Apoptotic neurons in brains from paediatric patients with HIV‐I encephalitis and progressive encephalopathy

Abstract

The pathogenesis of human immunodeficiency virus type 1 (HIV-1) associated dementia in adults involves neuronal loss from discrete areas of the neocortex and subcortical regions, but the mechanism for neuronal death is poorly understood. Gene-directed cell death resulting in apoptosis is thought to be a normal feature of neuronal development, but little is known about neuronal apoptosis in disease states. We investigated whether HIV-1 infection of the central nervous system is spatially associated with apoptosis of neurons. Using an in situ technique to identify newly cleaved 3'-OH ends of DNA as a marker for apoptosis, we demonstrate the presence of apoptotic neurons in cerebral cortex and basal ganglia of children that had HIV-1 encephalitis with progressive encephalopathy. Furthermore, an association was observed between the localization of apoptotic neurons and perivascular inflammatory cell infiltrates containing HIV-1 infected macrophages and multinucleated giant cells. Apoptotic neurons and p24-positive macrophages were observed infrequently in cerebral cortex and basal ganglia in children with HIV-1 infection without encephalitis or clinical encephalopathy. In nine control (HIV-1 negative) brains, ranging from the first post-natal month of life to 16.5 years of age, infrequent neuronal apoptosis was observed in three cases. These findings suggest that neuronal apoptosis is unlikely to be associated with post-natal development except in early post-natal germinal matrix, and that it may instead represent the end result of specific pathological processes, such as HIV-1 encephalitis.

Inhibition of Mixed Lineage Kinase 3 Prevents HIV-1 Tat-Mediated Neurotoxicity and Monocyte Activation

“…HAD is associated not only with the extensive loss of neurons within certain regions of the brain (56 -58) and elevated levels of neuronal apoptosis (59,60) but also with the chronic production of inflammatory mediators that includes a range of cytokines and chemokines and of viral gene products such as Tat and gp120 (61). As noted here, these two viral proteins are toxic to neurons (10,30,62) and are also capable of activating uninfected brain-resident macrophages and microglia (63,64), but the molecular mechanisms that contribute to these processes are incompletely understood.…”

HIV-1 infection and AIDS: consequences for the central nervous system

“…44,45 In contrast, increased numbers of microglia, 44 elevated TNF-a mRNA in microglia and astrocytes, 46 evidence of excitotoxins, [47][48][49] decreased synaptic and dendritic density, 45,50 and selective neuronal loss 51,52 constitute the pathologic features most closely associated with the clinical signs of HAD. Furthermore, signs of neuronal apoptosis have been linked to HAD, [53][54][55] although this finding is not clearly associated with viral burden 53 or a history of dementia. 56 The localization of apoptotic neurons is correlated with evidence of structural atrophy and closely associated with signs of microglial activation, especially within subcortical deep gray structures, 56 which may show a predilection for atrophy in HAD.…”

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

“…HIV encephalitis (HIVE) often accompanies HIV dementia and is characterized by prominent microglial activation, neuronal losses, dendritic pruning, and decreased density of synapses (Masliah et al, 1996;Lipton, 1997). Apoptotic changes are seen with HIVE in both neurons and nonneuronal cells (Ramirez et al, 2001;Bonavia et al, 2001;Corasaniti et al, 2001;AdleBiassette et al, 1995;Gelbard et al, 1995;Petito and Roberts, 1995;Shi et al, 1996;Kaul et al, 2001;Shi et al, 1998;Park et al, 2001). HIV-1 is neurotoxic by inducing inflammation and through the direct release of toxic viral proteins such as Nef, Vpr, gp120 and Tat (Haughey et al, 2001;Brenneman et al, 1988;Dreyer et al, 1990;Adamson et al, 1996;New et al, 1997;Kruman et al, 1998;Yeung et al, 1998;Huang and Bond, 2000;Trillo-Pazos et al, 2000;Nath, 2002).…”