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Winter 1997

Research Magazine > ARCHIVE > Summer 95 > Article

An Element of Survival
by David Hart

No one knows exactly why or how an HIV infection turns into AIDS, or why some HIV-positive people survive for many years without developing the disease.

Will Taylor believes diet may be part of the answer.

In particular, the key appears to be selenium, an element that is essential in trace amounts but, ironically, is toxic at high levels. And although it lacks the high-profile glamour of, say, vitamin C, selenium plays an important role in the human body. According to Taylor, selenium may be even more crucial to the human immune system, and to viruses, than anyone expected.

Taylor has discovered genes both in HIV and in human T cells that may be blueprints for selenium-containing proteins. Human T cells -- white blood cells that are part of the body's defense against disease -- normally repel invaders but, HIV successfully attacks them.

"As far as what these T cell genes are doing or what their purpose is, it's hard to say," said Taylor, a UGA associate professor of medicinal chemistry. "But I think that it certainly fits into the HIV story and is further reason to believe that selenium will have some beneficial effect. The idea that competition by the virus for selenium would mess something up certainly seems even more probable now."

In the AIDS mystery, most people accept that the butler -- HIV -- kills the patient, and their only question is how the crime is committed. Researchers generally have thought that selenium only plays a bit part in the story: After AIDS strikes, it causes selenium levels to drop because the victim's body loses its ability to absorb selenium. The reduced level of selenium then contributes to symptoms such as a weakened immune system and weakened heart tissue.

Taylor suggests just the opposite: HIV kidnaps selenium, thus lowering the body's selenium level and triggering the infection to develop into full-blown AIDS. In theory the revised story goes something like this: By producing selenoproteins, the newly discovered HIV genes create an additional demand for selenium that slowly depletes the body's supply. At the same time, the immune system needs more selenium to fight the infection. When selenium levels drop too low, HIV replicates out of control, wreaks havoc on the immune system by killing T cells and results in AIDS.

Although Taylor's work remains controversial, he makes a strong case for selenium's central role.

Until Taylor has experimental proof that these genes produce selenoproteins, it's hard to know whether the genes actually work the way he suggests. In the meantime, he has assembled two lines of circumstantial evidence for his case that implicates selenium.

Exhibit A: In several other diseases, a selenium deficiency triggers the worst from viruses.

Exhibit B: These genes provide a neat and tidy interpretation that links a lot of otherwise isolated findings on selenium and AIDS.

The upshot of all this is that the butler -- HIV -- may not be acting alone in a complicated plot that disrupts selenium's previously unsuspected activities in viruses and the human immune system. Solving this whodunit would be a big step toward stopping the disease.

"These genes certainly put all the information on HIV and selenium in a different light because they show that T cells are probably doing things with selenium that are far more involved than anyone has previously thought," Taylor said.

Missing Links and Smoking Guns

Until now, the chief suspect in this selenium mystery has been the enzyme glutathione peroxidase. Of the six known selenoproteins in the human body, glutathione peroxidase is the one most directly related to the "wasting syndrome" in AIDS. This enzyme protects cells from free radicals, oxygen byproducts that steal electrons and weaken cell membranes.

As AIDS progresses, the argument goes, the wasting syndrome causes selenium, along with other nutrients, to be poorly absorbed by the digestive system, which in turn lowers the supply of glutathione peroxidase and leads to the selenium deficiency symptoms.

However, this seems to be a chicken-or-egg scenario, since selenium deficiency not only results from the wasting syndrome but also causes the wasting symptoms at the same time. The question remains: How, exactly, does the butler do it?

A more satisfactory explanation would eliminate the chicken-or-egg problem. It would be better if, say, some extra demand for selenium lowers the body's supply and triggers an HIV explosion that leads to the wasting syndrome and full-blown AIDS. All that's missing is the smoking gun.

Enter Taylor and his HIV "selenium genes."

Taylor initially was studying how therapeutic drugs, such as AZT, might disrupt the way the virus reproduces. But deep down in the genetic nuts and bolts of HIV he ran across the clues for solving an entirely different mystery.

"You have to realize I was not out looking for new genes in HIV," Taylor said. "How could there possibly be new genes in HIV? I mean, HIV's been around for 10 years. The genetic sequence of HIV has been thoroughly dissected by the greatest scientific minds. That's not something you'd even be looking for."

But he found them, and now Taylor finds himself outside of mainstream AIDS research, arguing that maybe the butler's doing something completely unexpected.

Besides Taylor's work, a trickle of other research and anecdotal evidence points to selenium as a major player in this mystery. Selenium can slow the replication of HIV and the progress of AIDS, and poor nutrient absorption alone can't explain the dramatic loss of selenium in many AIDS patients. These are the clues for which Taylor's HIV genes are the candlestick in the billiard room.

These HIV genes and their selenoproteins also spell out a link between selenium and the virus in which the egg definitely comes first, so to speak. Taylor said he suspects one of the HIV selenoproteins acts as HIV's built-in form of birth control. To build these proteins, such genes demand a good supply of selenium. When the selenium is gone, the egg hatches and an HIV population explosion results. On top of that, the body can't produce glutathione peroxidase, and so the wasting symptoms appear.

But just when it looked like Taylor had the case against selenium wrapped up, critics pointed out that, even with all these new genes, the virus alone probably couldn't deplete selenium to the levels seen in many AIDS patients. Taylor initially worked around this discrepancy, but he wasn't completely happy with his explanation.

Something was still missing -- something to explain the correlation between selenium levels and immune system T cell counts that has been observed in the elderly, in AIDS patients and in animals. He dove into the literature and surfaced with a few choice tidbits.

First, Japanese researchers had noticed a statistical anomaly in the makeup of the virus's DNA, a region that resembled human DNA. And it was in precisely the same region as one of his selenium genes. A second paper proposed an evolutionary link between that very same genetic region of HIV and a surface protein on human T cells, called CD4. That's when the case cracked wide open.

"My logic was, if my gene overlaps with this region of the HIV envelope gene, and this gene has some relationship to CD4, I'd better look in CD4 and see what I find," said Taylor, whose results were published in the August 1995 issue of Biological Trace Element Research. "It's very common that viruses will simply steal genes from their host, because it's part of their Trojan horse mechanism for getting inside the host cells."

When he looked at the genetic code for human T cells, Taylor saw selenium's unmistakable footprints. The clues that had led to new HIV genes directed him right to new human genes that could produce selenoproteins.

Forget AIDS for a second. These new T cell genes open up a whole new set of questions about the human immune system. "There's just so much literature out there on selenium as a sort of immune stimulator," Taylor said. "That certainly begins to make a lot more sense in the light of this finding of new selenoproteins in T cells." What these genes could mean to immunology has intrigued researchers at the Centers for Disease Control and Prevention, who are now taking a new look at T cells.

With respect to the AIDS mystery, these new human genes -- one in CD4 and another in a similar T cell protein -- could explain the rest of the missing selenium, especially considering recent findings about T cells in AIDS patients: Several teams of U.S. researchers found that between 1 billion and 8 billion T cells are destroyed and replaced every day in the bodies of AIDS patients. If each T cell tries to create a protein with 10 selenium atoms per molecule, that creates an enormous demand for selenium.

A Common Modus Operandi

This massive turnover of T cells fleshes out the modus operandi for selenium's disappearance. As long as there's enough selenium to go around, the virus coexists with its host, as it does in long-term HIV-positive survivors. However, when selenium supplies run low, the virus population explodes and sets off a chain reaction that causes T cells to be destroyed and replaced by the billions, sucks the selenium well completely dry and results in all the symptoms of full-blown AIDS.

This scenario, while novel for HIV, may mimic a pattern researchers have seen in other diseases. In the literature, Taylor found extensive evidence of a link between selenium deficiency and other viral diseases.

Kaposi's sarcoma, which causes cancerous lesions on the victim's body, and Keshan disease, which causes heart damage in women of child-bearing age and even small children, both seem to follow a similar path from selenium deficiency to viral disease.

As well as being common in AIDS patients, Kaposi's sarcoma is endemic to some African regions with selenium-poor volcanic soils. The people who live there are often selenium-deficient because they subsist on the plants and animals raised on those soils. Similarly, Keshan disease affects people in regions of China that have selenium-poor soil, and the disease has been controlled largely by nutritional supplements that include selenium.

However, in each case, not everyone living in the region suffers from the disease, which suggests that some infectious agent triggers it. In fact, a herpes virus recently has been found in Kaposi's lesions. From Keshan patients, Chinese researchers isolated several viruses, and their No. 1 suspect was a strain of coxsackievirus, a class of viruses that cause a wide variety of human ailments ranging from sore throat and muscle aches to skin lesions and heart inflamation.

Taking the finding from Keshan disease one step further, teams led by Melinda Beck at the University of North Carolina at Chapel Hill and Orville Levander at the U.S. Department of Agriculture recently showed that coxsackieviruses turn nasty without their selenium "fix." The researchers injected a benign strain of coxsackievirus into selenium-deficient mice, and the virus mutated into a harmful strain that caused heart damage. In fact, when this mutated strain was injected into selenium-normal mice, it still damaged the heart muscle.

Speculations on why the virus goes on its rampage range from weakened immune response to weakened ability to eliminate free radicals -- the same reasons currently used to explain how HIV causes AIDS. On the other hand, Taylor has found selenium-encoding genes in the same strain of coxsackievirus, which suggests that this virus may have followed the same path to heart disease in mice that Taylor proposes for HIV leading to AIDS.

"Maybe there are evolutionary reasons why viruses would actually be just as happy not to kill you," Taylor said. "They'd like to keep themselves in balance with their host. So I think we need to ask more if things have been in balance in the past, and maybe in long-term survivors, HIV is in balance."

Although Taylor has built a substantial case based on theoretical and circumstantial evidence, he does not have quite enough to convict. To convince the jury of his peers, experiments must show that at least one of his genes produces a selenoprotein with some kind of biological function.

Because the proteins could be created only in minute quantities, detecting them in HIV-positive patients is difficult. So Taylor is taking another approach.

Along with a collaborator at Ohio State University, he is trying to clone one of the selenium proteins and show that it has some biological function. This particular protein bears a suspicious resemblance to DNA-binding proteins, which stick to DNA and regulate the activity of genes.

"If we can prove that protein has any kind of biological activity, that would pretty much substantiate it," Taylor said. "It would be nice if we can prove it really has the activities we predicted, but you can only expect so much out of the theory. We can suggest possibilities, but the reality might be something different."

-For more information go to http://bioinfo.chem.uga.edu/homepage/wtaylor/ or e-mail wtaylor@rx.uga.edu


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