Expression of the endoplasmic reticulum stress response marker, BiP, in the central nervous system of HIV-positive individuals.
The prevalence of HIV-associated neurocognitive impairment (NCI), which includes HIV-associated dementia (HAD) and minor cognitive and motor disorder (MCMD), has been increasing. HIV-infected and/or activated macrophages/microglia in the brain initiate the neurodegeneration seen in HIV-associated NCI via soluble neurotoxic mediators, including reactive oxygen species, viral proteins and excitotoxins. Neurotoxic factors released by macrophages/microglia injure neurones directly and alter astrocytic homeostatic functions, which can lead to excitotoxicity and oxidative stress-mediated neuronal injury. Often, cells respond to oxidative stress by initiating the endoplasmic reticulum (ER) stress response. Thus, we hypothesize that ER stress response is activated in HIV-infected cortex. We used immunofluorescence and immunoblotting to assess expression patterns of the ER stress proteins, BiP and ATF6, in HIV-positive cortical autopsy tissue. Additionally, we performed immunofluorescence using cell type-specific markers to examine BiP staining in different cell types, including neurones, astrocytes and macrophages/microglia. We observed a significant increase in BiP expression by both immunoblotting and immunofluorescence in HIV-positive cortex compared with control tissue. Additionally, phenotypic analysis of immunofluorescence showed cell type-specific increases in BiP levels in neurones and astrocytes. Further, ATF-6beta, an ER stress response initiator, is up-regulated in the same patient group, as assessed by immunoblotting. These results suggest that ER stress response is activated in HIV-infected cortex. Moreover, data presented here indicate for the first time that numbers of macrophages/microglia increase in brains of MCMD patients, as has been observed in HAD.
Lindl
K A
KA
Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA.
Akay
C
C
Wang
Y
Y
White
M G
MG
Jordan-Sciutto
K L
KL
D000328:Adult; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D015658:HIV Infections / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D017628:Microglia / Q000378:metabolism; D018613:Microscopy, Confocal; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism
D006360:Heat-Shock Proteins