Viral and Cellular Determinants of HIV Dementia
S Gartner, Y Liu, E Hunter and JC McArthur
Current models for HIV dementia implicate not only HIV
infections and replication, but also immune activation within the brain.
The temporal relationship between these, however, and the relative contributions
of each to the disease process, remain points of controversy. Reports have
detailed the neurotoxic effects of both HIV proteins and macrophage
products. Surprisingly, however, there appears to be no relationship
between clinical dementia and the presence, or extent of HIV infection in brain,
suggesting that only certain strains of HIV may exhibit neurovirulence.
Encephalitis has been proposed by others as the correlate of HIV dementia, but
why this develops is only a subset of HIV-infected brains is unclear. An
overview of these issues will be presented.
Recent studies from our laboratory have focused on the role of
monocyte trafficking in the development of HIV dementia. As reported by
Pulliam et al (1997), we have observed an increase in the number of circulating
CD16+ monocytes in the blood of patients with HIV-associated cognitive
impairment. Increased levels of serum M-CSF, a known inducer of CD16
expression on monocytes, were also detected. Phylogenetic analyses of
viral envelope gp160 sequences recovered from uncultured post-mortem tissues
from a patient with HIV dementia showed that the viral species present within
deep white matter of brain were more closely related to those in bone marrow,
than to those within the choroids plexus, meniges, head of the caudate, lymph node
or lung. Moreover, the sequences from deep white matter were most closely
related to sequences recovered from blood monocytes obtained 5 months prior to
From these and other data, we propose that the initial critical
event leading to HIV dementia is an increase in monocyte trafficking into
brain. We postulate that systemic events associated with late-stage HIV
infection result in increased production of M-CSF within the bone marrow, which,
in turn, leads to activation of greater numbers of the exiting monocytes.
Being already activated, these cells can now more readily cross the blood-brain
barrier and enter the brain parenchyma.