AIDS and the Brain

By Jason Socrates Bardi

"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 lines—keeping the T-helper lymphocyte cell count up or the viral load down. Even Webster’s 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 that’s 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 cells—such as neurons—that 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 the body.

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 Brain—What 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 blood–brain barrier permeability and allowing them through. These cells cross the blood–brain 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 blood–brain 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 virus—a reality that makes unlikely the possibility that medicine will ever be able to successfully clear the virus from an infected patient.

After the initial viremia, patients typically experience a stable period of variable length—a 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. Indefinitely, perhaps.

But Fox and others are beginning to suspect that treating HIV over the course of a lifetime may require a bit more thinking through.

Next Page | HIV and the Brain—What We Don’t Know

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Neuropharmacology Professor Howard Fox investigates some troubling effects of HIV on the brain.