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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."

Next Page | A Number of New Possibilities

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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