|Selenium and Mutations|
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Selenium supplementation suppresses tumor necrosis factor alpha-induced human immunodeficiency virus type 1 replication in vitro
Selenium is a nutritionally essential trace element that is important for optimal function of the immune system, It is incorporated into selenoproteins as the amino acid selenocysteine and it is known to inhibit the expression of some viruses, In this study, we show that selenium supplementation for 3 days prior to exposure to tumor necrosis factor alpha (TNF-alpha) partially suppresses the induction of human immunodeficiency virus type 1 (HIV-1) replication in both chronically infected T lymphocytic and monocytic cell lines, In acute HIV-1 infection of T lymphocytes and monocytes in the absence of exogenous TNF-alpha, the suppressive effect of selenium supplementation was not observed, However, selenium supplementation did suppress the enhancing effect of TNF-alpha on HIV-1 replication in vitro in acutely infected human monocytes, but not in T lymphocytes, Selenium supplementation also increased the activities of the selenoproteins, glutathione peroxidase (GPx) and thioredoxin reductase (TR), which serve as cellular antioxidants, Taken together, these results suggest that selenium supplementation may prove beneficial as an adjuvant therapy for AIDS through reinforcement of endogenous antioxidative systems.Author(s): Hori K (REPRINT) ; Hatfield D; Maldarelli F; Lee BJ; Clouse KA
Journal: AIDS RESEARCH AND HUMAN RETROVIRUSES, 1997, V13, N15 (OCT 10), P
Increased virulence of coxsackievirus B3 in mice due to vitamin E or selenium deficiency
Nutrition has long been known to affect the ability of the host to respond to infectious disease. Widespread famines are often accompanied by increased morbidity and mortality due to infectious diseases. The currently accepted view of the relationship between nutrition of the host and its susceptibility to infectious disease is one of a direct relationship with host immune status. That is, if the nutritional status of the host is poor-due to either single or multiple nutrient deficiencies-then the functioning of the host immune system is compromised. This impairment of the immune response will lead to an increased susceptibility to infectious disease. Clearly, the immune response has been shown to be weakened by inadequate nutrition in many model systems and in human studies. However, what about the effect of host nutrition on the pathogen itself? Our laboratory has shown, using a mouse model of coxsackievirus-induced myocarditis, that a host deficiency in either selenium or vitamin E leads to a change in viral phenotype, such that an avirulent strain of the virus becomes virulent and a virulent strain becomes more virulent. The change in phenotype was shown to be due to point mutations in the viral genome. Once the mutations occur, the phenotype change is stable and can now be expressed even in mice of normal nutriture. Our results suggest that nutrition can affect not only the host, but the pathogen as well, and demonstrate a new model of relating host nutritional effects to viral pathogenesis.
Author(s): Beck MA
Journal: JOURNAL OF NUTRITION, 1997, V127, 5 (MAY), PS966-S970
Interacting nutritional and infectious etiologies of Keshan disease- Insights from Coxsackie virus B-induced myocarditis in mice deficientin selenium or vitamin E
In 1979, Chinese scientists reported that selenium had been linked to Keshan disease, an endemic juvenile cardiomyopathy found in China. However, certain epidemiological features of the disease could not be explained solely on the basis of inadequate selenium nutrition. Fluctuations in the seasonal incidence of the disease suggested involvement of an infectious agent. Indeed, a coxsackievirus B4 isolated from a Keshan disease victim caused more heart muscle damage when inoculated into selenium-deficient mice than when given to selenium-adequate mice. Those results led us to study the relationship of nutritional status to viral virulence. Coxsackievirus B3/0 (CVB3/0), did not cause disease when inoculated into mice fed adequate levels of
Se and vitamin E. However, mice fed diets deficient in either Se or vitamin E developed heart lesions when infected with CVB3/0. To determine if the change in viral phenotype was maintained, we passaged virus isolated from Se-deficient hosts, designated as CVB3/0 Se-, back into Se-adequate hosts. The CVB3/0 Se- virus caused disease in Se-adequate mice. To determine if the phenotype change was due to changes in the viral genome, we sequenced viruses isolated from Se-deficient mice and compared them with the input CVB3/0 virus. Six point mutations differed between the parent strain and the recovered
CVB3/0 Se- isolates. When the experiment was repeated using vitamin E-deficient mice, the same 6 point mutations were found. This is the first report of a specific host nutritional deficiency altering viral genotype. Keshan disease may be the result of several interacting causes including a dominant nutritional deficiency (selenium), other nutritional factors (vitamin E, polyunsaturated fatty acids), and an infectious agent (virus).
Author(s): Levander OA; Beck MA
Journal: BIOLOGICAL TRACE ELEMENT RESEARCH, 1997, V56, N1 (JAN), P5-21
Genomic structures of viral agents in relation to the biosynthesis of selenoproteins
The genomes of both bacteria and eukaryotic organisms are known to encode selenoproteins, using the UGA codon for elenocysteine (SeC), and a complex cotranslational mechanism for SeC incorporation into polypeptide chains, involving RNA stem-loop structures. These common features and similar codon usage strongly suggest that this is an ancient evolutionary development. However, the possibility that some viruses might also encode selenoproteins remained unexplored until recently. Based on an analysis of the genomic structure of the human immunodeficiency virus HIV-1, we demonstrated that several regions
overlapping known HIV genes have the potential to encode selenoproteins (Taylor et al. , J. Med. Chem. 37, 2637-2654 ). This is provocative in the light of overwhelming evidence of a role for oxidative stress in AIDS pathogenesis, and the fact that a number of viral diseases have been linked to selenium (Se) deficiency, either in humans or by in vitro and animal studies. These include HIV-AIDS, hepatitis B Linked to liver disease and cancer, Coxsackie virus B3, Keshan disease, and the mouse mammary tumor virus (MMTV), against which Se is a potent chemoprotective agent. There are also established biochemical mechanisms whereby extreme Se deficiency can induce a proclotting or hemorrhagic effect, suggesting that hemorrhagic fever viruses should also be examined for potential virally encoded selenoproteins. Ln addition to the RNA stem-loop structures required for SeC insertion at UGA codons, genomic structural features that may be required for selenoprotein synthesis can also include ribosomal frameshift sites and RNA pseudoknots if the potential selenoprotein module overlaps with another gene, which may prove to be the rule rather than the exception in viruses. One such pseudoknot that we predicted in HIV-1 has now been verified experimentally; a similar structure can be demonstrated in precisely the same location in the reverse transcriptase coding region of hepatitis B virus. Significant new findings reported here include the existence of highly distinctive glutathione peroxidase (GSH-Px)-related sequences in Coxsackie B viruses, new theoretical data related to a previously proposed potential selenoprotein gene overlapping the HIV protease coding region, and further evidence in support of a novel frameshift site in the HIV nef gene associated with a well-conserved UGA codon in the -1 reading frame.
Author(s): Taylor EW (REPRINT) ; Nadimpalli RG; Ramanathan CS
Journal: BIOLOGICAL TRACE ELEMENT RESEARCH, 1997, V56, N1 (JAN), P63-91
Selenium and cellular-immunity. Evidence that selenoproteins may be encoded in the +1 reading frame overlapping the human CD4, CD8, and HLA-DR genes
Selenium deficiency can lead to impaired immune function and reduced T-cell counts, as well as various specific disorders.
Significantly, in ARC and AIDS patients, a progressive decline in plasma Se, paralleling T-cell loss, has been widely documented. Since evidence now suggests that there is an extremely high turnover of CD4+ T-cells in AIDS patients, with billions of new cells lost and replaced daily, any exceptional requirement for Se in lymphocytes could contribute to this progressive Se depletion. Thus, it may be significant that, overlapping the known genes in the +1 reading frame, the mRNAs of several T-cell associated genes (CD4, CD8, HLA-DR p33) have open reading frames (ORFs) with as many as 10 in-frame UGA codons (CD4, p33), a clustering that is highly improbable by chance alone, and reminiscent of selenoprotein P, the predominant plasma form of Se. The presence of these ORFs, along with potential stem-loop RNA structures
displaying consensus selenocysteine insertion sequences, AUG(N)(m)AAA(N)(n)UGR, suggests that these mRNAs may encode
selenoproteins, in addition to the known T-cell glycoproteins. If so, the roles of Se in the immune system may be more diverse than previously suspected.
Author(s): TAYLOR EW
Journal: BIOLOGICAL TRACE ELEMENT RESEARCH, 1995, V49, N2-3 (AUG-SEP), P
Rapid genomic evolution of a nonvirulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates
Previous work from our laboratory demonstrated that selenium deficiency in the mouse allows a normally benign (amyocarditic) cloned and sequenced Coxsackievirus to cause significant heart damage. Furthermore, Coxsackievirus recovered from the hearts of selenium-deficient mice inoculated into selenium-adequate mice still induced significant heart damage, suggesting that the amyocarditic Coxsackievirus had mutated to a virulent phenotype. Here we report that sequence analysis revealed six nucleotide changes between the virulent virus recovered from the selenium-deficient host and the avirulent input virus. These nucleotide changes are consistent with known differences in base composition between virulent and avirulent strains
of Coxsackievirus. To the best of our knowledge, this is the first report of a specific nutritional deficiency driving changes in a viral genome, permitting an avirulent virus to acquire virulence due to genetic mutation.
Author(s): BECK MA; SHI Q; MORRIS VC; LEVANDER OA
Journal: NATURE MEDICINE, 1995, V1, N5 (MAY), P433-436
Increased virulence of a human enterovirus (coxsackievirus B3) in selenium deficient mice
Coxsackievirus B3 (CVB3/20)-induced myocarditic lesions occurred more quickly and were more severe and virus titers in heart and liver were higher in selenium (Se)-deficient than Se-adequate mice. NK cell activity and serum neutralizing antibody titers were similar in both Se-adequate and -deficient CVB3/20-infected mice; however, lymphocyte proliferation to both mitogen and antigen was decreased in Se-deficient mice. CVB3/20 isolated from Se-deficient donor mice and inoculated into
Se-adequate recipient mice induced severe myocarditis. In contrast, CVB3/20 isolated from Se-adequate donor mice and inoculated into Se-adequate recipient mice induced only moderate myocarditis, similar to that caused by the original virus stock. Thus, the general population of CVB3/20 virions, as a consequence of replicating in an Se-deficient host, underwent a phenotypic change to increased virulence. These results have important implications for the emergence of virulent viruses.
Author(s): BECK MA; KOLBECK PC; SHI Q; ROHR LH; MORRIS VC; LEVANDER OA
Journal: JOURNAL OF INFECTIOUS DISEASES, 1994, V170, N2 (AUG), P351-357