Cingles Info

Brain's Immune Response to HIV a Double-Edged Sword
By Michael Smith, MedPage Today Staff Writer
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of
Pennsylvania School of Medicine.
April 28, 2006
Review
LA JOLLA, Calif., April 28 - An immune response in the brain to HIV infection
probably acts as a double-edged sword-holding the virus at bay for a time but
causing neurological damage in the process, according to researchers here.
The finding was based on a detailed study of the effects of simian
immunodeficiency virus (SIV) infection in Rhesus macaques during the chronic
phase of infection, which is often thought to be asymptomatic both in animals
and humans, said Howard Fox, M.D., Ph.D., of the Scripps Research Institute
here.
One implication of the study is that "labeling this phase 'asymptomatic' is a
dangerous misnomer," Dr. Fox and colleagues said in the April 26 issue of the
Journal of Neuroscience.
Before end-stage disease, most people with HIV have a variably long period of
chronic infection that is often associated with aberrant central nervous system
function, including impairments in verbal memory, psychomotor speed, attention
performance, and fine motor control. Imaging studies have documented decreased
volumes in cortical, limbic, and striatal structures, as well as thinning of the
cerebral cortex.
"Although the period between acute HIV infection and overt AIDS may be
reasonably asymptomatic," Dr. Fox and colleagues reported, "the CNS undergoes
changes that could be progressive and cause additional damage as the disease
worsens."
Because studying the brains of HIV patients is difficult, the researchers turned
to animal models. Four rhesus macaques were first trained in a series of
cognitive tasks and then infected with SIV.
The researchers monitored their post-infection cognitive abilities and after
death their brains were examined for both levels of HIV infections and other
alterations.
All of the infected animals developed significant deficits in bimanual motor
skills, and three of the four had other abnormalities, including deficits in
spatial working memory and slowed reaction times, Dr. Fox and colleagues found.
Also, the investigators studied the electrophysiology of brainstem auditory
evoked potentials, both before and after SIV infection. The P3, P4, and P5 waves
were significantly delayed post-infection and analysis of the latency between
the P1 and P3 waves indicated the problem was in the CNS. The differences were
statistically significant at P<0.001.
Post-mortem analysis showed that the brains of the infected animals contained
SIV, although there was no correlation between viral RNA levels in the brain and
levels in the blood or cerebrospinal fluid. Indeed, one animal-with undetectable
virus in plasma and CSF-had a higher viral load in its frontal lobe than in any
brain structure of the other animals.
Using gene array technology, the researchers found seven genes up-regulated in
the frontal lobes of the animals, including chemokine (C-C motif) ligand 5
(CCL5), or RANTES; HLA-DR-alpha; immunoglobulin heavy constant gamma-3; G1P3,
also known as interferon alpha-inducible protein 6-16; interferon-induced
transmembrane protein-1, (also known as Leu 13); HLA-A; and HLA-C.
Several of those genes have immune system functions, while others have antiviral
functions, the researchers noted.
In particular, CCL5 has direct antiviral activity, and also is able to recruit
immune cells, including cytotoxic T-lymphocytes, into the brain, the researchers
said. In turn, the enhanced immune response results over time in damage to
neurons.
The implication, Dr. Fox said in a statement, is that "as in the rest of the
body, in the brain immune cells achieve a level of control of the virus, but are
unable to clear the infection."
As the infection persists, "this immune response may act as a double-edged
sword, protecting against rampant viral replication in the brain but leading to
brain dysfunction," he said.
http://www.medpagetoday.com/InfectiousDisease/HIVAIDS/tb/3199