Welcome to The AIDS Pandemic, a podcast hosted by Dr. David Wessner from the Department of Biology at Davidson College. I'm Steve Halliday.
One of my most striking memories from my time spent in the hospital in Mwandi was towards the end of my stay when I saw a woman suffering from AIDS dementia who was in the courtyard screaming at the top of her lungs. I asked one of the hospital employees what was going on, and he responded “oh, she is confused.” Since that moment I’ve been interested in this symptom of late stage AIDS, and in today’s installment I am going to look at a paper that examines one possible cause of AIDS dementia, titled HIV-1 Promotes Quiescence in Human Neural Progenitor Cells by Krathwohl and Kaiser.
AIDS dementia is a purely clinical diagnosis, based on observations of cognitive decline and motor dysfunction, and occurs in approximately 6-15% of AIDS patients. The pathology of AIDS dementia remains elusive, however, and this article represents only one theory of how it is caused.
The article examines the possibility that HIV could inhibit the activity of recently discovered neural progenitor cells. These cells have been found to be capable of differentiating into new astrocytes and neurons, which are thought to then form synaptic connections with other neurons, increasing memory and replacing lost neurons in the hippocampus. These progenitor cells exist in quiescent states until they are needed, and it has been found that these cells can be forced into quiescence by chemokines, which can be mediated by CXCR4 or CCR3. Because HIV-1 uses chemokine coreceptors it is thought that it may inhibit proliferation of progenitor cells and force them into quiescence.
To test whether HIV-1 could induce quiescence, the researchers used purified recombinant coat proteins from several stains of HIV-1 using proteins that signal through either CXCR4 or CCR3. They found that two strains caused plated progenitor cells to enter a quiescent state, reducing proliferation by 67 and 74%, while a third strain had no visible effect. They also discovered that by washing the plates the cells were able to begin differentiating again. The researchers went on to determine that the coat proteins of the effective strains induced expression of cyclin-dependent kinase inhibitors p21 and p27.
The researchers then sought to prove the HIV-1 coat proteins were mediated by chemokine receptor binding. They found that by adding pertussis toxin, which affects the G-proteins linked to chemokine receptors, the inhibitory effects of both effective strains were blocked, suggesting the suppressive effects of HIV-1 are mediated by chemokine receptors. In addition to direct inhibition, HIV-1 was found to suppress phosphorylation of ERK, which stimulates neural progenitor cells. The two effective strains of HIV-1 were found on to inhibit ERK by 34 nad 77%. This was also shown to occur by signaling through chemokine receptors.
Having established that HIV-1 can inhibit neural progenitor cell differentiation, the researchers examined CerebroSpinal Fluid from patients suffering from AIDS dementia, and discovered that the CSF from patients suffering from dementia was able to suppress progenitor cells by 67% whereas CSF from patients without dementia showed no inhibitor effect. They also determined that gp120 was responsible for this inhibition. Furthermore they determined that viral load for patients with and without dementia was similar, and presence or absence of antiretroviral therapy had no effect on the inhibitory effect of the CerebroSpinal Fluid.
The researchers then proved that both the HIV-1 coat proteins and the CSF from patients with dementia could reduce neural cell proliferation in human hippocampal tissue in vitro, and that autopsied hippocampal tissue from patients with dementia was found to contain 75% fewer neural progenitor cells than in patients without dementia.
This paper provides seemingly very conclusive evidence for the role of neural progenitor cells in AIDS dementia, but this is by no means the only area of research going on in AIDS dementia. Another paper, Pharmacological frontiers in the treatment of AIDS dementia by McGuire and Marder, discusses possibilities that reactants to viral products and macrophages may cause neuronal cell death, leading to dementia via a more direct route.
The pathology of AIDS dementia is complex and not easily deciphered, but hopefully with this continuing research an effective treatment can be found for this devastating AIDS related illness.