356(9225), 2000 T
The importance of selenium to human health
trace mineral, selenium, is of fundamental importance to human
health. As a constituent of selenoproteins, selenium has structural
and enzymic roles, in the latter context being best-known as
an antioxidant and catalyst for the production of active thyroid
hormone. Selenium is needed for the proper functioning of the
immune system, and appears to be a key nutrient in counteracting
the development of virulence and inhibiting HIV progression
to AIDS. It is required for sperm motility and may reduce the
risk of miscarriage. Deficiency has been linked to adverse mood
states. Findings have been equivocal in linking selenium to
cardiovascular disease risk although other conditions involving
oxidative stress and inflammation have shown benefits of a higher
selenium status. An elevated selenium intake may be associated
with reduced cancer risk. Large clinical trials are now planned
to confirm or refute this hypothesis. In the context of these
health effects, low or diminishing selenium status in some parts
of the world, notably in some European countries, is giving
cause for concern.
Journal of Orthomolecular Medicine,
Selenium and Viral Diseases: Facts and Hypothesis
Ethan Will Taylor, Ph.D.
Department of Pharmaceutical
and Biomedical Sciences,
College of Pharmacy, The
University of Georgia, Athens, GA 30602
This review is based upon
an article posted to the Internet newsgroup sci.med.aids in August
1995 (at the request of one of the newsgroup moderators), in an
effort to clear up some of the confusion surrounding the issue
of selenium (Se) and AIDS. It has been updated with new developments
and data (theoretical, experimental and clinical) that have emerged
in the two years since it was first written.
Much of the current interest
in the role of Se in viral diseases and AIDS in particular has
been stimulated by media coverage of several recent scientific
papers, specifically my theoretical paper showing that HIV-1 potentially
encodes Se-containing proteins , and more recently the work
of Dr. Melinda Beck and coworkers demonstrating that the cardiovirulence
of coxsackievirus B3 is highly dependent upon the Se status of
the host, and that the virus actually mutates into a more virulent
form in Se-deficient mice . More recently (Christmas, 1996),
Se has been in the news in regard to the first definitive clinical
cancer study in the U.S., by Clark and coworkers at the University
of Arizona Cancer Center , showing that daily supplementation
with 200 micrograms of Se produced a significant chemopreventive
effect vs. several forms of cancer, with a 50% reduction in total
cancer mortality over the entire study period. The national media
coverage given to all of these papers has drawn much needed attention
to the issue of the potential roles of Se in viral diseases and
cancer, but naturally has led to some confusion as well, since
the science involved is not easily explained in a few paragraphs.
It must also be noted
that researchers like Dr. Gerhard Schrauzer have for many years
been accumulating evidence for the potential benefits of Se, not
only against cancer, but also in viral diseases (and retroviral
diseases in particular; ), only to be widely ignored by "mainstream"
researchers and clinicians. Hopefully, this review will help to
rectify that situation.
I will begin by summarizing
some of the FACTS about Se, AIDS, and other viral diseases. To
keep the number of references within reason, I will generally
only include citations directly related to the question of the
role of Se in AIDS or other viral diseases.
2. The FACTS
2.1 FACT: Se is an essential trace mineral, which can be specifically
incorporated into proteins as the rare amino acid selenocysteine
(the Se analog of cysteine, which contains sulfur). Se is known
to be critical for:
Antioxidant defenses, because it is an
essential component of glutathione peroxidase (GPx).
Along with vitamin E, a form of this enzyme is essential for combating
the ubiquitous and harmful process of lipid peroxidation (a result
of "oxidative stress"). Another antioxidant protein,
selenoprotein P, is the major form of Se in human plasma. Unreversed
lipid peroxidation leads to cell membrane destruction and can
be induced during apoptosis (programmed cell death).
Thyroid hormone function, specifically formation of
the active T3 form of thyroid hormone. This hormone is critical
in regulating metabolism.
Formation of sperm in the male. Sperm have a high Se
content, and Se deficiency can lead to infertility in males.
- Immune function, particularly
cellular immunity. Because of the potential significance for AIDS,
this will be discussed in more detail.
2.2 FACT: Adequate
levels of Se are necessary for the immune system, and particularly
T-cells, to function properly.
Se supplementation in
culture increases the cytotoxicity of killer T cells as well as
the proliferation of T cells in response to mitogens and antigens
(e.g. ), whereas Se deficiency has the opposite effect, and
is commonly associated with impaired immune function. The supporting
data have been reviewed by Turner and Finch  and more recently
by me . Correlations between CD4+ T cell counts and plasma
Se levels have been documented in animals, the elderly, and, most
significantly, in HIV-infected patients (see 2.4). The mRNA for
a gene called Sps2, involved in biosynthesis of the Se donor compound
required for formation of selenocysteine, is up-regulated upon
activation of T lymphocytes . This shows that selenoprotein
synthesis is required for some aspect of T cell function. Comment:
because HIV can only replicate in activated T cells, this also
suggests that selenoprotein synthesis may be important for HIV.
2.3 FACT: Se potentiates the action of interleukin 2 (IL-2).
IL-2 is a cytokine that
has recently shown promise in the treatment of AIDS patients,
but is unfortunately associated with unpleasant side effects.
Se has been shown to potentiate (amplify) the action of IL-2 by
upregulating the IL-2 receptor, i.e. increasing the receptor levels
. This suggests that Se supplementation might permit lower
doses of IL-2 to be used, thus reducing side effects.
2.4 FACT: A progressive decline in Se levels, paralleling T
cell loss, has been widely documented in HIV patients, and Se
status is a significant independent predictor of survival in HIV
More than 20 papers documenting
aspects of this decline, as well as many research abstracts, have
been published over the last decade. This has been noted in asymptomatic
as well as symptomatic patients, and children as well as adults.
Research groups from New York, California, Florida, Italy, Spain,
Germany, France and Belgium, have all reported such observations
The obvious and traditional
explanation for these observations has been that any HIV-associated
decline in plasma Se levels is due to malnutrition and/or nutrient
malabsorption, and thus is merely a consequence or feature of
the wasting syndrome. However, a number of these authors suggest
that something more complex must be taking place. Dr. Brad Dworkin
 reports that plasma Se and GPx levels in ARC and AIDS patients
are "significantly correlated with total lymphocyte counts"
but that this appears to be "irrespective of the presence
or absence of diarrhea or gastrointestinal malabsorption".
This suggests that the decline in Se levels parallels the progression
of HIV disease (decline in T-cell levels) in a way that cannot
be entirely ascribed to GI malabsorption. Similarly, other authors
talk about "a surprisingly high prevalence of low levels
of Se in early stages of the disease"  (before wasting
is commonly detectable), or make comments such as "a low
selenium intake seems unlikely, because urinary excretion, which
closely reflects the actual selenium intake, was similar in HIV-1
infected patients and controls" . Most recently, Allavena
et al.  rule out malabsorption as the underlying cause, correlate
Se levels with survival prognosis, and conclude that "the
measurement of trace elements, especially Se, may be a useful
marker to predict the HIV infection progression".
In the most recent studies,
there is compelling evidence that Se status is actually a significant
predictor of outcome in HIV infection , and that the relative
risk for mortality is much higher in Se-deficient patients .
Thus, at the least, the selenium status of HIV-infected patients
appears to be an excellent "surrogate marker" of HIV
2.5 FACT: Simple Se compounds DO inhibit HIV-1 in the test
There is also other experimental
evidence for an effect of HIV upon levels of cellular selenoenzymes,
and for Se inhibition of the replication and effects of HIV-1
and other retroviruses. Furthermore, recent work demonstrates
a direct effect of Se in regulating the expression of an isoform
of an HIV gene in vitro (see section 3.4.5). Examples:
hydroperoxides induce apoptosis in T cells displaying a HIV-associated
glutathione peroxidase deficiency", Sandstrom et al. .
Quote from abstract: "Since oxidized lipids have been reported
to accumulate in oxidatively stressed, HIV-infected individuals,
a HIV-associated glutathione peroxidase deficiency may contribute
to the depletion of CD4 T cells that occurs in acquired immune
deficiency syndrome (AIDS)." Note: Se is an essential component
of glutathione peroxidase, so the results show that even in this
cell culture model - where malabsorption cannot be blamed - HIV
is somehow causing a deficit in the levels of an important cellular
of glutathione peroxidase activity decreases HIV type 1 activation
after oxidative stress", Sappey et al. . This was a study
of effects of Se supplementation on HIV-1 replication induced
by oxidative stress in cell culture. Noting that existing data
"implicate an HIV-1 mediated antioxidant imbalance as an
important factor in the progressive depletion of CD4+ T cells
in AIDS, the authors demonstrate that at concentrations of 25
to 50 micrograms Se per liter as sodium selenite, Se supplementation
has the following effects in ACH-2 cells:
o inhibits viral cytotoxic
effects and the reactivation of HIV-1 by hydrogen peroxide.
o decreases activation of
NF-kappaB, an important cellular transactivator of HIV-1.
o protects against activation
of HIV-1 by tumor necrosis factor alpha.
results from the lab of Dr. Raymond Schinazi from screening several
organic and inorganic Se compounds in a standard assay for anti-HIV
activity show that certain simple Se compounds are active vs.
HIV-1 at micromolar concentration (abstract published in Antiviral
before the "AIDS virus" was shown to be a retrovirus
(i.e. earlier than 1983), it had been demonstrated that simple
inorganic Se compounds were able to inhibit other retroviruses
both in vitro (bovine leukemia virus) and in vivo (mouse mammary
tumor virus), as referenced in Schrauzer and Sacher . These
early leads have never been pursued by AIDS researchers.
only significant counterexample is a 1983 paper showing that selenomethionine
induced the expression of endogenous retroviruses in cultured
cells . The effect appears to involve the nonspecific replacement
of methionine by selenomethionine (SeMet), because addition of
an equivalent amount of methionine (i.e. a 50-50 mixture of Met
and SeMet) inhibited the induction by 96%. However, this induction
of viral expression was only observed at extremely high (millimolar)
concentrations, at which many other Se compounds tested were "highly
toxic" to the cultured cells. The selenomethionine concentrations
at which induction was observed were at least 100 to 1000 times
higher than concentrations observed to inhibit the activity of
HIV and other retroviruses in the experiments described above
(2.5.2 - 2.5.4), as well as being at least 100 to 1000 times higher
than the Se concentration in normal human blood. Such concentrations
could never be attained in human plasma unless highly toxic doses
were being ingested. Thus, this is not a physiologically significant
effect. In the light of all the other evidence cited above, there
is no reason to believe that Se supplementation at rational dose
levels would have anything other than a beneficial effect in HIV
2.6 FACT: A
hypothyroid-like or low T3 syndrome is well-documented in AIDS
A common deficit in thyroid
hormone has been widely noted in AIDS patients, and specifically
involves reduced levels of T3 [36-39]. The conversion of T4 to
T3 depends on a deiodinase enzyme that contains Se, so a reduction
in T3 formation would be a logical consequence of Se deficiency.
It has been suggested that these thyroid-related abnormalities
could be a factor in the AIDS wasting syndrome. Human growth hormone,
a current preferred treatment for wasting, is known to stimulate
conversion of T4 to T3 by inducing the deiodinase [40,41], a process
which will be more effective if adequate levels of Se are present.
2.7 FACT: An immense body of evidence demonstrates the role
of oxidative stress in stimulating HIV replication, that certain
antioxidants can inhibit this process, and suggests the presence
of an antioxidant defect in HIV patients.
This evidence was reviewed
in the symposium on "The place of oxygen free radicals in
HIV infections" that was held in France early in 1993, with
proceedings published in Chemico-Biological Interactions, Vol.
91. In his preface to the proceedings, in regard to oxygen radicals
Dr. Alain Favier states "their place in HIV appears as a
very strong hypothesis" and that "...the time is right
to conduct trials to evaluate the efficacy of antioxidants."
Since Se is one of the most critical antioxidant nutrients, a
Se deficiency in an AIDS patient could be expected to lead directly
to the stimulation of HIV replication, by increasing oxidative
stress, and Se supplementation would be expected to counter that
process, as has now been shown in the test tube (see 2.5.2).
2.8 FACT: There is extensive evidence of correlations between
Se deficiency in humans and animals and the severity of diseases
associated with certain other viruses. Examples:
2.8.1 Hepatitis B: in
certain low Se regions of China, both hepatitis B viral infection
and associated cases of liver cancer have been endemic. In extensive
5-year trials of Se supplementation in the human population, Chinese
researchers were able to attain significant reductions in the
incidence of both viral hepatitis  and liver cancer .
Note that hepatitis B, a hepadnavirus that encodes a reverse transcriptase,
is a close relative of retroviruses.
2.8.2 Keshan disease,
a Se-deficiency disease with a viral cofactor: a precedent for
HIV? Keshan disease is a classical Se-deficiency disease, named
after a county in China where outbreaks occurred due to the very
low Se levels in soils of the region. The disease presents as
a non-obstructive cardiomyopathy. Due to the seasonal and clustered
nature of outbreaks of the disease, Chinese investigators suspected
the involvement of an infectious agent or other cofactor, and
eventually isolated coxsackievirus from the hearts of disease
victims. The probable role of coxsackievirus in Keshan disease
is strongly supported by demonstrations that a deficiency of Se
can trigger a similar cardiomyopathy in coxsackie-infected mice
. Recently, Beck and coworkers have shown that even a "benign"
strain of CVB3 becomes virulent in Se-deficient animals, where
it can mutate into a more virulent strain that can produce myocarditis
even in Se-adequate mice [2,45]. This research was recently reported
in the popular press, including Science News (V.147, p.276), and
by Laurie Garrett in Newsday (5-1-95, City Edition, News, pg.
A27, under the headline "Study: Diet Can Start Virus' Lethal
2.8.3 Animal viruses:
Many examples can be found in the veterinary/agricultural literature
linking viral infections with Se deficiency in various animals.
3.0 HYPOTHESES: Is there a common basis for all these observations?
The biochemical roles of Se, and the mechanisms involved in viral
pathogenesis, are both sufficiently complex that the apparent
antiviral effects of Se are probably multifactorial in origin.
Although the preceding review has focused on evidence for a potential
role of Se in AIDS, this is not intended to imply that Se is a
cure for AIDS, or to minimize the importance of other factors
that contribute to HIV pathogenesis. It is intended to demonstrate
that something unusual is probably going on with Se in HIV infections,
and that supplementation is likely to be necessary and beneficial,
at least in some cases. The question is, why? The following sections
briefly outline my theoretical findings that may help explain
some of the data reviewed above, as well as new clinical and experimental
results that appear to confirm the theoretical predictions. Note
that this is not intended to rule out other possible explanations
or factors that might also contribute to the observations, or
other mechanisms that contribute to HIV pathogenesis.
3.1 Se, HIV and AIDS: the "Viral selenoprotein theory".
On Aug. 19th, 1994 (coincidentally, the day Linus Pauling died;
he was the first to suggest antioxidants could be of benefit in
viral diseases), my group published a study of the predicted RNA
structure of HIV in relation to potential novel open reading frames
(protein coding regions) of the virus . This analysis demonstrated
the potential for several new genes in HIV, that possibly encode
proteins containing selenocysteine (encoded in RNA by UGA codons,
which usually cause termination of protein synthesis). We also
identified the RNA structural features (e.g. pseudoknots) that
would be required for the expression of these genes. If active,
such genes would provide the basis of a role for Se in the biochemistry
and regulation of HIV.
Thus, we must seriously consider the possibility
that Se depletion may not only be a correlate of AIDS progression:
it may be directly involved in the mechanism by which HIV causes
AIDS. Virally-induced depletion of Se in HIV-infected cells, and
the potential existence of virally-encoded regulatory selenoproteins,
could help explain the increased susceptibility to oxidative stress
characteristic of AIDS. Various observations, some listed in sections
2.4-2.7, are highly consistent with this theory. The theory can
also potentially help explain the role of various cofactors that
stimulate HIV infection, since many infectious disease states
stimulate free radical formation, producing oxidative stress.
One source of confusion relates to the
question that, if the virus requires Se, why is it that a deficiency
of Se appears to be associated with increased viral replication,
and Se supplementation inhibits the virus (section 2.5), rather
than "feeding" the virus?
This is best understood by analogy to
a classical example of a nutrient effect on viral replication:
the well- documented induction of retrovirus expression in cells
cultured in arginine-deficient media. Note that arginine is an
essential component of most viral proteins. Thus, paradoxically,
in this case also viral replication appears to be triggered by
a deficiency of something the virus requires. This would most
likely involve some sort of repressor type of mechanism, analogous
to known situations in bacteria, like the famous tryptophan repressor.
Based on the data that I have reviewed here, it seems quite possible
that viruses like HIV and coxsackie B3 may respond to Se deficiency
by a mechanism analogous to that involved in this arginine effect.
Note that a viral glutathione peroxidase enzyme might also have
a repressive effect on viral replication, because it is known
that oxidative stress (e.g. H2O2 exposure) activates the replication
of HIV and other viruses: a viral glutathione peroxidase would
reduce oxidant tone, this reducing viral activation.
This is highly significant because genes
apparently encoding a selenium-dependent glutathione peroxidase
(the prototypical selenoprotein) have now been identified in several
viruses, including HIV-1 and hepatitis C virus (see sections 3.2,
3.4.3, 3.4.6, and 3.4.7). A virally encoded glutathione peroxidase
could also help a virus defend against free radical mediated attacks
on infected cells by the immune system, and also increase the
extracellular viability of virus particles in the blood stream,
because without that enzyme, enveloped virions are more susceptible
to membrane lipid peroxidation once they have budded off the host
cell and lost the benefit of cellular antioxidant defenses.
3.2 Potential selenoprotein genes in other viruses: Coxsackie
B3, Ebola Zaire, M. contagiosum, and Hepatitis C Virus.
A similar analysis has now been applied to a number of other viruses,
yielding consistent and surprising results. There is strong theoretical
evidence that similar Se-utilizing genes may exist in coxsackievirus
B3 (CVB3), the same strain studied by Beck et al. as a model for
Keshan disease (section 2.8.2), and that one of these appears
to encode a highly truncated glutathione peroxidase module. These
theoretical results regarding CVB3 have been outlined in several
A striking example of potential selenoprotein
genes in a virus is provided by the highly pathogenic Zaire strain
of Ebola virus, where one such potential gene has 16 UGA selenocysteine
codons, as well as potential structural features that might be
involved in expression of this selenoprotein, which would require
16 Se atoms per molecule [48,49]. This suggests that infection
with Ebola Zaire may place an unprecedented demand for Se on the
host, potentially causing a more drastic Se depletion in a matter
of days than HIV infection can accomplish in 10 years. Significantly,
this potential gene and related structural features are absent
in the Ebola Reston strain, which was essentially non-virulent
in humans. A potential role for Se is highly consistent with key
aspects of Ebola pathology , including its effects on Se-rich
tissues like blood cells and liver, and the hemorrhaging due to
rupture of capillaries obstructed by blood clots (because Se normally
plays a role in inhibiting clotting , and Se deficiency has
been associated with thrombosis and even hemorrhaging in extreme
cases in animals). However, the experimental investigations required
to confirm this theoretical possibility have not been performed.
Nor have indicators of Se status and lipid
peroxidation ever been examined in Ebola patients. However, there
are some compelling clinical results: Se has apparently been used
with considerable success by the Chinese in the palliative treatment
of viral hemorrhagic fever caused by Hantaan virus infection.
In an outbreak involving 80 patients, oral sodium selenite at
2 mg. per day for 9 days was used to achieve a dramatic reduction
in the overall mortality rate, which fell from 38% (untreated
control group) to 7% (Se treatment group), thus giving an 80%
reduction in mortality . This result, obtained using Se at
a dose of about 13 times the RDA as the sole therapy, is all the
more striking in light of the fact that, according to conventional
medical science, there is no effective treatment for hemorrhagic
fever (viral infections with Ebola-like symptoms). Although this
did not involve Ebola virus, there are a number of different hemorrhagic
fever viruses, and they may share common mechanisms . This
example suggests that pharmacological doses of Se may also have
some benefit in infections due to other hemorrhagic fever viruses,
Less hypothetical is the recent identification
in a DNA virus of a gene that is an obvious homologue of the mammalian
selenoprotein glutathione peroxidase. In a paper published in
August 1996, the group of Dr. Bernard Moss from NIH published
their results on the newly sequenced genome of the pox virus Molluscum
contagiosum, where they identified a gene that is 76% identical
to glutathione peroxidase at the amino acid level . While
not yet confirmed by functional studies, the high degree of similarity
of this sequence to cellular homologues leaves little doubt that
this is a real gene (see section 3.4.3).
Unmistakable glutathione peroxidase modules
have now been identified by comparative sequence analysis in both
HIV-1 (one of the selenoprotein genes I predicted in 1994 ;
see section 3.4.6) and in hepatitis C virus (see section 3.4.7).
Thus, this antioxidant selenoprotein module may ultimately prove
to be a consitutent of a number of RNA and DNA viruses.
3.3 Endemic Kaposi's Sarcoma in Africa.
Recent work has implicated a new herpes virus in Kaposi's Sarcoma.
Ziegler has demonstrated a correlation between the incidence of
"endemic" Kaposi's Sarcoma in African subsistence farmers
and geographic regions with volcanic soils . Significantly,
it is well documented in the agricultural literature that plants
and animals raised on such soils are typically Se deficient, with
regions of Oregon and the East African Rift Valley often cited
as typical examples. The increased incidence of Kaposi's Sarcoma
in volcanic soil regions in Africa suggests a possible parallel
to Keshan disease: a disease with a viral cofactor associated
with geographic regions where plants may be low in Se.
3.4 Summary of key data consistent with predictions of the viral
Based on evidence that has emerged in the last few years, there
is now little reason to doubt that some viruses encode selenoproteins.
Recent developments and confirmations of the theoretical predictions
include the following:
3.4.1 My 1994 prediction
that Se levels should be a factor in disease progression in AIDS
 has now been amply confirmed in several recent papers, e.g.
Constans et al. (1995), "Serum selenium predicts outcome
in HIV infection" , as well as other current papers by
several groups (of course, these are only the most recent of a
series of over 20 papers published over the last decade documenting
Se depletion in HIV/AIDS; see section 2.4). Dr. Marianna Baum
of the Univ. of Miami has been studying nutrient abnormalities
in HIV/AIDS for some years, and had earlier reported such Se abnormalities
in several papers [21,26]. Her latest analysis of a cohort of
HIV+ IV drug users shows that low serum Se is 15 times higher
(more significant) than low CD4 count as a risk factor for mortality
. The pathology of muscle weakness in HIV infection (myopathy)
has also recently been associated with Se deficiency in AIDS .
Furthermore, Se has been shown to inhibit HIV in vitro by at least
two independent labs (see section 2.5).
3.4.2 The RNA pseudoknot
that I predicted overlapping the active site coding region of
HIV-1 reverse transcriptase has now been experimentally verified
by enzymatic and chemical stability studies, published in a recent
paper and thesis from Dr. Barbara Carter's group at Univ. of Toledo
3.4.3 My 1994 proposal
that some viruses may encode selenoproteins, initially received
with considerable skepticism, is no longer in doubt, although
it has yet to be definitively proved in the case of HIV. The most
indisputable example of a viral selenoprotein is the homologue
of glutathione peroxidase (GPx) recently identified by Moss and
coworkers in Molluscum contagiosum virus . My group has also
demonstrated GPx- related sequences in coxsackie B virus, the
cofactor in Keshan disease, a classical Se-deficiency disease
. More recently, we have shown that one of the potential selenoprotein
genes we predicted previously in HIV is a GPx homologue (see section
3.4.6), and we have now identified the same gene (GPx) in hepatitis
C virus (see section 3.4.7).
3.4.4 The growing body
of evidence that Se has apparent chemoprotective effects vs. a
number of viral infections including HIV was attested by and documented
in the recent conference on selenium and human viral diseases
held in Germany in April 1996, with proceedings (edited by G.
Schrauzer and L. Montagnier) published in a peer-reviewed journal,
Biological Trace Element Research (Vol. 56 #1).
3.4.5 In my lab, we have
now obtained firm in vitro evidence for a novel -1 frameshift
site associated with highly conserved UGA codons (potentially
encoding selenocysteine) in the HIV-1 nef gene coding region,
that we predicted previously [46,47]. Furthermore, Dr. Benjamin
Blumberg, a collaborating virologist at U. of Rochester Medical
Center, has obtained in vitro and immunocytochemical evidence
for the predicted nef variants in post- mortem HIV+ brain tissues
(where nef is overexpressed). This is particularly significant
because one of the reactive antisera was to a peptide located
downstream of a highly conserved UGA codon at the 3' terminal
of nef, proving that readthrough of that UGA codon MUST be
taking place, as we first proposed in 1994 . Most significantly,
the results of in vitro translation experiments show that this
event is Se-dependent: addition of small amounts of Se to the
medium greatly enhances the production of this novel HIV-1 gene
product, and 75Se incorporation in an isoform of the HIV nef protein
can be demonstrated .
3.4.6 In a recent paper
, we show that a potential selenoprotein that we previously
identified in HIV-1, overlapping the envelope gene coding region,
is in fact a homologue of glutathione peroxidase (GPx), the prototypical
eukaryotic selenoprotein. The sequence encoded in this HIV-1 gene
region contains a common variant of the GPx active site consensus
sequence, spanning the catalytic selenocysteine. The similarity
score of this novel HIV sequence vs. an aligned group of GPx sequences
is 5 standard deviations (SD) above the average similarity score
of randomized sequences of identical composition; thus, the probability
of obtaining this degree of similarity purely by chance is less
than one in a million. This gene has now been cloned for experimental
verification of GPx activity.
3.4.7 We have now identified
the same gene in hepatitis C virus (HCV), a very common infection
in the U.S. (about 1.5% or 4 million people are seropositive).
In both HIV and HCV the GPx gene is in the -1 reading frame overlapping
a known gene (the NS4a gene in the case of HCV), contains an in-frame
"stop" codon, UGA, that can also encode selenocysteine,
and also lacks an apparent start codon, thus explaining why these
genes have escaped detection up to now. The putative HCV GPx sequence
is highly similar to known GPx sequences; the similarity encompasses
the entire enzyme active site region, and is statistically significant
at 6.2 SD relative to random sequences of similar composition,
or 6.7 SD if compared only to the mammalian extracellular plasma
GPx enzymes (Taylor and Zhang, paper in preparation). The HCV
GPx (active site amino acid sequence VQVASPUGLLG) is most similar
to the human plasma GPx (active site sequence VNVASYUGLTG, where
U signifies the selenocysteine codon). The Se-dependent GPx sequence
and UGA codon are highly conserved in HCV genotype 1b, which is
predominant in North America. Significantly, genotype 1b is associated
with the highest risk of progression to cirrhosis and hepatocellular
carcinoma, and poor response to interferon. An HCV-encoded GPx
gene may help explain why oxidant stressors like alcoholism and
iron overload are associated with HCV disease progression. The
best direct evidence consistent with an HCV-Se link is the clinical
data of Look et al., who found that in HIV+ patients, the progressive
decline in Se levels characteristic of HIV infection was greater
in those with HCV co-infection, who "showed markedly lower
selenium concentrations compared to those without concomitant
4. Clinical implications
My theoretical findings
outlined in section 3 provide a new theory as to why Se
may be critical in HIV infection and other viral diseases - but
even before that theory was developed, there was already abundant
evidence supporting the idea that Se supplementation could be
of benefit to HIV-infected patients. Even if the HIV-selenoprotein
theory proves to be incorrect (which now seems very unlikely!),
the facts listed in section 2 cannot be denied. Thus, based
on currently available data, it seems advisable to seriously consider
some level of supplementation, at least as a precautionary measure.
However, patients are strongly advised to consult with their physicians
on this question, particularly if they are in a symptomatic stage
of the disease. It is important to realize that when we talk about
Se we are fundamentally talking about nutrition, not a drug. Furthermore,
some physicians already recommend the use of Se supplements to
their HIV-infected patients, and such recommendations can also
be found in literature published by various AIDS activist and
self-help groups, so this is nothing new or untried. In several
very brief clinical trials, symptomatic improvements in ARC and
AIDS were reported [12,16,19]. A leading US research group has
already completed preliminary studies for a new, double-blind,
placebo controlled clinical trial of Se supplementation in HIV
patients who are not Se deficient.
Because research has shown
that there are problems in nutrient absorption even in asymptomatic
HIV+ individuals, the suggestion has been made that HIV patients
need to take larger amounts of vitamins than uninfected individuals
to attain the same blood levels . Since the USDA states that
nutritional supplementation in the range of 50-200 mcg of Se daily
is safe and effective for healthy individuals, a dose of 400 mcg
seems reasonable for HIV infected individuals, if they do have
impaired absorption. For an AIDS patient who is demonstrably deficient
in Se, an even higher daily dose (up to 800 mcg) for a brief period
of time (say several weeks) to get their blood levels up, followed
by a decrease to 400 mcg, is an effective strategy that was used
in one published clinical study involving AIDS patients .
This question of dose
level naturally arouses concerns, because in the past so much
has been made of the potential toxicity of Se. I believe that
the danger of serious toxicity with Se supplementation has been
exaggerated. The threat of serious acute toxicity with
supplementation is in my opinion nonexistent at doses less than
1000 mcg per day, and in several studies people in certain geographical
locations have been shown to be ingesting from 600 to over 700
mcg per day for extended periods of time without evidencing any
ill effects - in northern Greenland, as much as 1000 mcg per day
in some individuals. Thus, doses in the 400 mcg range are undoubtedly
safe. In any case, the signs of chronic Se toxicity - garlic odor
of breath and sweat, metallic taste in mouth, brittle hair and
fingernails - are very distinctive, and easily reversed by lowering
In regard to Se and viral
diseases in general, I find myself in the position of Linus Pauling
in regard to the anticancer and antiviral benefits of vitamin
C: I believe that there is a sufficient body of clinical and basic
research data to support the conclusion that Se has not only anticancer
benefits, but also chemoprotectant effects vs. a broad spectrum
of viral infections. Furthermore, Se may have not only preventive,
but also therapeutic potential in active viral infections - even
some that can be acutely lethal - because the life-saving benefits
of a brief course of treatment with reasonable pharmacological
doses (i.e. in the milligrams per day range) have been demonstrated
in at least one case . The full potential of Se therapy in
the treatment of HIV infections has yet to be rigorously assessed
in a large-scale study.
Considering that Se deficiency
is associated with increased incidence of various cancers, and
increased morbidity and mortality due to infectious diseases like
AIDS, we must seriously consider evidence suggesting that there
may be a global trend towards a decrease of Se in the food chain,
caused by various factors, including modern agricultural practices,
fossil fuel burning and acid rain (primarily because SO2 reacts
with Se compounds in soil, forming elemental Se that plants cannot
absorb ). Studies have shown that Se levels in the British
diet have decreased by almost 50% over the last 22 years .
If dietary Se levels have decreased so drastically over 22 years
in Britain, a wealthy and highly developed nation, then what is
the situation in rapidly developing Third World countries? In
light of the evidence showing that Se deficiency is associated
with adverse outcomes in viral infections, and can foster the
emergence of more virulent viral strains, any localized or global
depletion of Se in the food chain could be a significant factor
contributing to our increased susceptibility to emerging viral
diseases, as well as to recent increases in cancer mortality rates
in developed nations.
5. Final comments
A considerable body of
evidence supports the hypothesis that some viruses may encode
selenoproteins. Much of the evidence at present is still theoretical.
We have found potential selenoproteins encoded in HIV and other
retroviruses, some strains of coxsackievirus, definitely in hepatitis
C virus, and possibly in Ebola Zaire, hepatitis B, and several
human herpes viruses [1,34,46-49,56,57]. A similar theoretical
analysis by an independent research group has revealed an unmistakable
glutathione peroxidase gene in the human pox virus, M. contagiosum
. At least in the case of coxsackievirus, there is substantial
in vivo evidence that Se plays a role in regulating viral pathogenicity
[2,45]. The evidence for Se deficiency as a high risk factor for
HIV disease progression and mortality is now very strong [29,31,54,58,62],
and there is firm evidence that Se compounds can inhibit HIV cytopathicity
and the activation of HIV by oxidative stress (section 2.5). Although
such results do not prove that Se inhibits HIV by the mechanism
I have proposed (i.e. that viral selenoproteins are involved),
they are highly consistent with the predictions of the theory.
Our recent identification of a glutathione peroxidase homologue
in HIV-1  leaves little room for doubt that a direct interaction
between HIV and Se can occur, particularly since the same gene
has now been identified in several other viruses.
Despite all the compelling
evidence regarding a central role for oxidative stress in HIV
activation and AIDS pathogenesis, no one has previously explained
how the virus produces the well-documented "HIV-1
mediated antioxidant imbalance" . Nothing could be simpler
than the depletion of Se in infected cells due to the formation
of virally-encoded selenoproteins, the mechanism I have proposed.
Two of the potential selenoprotein
genes that we identified in HIV have now been cloned, and experimental
evidence of their function, if any, should be available in the
Let me conclude with a
quote from Dworkin's 1994 paper :
may be associated with myopathy, cardiomyopathy and immune dysfunction
including oral candidiasis, impaired phagocytic function and decreased
To that I would add: hypothyroid
(low T3) syndrome, increased risk of thrombosis , and psoriasis
. Do any of those symptoms sound familiar? Think about it...
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