AIDS and the Brain
By Jason Socrates
"When most people think of Acquired Immune Deficiency Syndrome
(AIDS)," says Scripps Research Institute (TSRI) Professor
Howard Fox, "They think of the immune system and not the brain."
And why not? AIDS is, after all, about the immune system.
The human immunodeficiency virus (HIV) kills cells of the
immune system and this leads to opportunistic infections and
AIDS. The clinical battlegrounds have always been drawn along
immune cell lineskeeping the T-helper lymphocyte cell
count up or the viral load down. Even Websters dictionary
defines AIDS as, "a disease of the human immune system...."
The brain cannot be ignored therapeutically, though, because
it is not ignored virologically. HIV, like all lentiviruses,
is a neurotropic virus and infects cells of the central nervous
system (CNS) early in the course of infection. As in other
tissues in the body, HIV injures or kills these cells and
spreads to infect others. And thats only the beginning
of the story.
Infected macrophages and microglial cells may be more active
than non-infected ones and may overproduce chemokines and
cytokines as part of a natural immune response. These molecules
may disrupt the function of other, third-party cellssuch
as neuronsthat get caught in the crossfire.
The punchline is that HIV has a deleterious effect on the
brain that can lead to subtle and pronounced complications
and these complications may become more prevalent even though
we are finding new ways of treating the virus elsewhere in
About one quarter to one third of all AIDS patients suffer
from some form of CNS disorder in the course of their infection,
ranging from minor cognitive and motor disorders to severe
dementia, collectively known as neuroAIDS. "We had all hoped
that these disorders, much like all the other untoward illnesses
associated with HIV, would disappear with therapy," reflects
Fox. "But that has not been the case." Now Fox and his colleagues
seek to discover why.
HIV and the BrainWhat We Know
HIV enters the bloodstream through a mucous membrane or
directly-as with a contaminated needle stick. The virus
infects cells, replicates, infecting more cells, and so on
for the next several weeks in an active "initial viremia"
stage of infection. This three to four week period is characterized
by the rapid turnover of infected cells, a burst of virus
in the blood, and migration of the virus to the lymphatic
tissues and to the brain via white blood cells.
These infected cells become activated and secrete nitric
oxide, increasing bloodbrain barrier permeability and
allowing them through. These cells cross the bloodbrain
barrier like Trojan horses loaded with virus.
Macrophages and microglia in the brain and throughout the
cerebrospinal fluid are then infected. These macrophages support
viral replication independent of the dynamics and turnover
in the circulatory system. They have a notoriously slow turnover
rate, and HIV may long remain dormant in these cells after
it inserts itself into their genome.
A further complication is that while macrophages are behind
the bloodbrain barrier and beyond the reach of most
available antiretroviral drugs, they are believed to traffic
outside of the cerebrospinal fluid and become peripheral sources
for HIV in the bloodstream. All these traits have led researchers
to classify CNS cells as anatomical reservoirs for the virusa
reality that makes unlikely the possibility that medicine
will ever be able to successfully clear the virus from an
After the initial viremia, patients typically experience
a stable period of variable lengtha so-called asymptomatic
period lasting from several months to several years and characterized
by an ongoing immune response, an absence of AIDS-defining
illnesses, and less virus in the bloodstream. The goal of
modern therapy is to stretch this period out as long as possible.
But Fox and others are beginning to suspect that treating
HIV over the course of a lifetime may require a bit more thinking
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