Viral and Cellular Determinants of HIV Dementia

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.