Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia

The pathogenesis of HIV-associated dementia (HIVD) has been postulated to b e due to the indirect effects of HIV infection, including the aberrant cent ral nervous system production of cytokines and other neurotoxins. A correla tion between the severity of dementia and production of neurotoxins in HIVD has been demonstrated, We have previously identified nonproductive HIV inf ection of astrocytes. Because astrocytes participate in the inactivation of neurotoxins, we hypothesize that HIV nonproductive infection of astrocytes may lead to an environment in which there is a significant level of astroc yte apoptosis and a consequent increase in the levels of neurotoxins and th at this results in more rapidly progressing dementia. Postmortem brain tiss ue was examined from clinically well-characterized HIV-positive demented pa tients, HIV-positive nondemented patients, and HIV-seronegative nondemented control subjects. The HIVD group was further categorized into subjects wit h rapid and those with slow progression of dementia, Tissue was paraformald ehyde tired and paraffin embedded, and 6-mum sections from the basal gangli a and mid-frontal gyrus were processed to detect apoptosis by in situ trans ferase dUTP nick end labeling. Astrocytes were co-localized using immunohis tochemical techniques. In situ polymerase chain reaction (PCR) techniques w ere utilized to detect HIV DNA in astrocytes. The density of apoptotic astr ocytes was significantly greater in the HIV-positive groups than in the HIV -negative group (p < 0.01). The HIVD rapid progressors had a significantly greater number of apoptotic astrocytes in the basal ganglia than did the HI VD slow progressors (p < 0.05). In addition, there were a greater number of HIV DNA-positive astrocytes, as demonstrated by in situ PCR, in the HIVD r apid progressors than in the slow progressor and HIV-nondemented groups. Th ese data suggest that there is an increased rate of astrocyte loss in the s ubjects with rapidly progressive dementia, in association with an increased number of HIV DNA-positive astrocytes. The results emphasize the importanc e of understanding more completely the role of HIV infection of astrocytes in the neuropathogenesis of HIVD.