1 encephalitis and progressive encephalopathy. These findings suggest that vulnerable neurones in brain tissue from patients with HIV virus type 1 encephalitis and progressive encephalopathy undergo apoptosis by a mechanism that involves upregulation of caspase-3 in a pathway that is independent of Bax-Bcl-2 dysregulation. Furthermore, caspase-3 upregulation in apoptotic neurones likely occurs prior to DNA fragmentation.

Neuronal Apoptosis Is Mediated by CXCL10 Overexpression in Simian Human Immunodeficiency Virus Encephalitis

“…This is the first report showing that capsase-3-positive cells also expressed CXCL10, extending previous reports that HIV-E is associated with an increase in neuronal immunoreactivity for the active form of caspase-3. 39,40 Clinical relevance of our findings was further demonstrated by localization of overexpressed CXCL10 in the neurons in brains of individuals with HIV-E. These results suggest a novel role for this chemokine in HIV dementia.…”

Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

“…Active caspase-3 has been detected by Western blot in human fetal neural cultures exposed to gpl20 (Zheng et al, 1999); however, the specific cell population undergoing caspase activation was not identified. Postmortem studies on the brains of pediatric patients with HIV dementia showed increased procaspase-3 immunoreactivity in neurons (James et al, 1999).…”

Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain

“…The neurotoxic effect of gp120 involves CXCR4-mediated activation of pro-apoptotic signal transduction cascades, including caspase-3 (Bachis et al, 2003;Biard-Piechaczyk et al, 2000;Hesselgesser et al, 1998;Zheng et al, 1999). These results imply a fundamental role for CXCR4 in HIV-Associated Dementia (HAD) pathogenesis, which includes neuronal apoptosis and atrophy (Gray et al, 2001;James et al, 1999;Masliah et al, 2000;McArthur, 2004), and suggest that targeted therapeutic interventions for HAD should include a downregulation of chemokine receptor function.…”