Use this URL to cite or link to this record in EThOS:
Title: Cellular mechanisms underlying HIV-1-associated dementia
Author: Pandey, Vinita
ISNI:       0000 0001 3466 4209
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2001
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Many HIV-1-positive individuals suffer from a variety of neurological problems known collectively as the HIV-1 associated dementia. However, as HIV-1 is not thought to replicate in neurones, the molecular mechanism involved in the demise of neurones is unclear. A number of laboratories have suggested that the HIV-1 coat protein gp120 damages neurones by inducing a large cytoplasmic calcium [Ca2+]c increase. Thus, began my project to find out what is the exact mechanism by which gp120 causes a rise in neuronal [Ca2+c and if there is a way to block the rise and rescue the neurones from dying. I cultured neonatal rat primary hippocampal and cortical cells with or without 5% horse serum (HS) for 18 days or more and imaged [Ca2+]c with fura-2. In many of these hippocampal cultures grown with HS, gp120 (250 pM) evoked a large rise in [Ca2+]c in the majority of neurones; in other cultures this [Ca2+]c signal was absent. Where present the neuronal [Ca2+]c signal was blocked by the peptide VSLSYRCPCRFF (50 μM), a competitive inhibitor of the CXCR4 chemokine receptor. Whereas, hippocampal cultures grown without HS, showed a slower rise in [Ca2+]c in neurones to a moderate level, on addition of gp120. Similarly to above a proportion of these cultures did not respond. I tested those cultures that did not show any rise in [Ca2+]c for neurotoxicity to check if gp120 still causes neuronal death. Under these conditions gp120 (250 pM) caused 30% neurotoxicity that was reduced by the blocking peptide VSLSYRCPCRFF (50 μM) or pertussis toxin (500 ng/ml) preincubation, indicating that CXCR4 activation of Gi/Go family members plays an important role in neurotoxicity. These results show that gp120-induced neuronal [Ca2+]Jc signals are not an essential component of the killing process. The biggest puzzle in my PhD project was why some cultures show a neuronal [Ca2+]c response to gp120 while others do not. I investigated the hypothesis that it is the number of microglia which is different in each culture. I stained for microglia in both cultures grown with or without HS. Only those cultures with high microglial density (irrespective of HS) gave a neuronal [Ca2+]c response to gp120. Thus, microglia play an obligate role in the [Ca2+]c response to gp120 although the increase in [Ca2+]c is not necessary for neurotoxicity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Neurones