Dr. Navia's research investigates the
pathogenesis of HIV-associated brain injury and cognitive
impairment known as AIDS Dementia Complex (ADC). Several studies
that have suggested that monocyte-derived host and viral factors
including tumor necrosis factor (TNF), chemokines, and possibly
oxygen free radicals may contribute to nervous system damage.
Over the past two years, Dr. Navia's laboratory has explored
the following hypothesis: 1) TNF acts directly on neurons
via the TNFRI-TRADD signaling cascade; this pathway is activated
in the HIV-infected brain and may mediate the effects of TNF-a
on neuronal cells; 2) NFkB activation may prevent neuronal
apoptosis and provide a critical neuroprotective mechanism
against host and viral neurotoxic signals; 3) The expression
of TNF and NFkB activation in the basal ganglia and white
matter correlated with ADC severity; 4) TNF-a induces the
surface expression of the chemokine receptor CXCR4 in a human
neuronal cell line which has been shown to directly mediate
the neurotoxicity of T-tropic HIV strains. Results suggest
an indirect mechanism by which TNF may render neuronal cells
vulnerable to the neurotoxic effects of HIV.
Future studies in Dr. Navia's lab will focus on the following
hypotheses: 1) Isolates from brain, CSF and blood compartments
within the same subject evolve independently. 2) Neurodegenerative
mechanisms will correlate with specific amino acid changes
within the HIV envelope region, particularly the V3 loop.
3) Such variations in sequence will lead to variability in
the expression of various host factors (TNF, oxygen free radicals)
and thus account for the differences in the extent and pattern
of brain injury between patients. 4) NFkB activation provides
a critical neuroprotective mechanism against HIV-related apoptotic
signals.
Dr. Navia is the PI on a major consortium grant investigating
HIV-associated neural injury (R01 NS36524).
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