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AIDS and the Brain"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 KnowHIV 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. 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 KnowAn 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 VistasFor 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." The problem is that most of the molecules that make up the HAART drugs do not readily cross the blood–brain barrier, or only do so in suboptimal amounts. And whatever drugs do get into the brain do not remain there very long, as drug efflux pumps transport them back across. Furthermore, the potential exists that the drugs themselves may damage brain cells if allowed access to the CNS. Fox and his colleagues will explore a number of new possibilities for addressing the inability to treat HIV-infected brains. There are brain-penetrating antiretrovirals, and the effect of these will certainly be studied, though Fox believes such an agent may not be necessary. "If you lower viral load [in the blood] effectively," he says, "there will be less virus entering the brain, and less of an immune response against it. Then you will have fewer abnormalities." In one already concluded study, for instance, PMPA, a reverse transcriptase inhibitor that does not cross the blood–brain barrier, was injected in a single daily dose and shown to reverse neural abnormalities. When the treatment stopped, the abnormalities returned. If brain macrophages are producing an inflammatory response and killing nerve cells, then the remedy may be something as simple as taking an anti-inflammatory drug, such as ibuprophen, which diffuses across the blood–brain barrier. "That’s certainly something we are going to look at," says Fox.
A New Effort at TSRIIn order to further research into the cause, prevention, and treatment of HIV infection in the brain, Fox has organized the Scripps NeuroAIDS Preclinical Studies center, funded last year through a $10 million grant from the National Institutes of Mental Health. The center will bring together researchers from across TSRI to look at all aspects of HIV brain infections and treatments as well as carrying the baton of the former Scripps AIDS Dementia center, which directed research in the area throughout the1990s. The goals of the new center are twofold: to support the existing neuroAIDS research at TSRI and to encourage other scientists to become interested in the area. Unlike that of its predecessor, the Scripps NeuroAIDS Preclinical Studies operating mechanism will be to establish core centers to support basic research into all the important molecular, cellular, genetic, immunological, virological, neurobiological, and chemical questions. Other cores will support the cognitive, physiological, and behavioral responses to treatments in animal models. Finally, a developmental core will award grants to junior and senior faculty so that they can develop projects related to neuroAIDS. Center scientists will develop novel in vitro molecular and cellular assays and new molecules to test. They will also support studies by producing DNA chip technology and transgenic knockout mice. They will correlate all possible therapeutics with cognitive and behavioral markers in animal models, measuring the effects of rampant chemokine and cytokine production. And they will look at immune activation markers, testing whether certain molecules interact with one another. All told, the center will support an enormous volume of research. Fox calls the core operating model the best one possible. "To fully understand the diseases that affect the brain," he says, "one also needs to study the other systems that interact with the brain." He expects that any research supported by the center will branch off into independent, investigator-initiated research grants. Fox himself directs two such independent research grants. "Scientists often want to try something new, but they either can’t pay for it or can’t invest a lot of time to learn how to do it," says Fox, "But we can do it. That’s one of the great advantages of [a center] such as ours. Paying a private company to do this kind of research, or trying to do it all in a single lab, would be prohibitive." "[Researchers] still shy away from the brain," he says. "Hopefully, the center will make it more accessible." The following TSRI researchers are associated with the Scripps NeuroAIDS Preclinical Studies center, directing cores or performing novel developmental studies funded by competitive grants from the center: Michael Buchemier, Iain Campbell, Monica Carson, Phil Dawson, John Elder, Howard Fox, Nick Gascoigne, Steve Head, Steve Henriksen, John Polich, Amanda Roberts, Nora Sarvetnick, George Siggins, Michael Taffe. The center holds monthly meetings focussing on recent research on neuroAIDS—both at TSRI and outside of it—and its basic scientific underpinnings. Attendance is open to all who wish to find out about this field or about use of the center’s resources.
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