Important AIDS Discovery Explains the Importance of Selenium: An Interview with Will Taylor, Ph.D.
by Richard A. Passwater, Ph.D.
It was only a few lines in the "Life" section of the USA Today on August 22, but it really got my attention. "University of Georgia researchers think the AIDS virus depletes the bodys store of the mineral selenium. If true, the process could shed light on how HIV infection leads to AIDS ..." The news got the attention of a lot of people. The next day, several of my friends had faxed me copies of articles from the Times of London and New York Times. Right away, it was obvious to most researchers and holistic physicians involved with Acquired Immune Deficiency Syndrome ( AIDS) and antioxidant nutrients that this new theory fit the unexplained facts, especially about the observations concerning selenium.
This new theory developed by Dr. Will Taylor arose out of a detailed analysis of the genetic code of the human immunodeficiency virus (HIV), which led to the discovery of a group of potential new viral genes. A literal translation of the genetic message in several of these genes strongly suggests that the proteins they encode have a requirement for selenium. Dr. Taylor's analysis suggests that one of these may be a regulatory protein, possibly even a "master switch" that could control the replication of HIV -- a switch that would be regulated by selenium levels. In that case, the progression of AIDS could be slowed by providing adequate selenium to the virus, so that it doesn't replicate in high numbers, and invade other cells seeking its needed selenium. This could help explain the long and variable latency period between HIV infection and AIDS, the declining selenium status of HIV-positive and AIDS patients, the route of transmission of HIV, and why some HIV-positive patients have never developed AIDS even after ten years.
After reading the news reports of Dr. Taylor's theory, I wanted to contact him and learn more about his research. However, before I had a chance to read the research article published in the Journal of Medicinal Chemistry (August 19, 1994, vol 37, pp 2637-2654) , a respected peer-reviewed medical journal, a photograph in Chemical and Engineering News (August 22, 1994, p23) stopped me in my tracks.
The photograph was of Dr. Taylor seated before his computer, but what caught my eye was the University of Georgia license plate mounted above the computer. The significance of the license plate is that the abbreviation for Dr. Taylor's University, UGA, is the same as the chemical symbols for a combination of RNA bases (uracil, guanine and adenine) that encode the amino acid selenocysteine. The photo drove the point home that not only did the exciting new theory involve my favorite nutrient, selenium, it also involved my oldest son's Alma Mater. Richard A. Passwater, Jr. is a 1985 graduate of the University of Georgia. At that instant, I put down the Chemical and Engineering News article and called the University of Georgia.
I had never had the opportunity to meet Dr. Taylor before, but he was kind enough to spend quite a bit of time explaining his research to me. Before getting into the theory, I want to share with you some of the personal aspects of the story behind the research and then discuss the role of selenium in surviving AIDS. Since Dr. Taylor's field of research is so new, and the field of virus replication is a specialized area of research beyond that of nutrition and basic biochemistry I hope that many readers will enjoy learning the fundamentals as they are discussed. For the readers who are not thrilled with the jargon of these new fields, please just bear with us until we discuss the exciting evidence of the role of selenium in the middle of the interview. The evidence for the protective role of selenium is so strong that it may surprise you. Even if you don't like theoretical biochemistry or are a skeptic, the selenium data will convince you to advise all HIV-positive or AIDS patients to be well nourished with selenium. Also, Dr. Taylor has written a non-technical summary of his theory which is presented at the end of the interview.
Dr. Will Taylor is an associate professor in the Department of Medicinal Chemistry in the College of Pharmacy at the University of Georgia in Athens. He has published over 30 research papers in the fields of pharmacology, medicinal chemistry and computer-assisted drug design. His AIDS research is funded by the National Institutes of Health.
Passwater: Dr. Taylor, you have been studying the molecular basis for the activity of anti-HIV agents for several years -- which came first -- your interest in researching how drugs work using computers or your interest in anti-HIV drugs?
Taylor: I became interested in computer-assisted molecular design while still a graduate student at the University of Arizona, and began to actually use it in my research while I was a "postdoc" there with Dr. Arnold Martin. My doctoral training was in the area of neuropharmacology, so most of my early molecular modeling work was in the area of drugs that act on the central nervous system, which is still an active area for my research group. I've only been seriously involved in AIDS research and theoretical virology for about five years, so my interest in computational pharmacology definitely predates my interest in anti-HIV agents.
Still, it was probably inevitable that I would get involved in AIDS research, since it is arguably the biggest challenge in biomedical research today. I feel that if I am going to work on a problem, it may as well be a big one that's well worth solving, even if I might only be able to contribute a small piece to a larger solution involving the efforts of many investigators.
In addition, having children has been a strong motivation. I have four, ranging in age from two to fifteen years. I think anyone with kids in or entering the teenage years would feel the same way. The specter of AIDS has negatively influenced the psyche of an entire generation, like a dense black cloud hanging over everyone. You can't help but feel compelled to do everything in your power to try to make it go away. It becomes very personal when you consider the possibility of one of your children contracting the disease. I'd like to see their generation able to explore their sexuality without having to constantly worry that SEX=DEATH, which is what the threat of AIDS has brought about, particularly as it is portrayed in some segments of the media and society at large.
I have no tolerance for religious bigots who attempt to exploit the disease for their own warped purposes, because of its early association with homosexuality. My sister-in-law's brother, a hemophiliac, and his wife, both died of AIDS within the last year or two. That's just one example of how the disease can strike anyone -- including millions of innocent children who are at risk worldwide. What is needed is a deeper understanding of the origins of the disease, not scare tactics arising from ignorance.
Passwater: Many of our readers have the opportunity to educate HIV-positive and AIDS patients on the need for supplements, especially antioxidant supplements including selenium. Most of the available information comes from conventional studies, but your approach using computer models is far from conventional. Perhaps it's the wave of the future. Often breakthroughs come from young scientists in new fields who look at the problem from a fresh perspective. What can your computer models tell us about how a drug may work? Is this information that is above that of animal and human studies, or is it the same information only obtained more cheaply and/or more safely?
Taylor: Computer models are of increasing importance in many fields of scientific inquiry, and pharmaceutical research is no exception. However, there are so many different ways in which computers can be applied that it is difficult to make generalizations. In a sense, computers can only help us extrapolate from data that is known, so there will always be a need for the accumulation of experimental data. On the other hand, as the theoretical models become more sophisticated, they can be used to predict many aspects of the real world, particularly if they are accurately parameterized, i.e., instructed about known real data. I have felt for some time that we already have incredible amounts of data (often available in computerized data banks), and that we would make much more progress if people would just spend more time analyzing and thinking about the data we DO have, instead of just blindly accumulating more.
In my AIDS research, I seem to have naturally fallen into this sort of role as a theoretical analyst, just digging deeper into all the existing data. My work in this area has followed a natural evolution, to a point where what I am doing now has little precedent in prior research. The "big" problem I wanted to pursue when I arrived at the University of Georgia as an assistant professor was the prediction of protein structure and/or function from primary sequence data. The primary sequence is merely the series of amino acids in a protein chain, which can be predicted from the DNA sequence once a gene has been cloned and sequenced. In a sense, we are making progress on this problem in our applied research. For example, we can analyze the hypothetical protein sequences of the novel genes whose existence we are predicting in HIV, and make reasonable guesses as to what their function and even structure may be in some cases, based on similarities and possible evolutionary relationships to known proteins. What was unexpected was that, using such a purely theoretical approach, we were able to come up with something as down-to-earth and potentially practical as the elucidation of the mechanism by which selenium may play a key role in the progression of the disease. Even I never would have expected that, and I believe in these methods. I would have been quite happy just finding some new genes in HIV -- anyone would -- but I was not really even looking for those, at least not initially.
Passwater: What were you looking for?
Taylor: At the instigation of my collaborator, Dr. Raymond Schinazi of Emory University, I became involved early in 1993 in the examination of the possibility that RNA structure in the coding regions of HIV might be a factor in determining the sites of mutations contributing to the pool of mutant viruses from which drug resistant strains were selected, leading to, for example, AZT-resistant virus. Such drug resistance is an almost insurmountable problem in anti-HIV chemotherapy, due to the high mutation rate of the virus, and the persistent nature of HIV infection, which gives ample time for the virus to mutate when a drug is administered. Dr. Schinazi and I published a research report in February of this year, showing that there was a significant correlation between features of the predicted RNA structure and sites where these mutations were occurring. This went against prevailing dogma, which held that messenger RNA does not have much in the way of structure in coding regions, and that mutations are "random." This would imply that mutations should occur everywhere with equal probability, which I think is an oversimplification.
As well as revealing mutation prone regions, our results suggested that the less mutation prone helical RNA structures appeared to be associated with regions coding for highly conserved protein sequences, containing catalytic amino acids, etc. These are precisely the regions where the virus could least tolerate mutations! Pursuit of the implications of this hypothesis led me to discover several RNA "pseudoknots" (interlocking helical structures) in the protease and polymerase coding regions of HIV.
A "codon" is a sequence of three adjoining nucleotides that specify the insertion of an amino acid in a specific structural position during protein synthesis. In addition to these pseudoknots being located precisely on codons for the most conserved protein regions, which was consistent with our hypothesis, these pseudoknots were also the key to discovering the novel genes, since pseudoknots are known to be involved in "frameshifting," a process required for the expression of these hypothetical proteins. Incidentally, the computer program we were using could not predict pseudoknots. Those I found essentially by manual inspection of the HIV sequence. This shows that the role of computers can easily be overrated in this kind of work -- there's still nothing that can replace the human brain.
Passwater: You have found that HIV may synthesize rare proteins that contain selenocysteine. Selenium-containing proteins are rare in man. In 1973, Dr. J. Rotruck and his colleagues found that selenium was needed to produce glutathione peroxidase (GPX). Since then about several more have been isolated, two more peroxidases (PHGPX and GSHPx-GI), iodothyronine deiodinase which is an enzyme that acts on a thyroid hormone , and a few others as described in my Health Connection column of June 1991. Are these new selenoproteins structural proteins or enzymes needed by HIV?
Taylor: It is unlikely that the potential HIV selenoproteins are used for structural purposes. The manner in which their genes are placed in the HIV genome (the complete set of genes of an individual) indicates that they could only be formed in very low levels compared to the known structural proteins. The most interesting one is probably a DNA binding protein, with the potential to regulate the expression of other HIV genes. Another may be an enzyme involved in integration or transcription. At this point, such predictions are still speculative and will have to be verified by experimental work. I discovered the genes because of a hunch, I suppose. When I found the new RNA pseudoknots in the coding regions of HIV, I was at first totally caught up in the amazing fact that they were precisely located on the codons for the most important amino acids in the entire gene, which was clearly an important discovery, supporting our mutation hypothesis.
Still, I had to consider the potential for these pseudoknots to cause certain regions of the genome to be expressed by frameshifting. At first it seemed there could not be any real genes in these locations, because of the presence of multiple "stop" codons, which would cause termination of any protein chain even if its synthesis could be initiated. Being stubborn, I finally decided to examine hypothetical peptide fragments from these regions, at first thinking that small regulatory peptides might be formed by this mechanism. That was an incorrect idea, but one that kept me going.
Then I continued because these fragments looked suspiciously like bits of known proteins that could do interesting things like bind to DNA, or act in the immune system. By acknowledging my own ignorance and reading a lot of the scientific literature on the processes in question, I learned enough to realize that in retroviruses, stop codons do not always mean stop, and that in animals and bacteria, the UGA stop codon can sometimes code for the rare amino acid selenocysteine. This was all I needed to get started, although the depth of the analysis that we were able to achieve went much beyond that.
Passwater: Your theory seems to answer all of the known observations -- even those observations that have caused others to downplay the role of HIV. Were you aware of the roles and interactions of selenium before you theorized that HIV was making selenoproteins or was it the other way around... that you theorized the selenoproteins and then looked for supporting evidence?
Taylor: It was the latter. Overall, I was really quite ignorant about selenium biochemistry as recently as February of this year. I had to learn a lot in a very short time. I was totally unaware of any literature linking selenium and AIDS, and even much of the work suggesting that oxidative stress might be a factor in AIDS (e.g., that glutathione is often depleted in AIDS patients). I found your book "Selenium as Food & Medicine" (Keats Publ., 1980) in the University of Georgia Science library and it was very helpful in making me aware of the amount of data that existed at that time in regard to the anticancer effects of selenium, by the way..
Passwater: Well, you evened the score. You have a lot of us poring through the molecular genetic literature trying to figure out all of the nuances of your research. Also, your research has stimulated me to do a new literature search on selenium and AIDS. I found 35 articles discussing selenium and AIDS or HIV. I'll put them in the bibliography for the benefit of readers. Also, readers may want to refer to the February 1992 Health Connection column for a discussion of glutathione, selenium and AIDS, and to the December 1991 interview with Dr. Gerhard Schrauzer for a discussion of selenium and the immune system. Did you learn anything else in your literature search?
Taylor: As I mentioned earlier, at the outset I did not even know that the UGA stop codon could also encode selenocysteine under special circumstances, or that retroviruses used termination suppression as an alternative to frameshifting. This information was critical. It was only after discovering the genes for potential selenoproteins, and confirming that the UGA selenocysteine codons were conserved in several cases, that I knew I had to check to see if there was a link between HIV and selenium. This was certainly one of the "eureka moments." It was near midnight, and I ran a search from my home computer of the scientific literature stored in "Medline," the computer database of the U. S. National Library of Medicine, using "selenium" and "HIV" as the keywords. This identified about eight research articles, which consistently documented a progressive decline in plasma selenium levels in AIDS Related Complex (ARC) and AIDS patients. I remember bouncing down the hall into the bedroom, to tell my wife Valarie that I thought I was really on to something, even beyond the discovery of the potential genes. It was one of a series of high moments over a period of several weeks. This was the beginning of an unrelenting search, still going on now, for evidence supporting a direct link between selenium and HIV.
As you suggest, the theory I develop in the Journal of Medicinal Chemistry is able to account for a number of observations that have led others to question the role of HIV as a cause of AIDS, or at least to suggest the need for various cofactors to activate HIV, which some have suggested could not produce such extreme pathology by itself. Proposed cofactors have included other infections, including mycoplasmas, or other viruses such as cytomegalovirus, the abuse of oxidant drugs such as nitrite inhalants, and immuno-suppression consequent to malnutrition and other factors. I believe that the common thread here could be oxidative stress, which can be aggravated by a deficiency of selenium and/or other antioxidants (i. e., malnutrition), or by antagonizing the antioxidant effects of selenium by means of direct oxidative damage due to nitrite abuse or certain infectious disease and inflammatory processes. We suggest a detailed hypothetical mechanism whereby the replication of HIV could be stimulated by oxidative stress and/or selenium depletion.
Passwater: You mentioned the studies revealing low plasma selenium levels in AIDS patients. Does the evidence suggest that HIV-positive patients tend to become depleted in selenium or does HIV preferentially infect those low in selenium status? Can we discount that HIV-positive patients absorb selenium poorly?
Taylor: At least eight different studies, from as early as the mid-1980s, have been published that document a decline in the plasma selenium of ARC and AIDS patients. One 1988 study showed that both selenium and glutathione peroxidase ( a key human antioxidant enzyme that contains selenium) were below normal in AIDS patients. Most recently, a group from Bonn, Germany showed that the depletion is progressive, correlating with the stages of HIV disease established by the Centers for Disease Control. Until now, most investigators assumed that the selenium depletion was just a consequence of the wasting syndrome and nutritional malabsorption characteristic of AIDS. If I am right about selenoproteins in HIV, then the virus must play a more active role, and probably contributes to the depletion inside infected cells, where selenium is most needed for proper functioning of the immune system. Unfortunately, it is difficult to prove either way, based on the current data. However, a cell culture study published earlier this year demonstrated an HIV-associated depletion of glutathione peroxidase in an infected cell line, which directly supports the theory.
Although much more research will be required to prove it, the theory is supported by a lot of circumstantial evidence. It is certainly true that AIDS seems to be very active in populations that are nutritionally at risk, including Haitians, Africans, and intravenous drug users. Widespread nitrite abuse among the gay population in the early days of the epidemic may have produced the equivalent of selenium depletion, by antagonizing the antioxidant effects of selenium.
Passwater: Is there evidence supporting the idea that as HIV disease progresses, the patient experiences selenium deficiency symptoms, consistent with the depletion of selenium stores as a disease mechanism?
Taylor: There are a number of facets of AIDS pathology that are very consistent with this idea. Prolonged selenium deficiency will reduce the levels of several important human selenoproteins: glutathione peroxidase, an essential antioxidant enzyme, and a deiodinase that is one of the enzymes required for the formation of the T3 thyroid hormone from T4. This is significant because there is abundant evidence that both antioxidant status and T3 hormone levels are frequently impaired or lowered in AIDS patients. The well-documented hypothyroid syndrome in AIDS has been proposed to be a factor in the wasting syndrome. AIDS is often characterized by premature aging, which can be caused by accumulated oxidative damage (Harman's free radical theory of aging), consistent with impairment of antioxidant defenses as a disease mechanism.
It is important to realize that recent work has shown that antioxidant status is critical for the proper function of healthy immune cells, and that impairment of antioxidant function is a key factor in AIDS. It has also been noted that nonobstructive cardiomyopathy in AIDS patients is similar to that due to selenium deficiency; selenium supplementation has been found to improve this condition. Combined with the observation that a decline in plasma selenium levels appears to be a hallmark of AIDS, these facts are all highly consistent with the new theory. There are of course many aspects of AIDS pathology in addition to these, that cannot be directly attributed to selenium involvement, including possible autoimmune aspects, and complex mechanisms for the loss of uninfected T-cells. However, if selenium levels and oxidant stress modulate viral expression in the manner we propose, even these other mechanisms of viral pathogenesis are at least indirectly dependent upon selenium status.
Passwater: Last November at a press conference in London with Dr. Raxit Jariwalla of the Linus Pauling Institute, who was lecturing on the suppression of HIV with vitamin C, we had the opportunity to meet reporters for several AIDS and/or gay-oriented magazines, as well as several long-term survivors of HIV. A common finding was that all of the long-term HIV-positive survivors were taking selenium and NAC supplements as well as generous amounts of other antioxidant nutrients. Do we have evidence that long term HIV-positive survivors tend to ingest more selenium and/or selenium-sparing nutrients?
Taylor: There is some anecdotal evidence of the type you just mentioned. In his book "Rethinking AIDS," Robert Root-Bernstein reviews a lot of data supportive of the idea that malnutrition can be a major factor in AIDS, and mentions a number of cases where successes have been claimed for nutritional therapies in prolonging the lives of HIV-positive survivors. We've all heard these stories, but they won't convince the skeptics. I'm hoping that a lot of these people will respond and tell their stories if selenium and other antioxidant nutrients have worked for them. Maybe now it will be taken seriously enough that more clinical researchers will take a deeper look.
Passwater: Is this an invitation to our readers and their associates to share their information with you? Are you willing to serve as a clearing house for this information? If so, what information would you like sent to you?
Taylor: I'm not sure I want to invite more direct contact, particularly by phone, as it is already more than I can handle. The problem is that if it's just anecdotal evidence, it will have little impact on the research and medical community. If any therapists have had consistent success with such an approach, that would be a little more convincing, and I'd like to hear about it. If people want to write to me, I could handle that. But, keep in mind that answering the mail takes time away from doing research. The most important thing is probably for those who are having success with such therapies to let other HIV-positive people know, through personal contacts or media such as the AIDS activist literature, Internet groups, etc.
Passwater: It seems that males may transmit HIV more easily than females. You note that semen has a higher priority for selenium than most other body compounds and that this may explain why semen is a HIV carrier and that other body fluids are less so. Please elaborate.
Taylor: This is something I learned from the literature during my crash education in selenium biochemistry. You even mention in your selenium book that selenium is concentrated in semen, and that sperm cells contain relatively high amounts of selenium, and that significant amounts of selenium can be lost by the male during sexual intercourse. Sterility is a common result of selenium deficiency.
It's intriguing in terms of retroviruses like HIV because they are known to occasionally integrate into the germline, becoming "endogenous," i. e., part of the host gene pool, which can happen only if a sperm or ovum is infected by the virus. This makes sense if they are programmed to seek out selenium, which sperm are apparently rich in.
The existence of endogenous retroviruses is something that many people are not aware of, but has tremendous significance. They have recently been implicated in certain autoimmune diseases, which have occasionally been linked to selenium deficiency in some of the literature.
Mammalian genomes contain many of these endogenous retroviruses, and their ancestors, which are all members of a general class called retroelements. A large portion of the human genome -- at least ten percent, and probably much more -- has been formed by the action of retroelements. We are riddled with retrovirus-like entities, and have coexisted with them throughout evolution -- we probably wouldn't even have evolved without their role in shaping our genomes. Thus, retroviruses are somewhat unique, being in a sense an escaped part of us (or related primates), in symbiotic relationships with us. Most retroviruses are comparatively benign or of low pathogenicity. Thus, we need to ask, if we have coexisted in the past, what has been thrown out of balance, leading to the current problems with HIV in certain populations? Has the virus just mutated to something deadly, or is something deeper going on? What would the virus stand to gain by killing people, anyway? Particularly for viruses like HIV, that establish a "persistent" infection by merging with the host DNA, the ultimate survival of the virus depends on the survival of the host.
Passwater: Are you suggesting that HIV infection may not necessarily have to be almost uniformly fatal, as many lead us to believe?
Taylor: What I am advocating here is a change in perspective, more along the lines of what you might call viral ecology. Instead of just saying "it's deadly, it's alien, we have to eradicate it" -- which in any case would be impossible with HIV -- perhaps we should be saying, "like it or not, retroviruses are part of us; we'd better figure out what's driving their agenda and try to coexist with them, as we have in the past."
If Dr. Douglas Frost was right that selenium is decreasing in the food chain, due to fossil fuel use and acid rain, then this perturbation in viral ecology may merely be part of a larger ecological picture that needs to be more closely examined in terms of its potential global impact. Until we resolve such questions, and verify the precise role of selenium in AIDS, I'd rather be optimistic and hope that having HIV is NOT a death sentence to its carriers.
Passwater: How has the response been to the publication of your theory in the Journal of Medicinal Chemistry? Are others now looking into selenium nutriture to prolong latency and survival?
Taylor: The response to the paper has been phenomenal in many ways. We went through a very rigorous review process with this paper, with seven referees rather than the usual two or three. I think that, justifiably, the journal editors wanted to make sure there was a strong consensus that we really had something, and that there was not some fatal flaw in the logic. Apparently, they were convinced.
Once the paper came out, and particularly with the coverage given in Chemical and Engineering News, there was a tremendous media demand for more information. What has been most encouraging is that essentially all the feedback I have received from scientists has expressed considerable enthusiasm for the concept, and many scientists are now examining the idea very seriously.
I've learned about other work that reinforces my conviction that the analysis is fundamentally correct. Still, I don't expect to be one hundred percent correct in all the details, as the paper is totally theoretical, covers a lot of territory involving four potential new genes, and presents speculations on alternative possibilities in some cases.
If it stimulates the scientific community to definitely resolve the AIDS-selenium question, it will have served a useful purpose. We are working on various fronts, with both formal and informal collaborators, to verify or disprove aspects of the hypothesis. Significantly, since doing the work, I learned of the efforts of Dr. Gerhard Schrauzer over the last decade to convince people of the potential benefits of selenium supplementation in HIV disease. In published work, he has provided a number of cogent arguments as to why this could work, based on years of observation of other related retroviral systems, and the growth in our knowledge about the biological roles of selenium. Due to his efforts, a small clinical trial of selenium in AIDS patients is now in progress in Germany. I hope my research will vindicate his work and vision by the elucidation of the molecular mechanisms involved.
Passwater: My sentiments as well. Dr. Taylor, thank you for taking the time to explain your theory to me and for preparing the following summary of your exciting new theory.
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