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Although patients may be outwardly healthy, the virus is
causing tiny inflammatory reactions in their brains. These
microscopic inflammations do not necessarily lead to serious
conditions, like encephalitis, but are probably still disrupting
neural circuitry and having an effect, however subtle.
Animal studies have revealed some strange physiological
effects of HIV on the brain. For instance, body temperature,
which is controlled by the brain in the perioptic area, increases
after infection by a half degree or so. Furthermore, this
increase is more pronounced at night. Other studies have shown
that these parameters do not change with treatment.
There are resulting behavioral changes as well. For instance,
basic motor activity—how much one moves—is reduced
during the course of infection. In animal models, motor activity
is cut in half after a couple months of infection, long before
the asymptomatic period is over.
“What this tells you,” says Fox, "is that the
brain may be affected [in a manner] analogous to depression,
Parkinson’s disease, or other disorders in which movement
is diminished." The animals can still perform routine tasks
that demand a high level of dexterity as well as they could
before infection and treatment, but their general fitness
has decreased.
HIV and the Brain—What We Don’t Know
An analogous situation exists in humans. A certain percent
have lower performance as measured by neuro–cognitive
testing. Furthermore, statistics show that HIV patients with
even the "minor" disorder have twice the normal likelihood
of incurring job loss, and two to three times the rate of
traffic tickets. People also widely report feeling fatigued.
"The general feeling of fitness is decreased," says Fox, "because
of a chronic low-level viral-host immune interaction in the
body including the brain."
There are many questions about the nature of this interaction
that are as yet unanswered. We still don’t know the pathological
substrates in the brain that lead to the severe conditions
like AIDS dementia, for instance. The exact mechanism by which
HIV damages the brain is also not known, though it is likely
indirect, as the virus does not infect the neurons themselves.
Regardless of the potential substrates, there is anomalous
expression of proteins in the course of an infection. The
MHC Class II molecule, for instance, which is normally expressed
in low levels in brain tissue, has increased expression in
animals infected with an HIV-like lentivirus, indicating cell
activation. Similarly, in the dementia caused by Alzheimer’s
disease, expression of MHC Class II molecules are also increased.
This type of "immune" activation in the brain may be a reaction
to damage induced by these diverse disease entities, and may
itself contribute to the pathogenic cascade.
Regardless of the mechanism, basic hypothalamic functions
are affected throughout the course of an infection and cognitive
responses may become delayed. "There are not necessarily any
visible lesions," Fox says, "but the virus is there in the
brain."
Fox’s concern is with what the virus is doing in the
brain. Any type of brain damage is cumulative over time, so
what will happen over a long period, say ten to fifteen years?
A person’s quality of life is inexorably linked to what
is happening in the brain, and the longer an infected person
is alive, the longer the virus will be able to exercise its
toxic reign of terror in the brain.
There may eventually—inevitably—be some sort of
brain response, perhaps not dementia or encephalitis, but
some chronic effect in the brain that arises independently
and in spite of any treatment.
Fox worries that treatments helping people survive AIDS
for potentially many more years, although clearly a great
advance, could cause the prevalence of neurological problems
due to HIV to increase. "If the incidence of AIDS dementia
goes down by half," warns Fox, "but people are living three
times longer, then the prevalence will go up by one and a
half fold."
Current Vistas
For the last several years, the greatest weapons doctors
have had for treating HIV infections have been antiretroviral
drugs that tightly bind specific viral enzymes necessary for
replication and infection—the protease and reverse transcriptase
inhibitors. Highly active antiretroviral therapy (HAART),
which combines both classes of drugs together into one treatment,
has proven particularly effective, as demonstrated by the
decline in AIDS mortality in the United States in the last
few years.
However, even though the incidence of many opportunistic
infections and other AIDS-defining conditions has decreased
with HAART, the incidence of AIDS dementia has decreased less.
"It’s fine to keep your CD4+ T cells up," says Fox, "but
it’s no fun if your brain is not working."
1 | 2 | 3 |
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These magnetic resonance images
show typical findings in AIDS dementia (top) as compared with
a normal brain (bottom). Patchy hypoperfusion with a multifocal
distribution tends to be seen prominently in the frontal lobes.
(Keith A. Johnson and J. Alex Becker and the Whole Brain Atlas,
http://www.med.harvard.edu/AANLIB/)
“If
the incidence of AIDS dementia goes down by half, but people
are living three times longer, then the prevalence will go
up by one and a half fold.”
—Howard
Fox
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