Brew BJ; Australasian Society for HIV Medicine. Conference.
Annu Conf Australas Soc HIV Med. 1999 Dec 9-11; 11: 73 (abstract no. IN59).
National Center in HIV Epidemiology and Clinical Research, Sydney, Australia.
The pathogenesis of AIDS dementia complex (ADC) is poorly understood. The broad observations are: i) ADC occurs late in HIV disease despite evidence that the cerebrospinal fluid (CSF) is affected early, ii) the degree of immune activation in the brain and CSF is correlated with the presence and severity of ADC, iii) HIV viral load in the brain is not correlated with ADC presence or severity but HIV viral load in the CSF is, iv) the degree of microglial cell activation correlates with ADC, v) the degree of astrocyte loss correlates with the severity of ADC and the rapidity of progression, vi) ADC is potentially reversible and vii) there is a large number of neurotoxins that have been found in ADC patients but it is not clear whether one neurotoxin is capable of inducing the production of other toxins. QUIN can address these observations. It is produced by activated and infected macrophages as well as microglial cells and the concentration in the CSF is correlated with the severity of ADC. QUIN can activate astrocytes via the NMDA receptor perhaps eventually leading to death and/or dysfunction of the cells. QUIN can cause neuronal death both acutely in high concentrations and chronically in low concentrations. Ultrastructural changes are seen first in neurons as a consequence of chronic exposure to QUIN which at this stage may be reversible. QUIN is capable of initiating a cascade of neural damage in the brain: it can act via the NMDA receptor on astrocytes and cause the production of a variety of chemokines (RANTES, MCP-1 in particular). The imported mononuclear cells then produce more QUIN and other neurotoxins as well as more chemokines and cytokines which in turn lead to production of QUIN by macrophage lineage cells and indirectly by astrocytes. HIV viral proteins such as tat and nef also may induce the production of QUIN by macrophages and microglia. Additionally, QUIN can upregulate the expression of CCR5 (preliminary data) thereby facilitating brain infection. It is therefore proposed that QUIN is among the most important pathogenetic factors in ADC.
Publication Types:
Keywords:
- AIDS Dementia Complex
- Acquired Immunodeficiency Syndrome
- Astrocytes
- Brain
- Chemokine CCL5
- Chemokines
- Cytokines
- Disease Progression
- Gene Products, tat
- HIV Infections
- Humans
- Macrophages
- Neurotoxins
- Quinolinic Acid
- Receptors, CCR5
Other ID:
UI: 102242710
From Meeting Abstracts