References

201. Reactive oxygen species and nitric oxide in viral diseases.
Peterhans E
Institute of Veterinary Virology, University of Berne, Switzerland. peterhans@ivv.unibe.ch
Biol Trace Elem Res, 1997 Jan, 56:1, 107-16

Metabolites derived from superoxide (O2.-) and nitric oxide (NO.) play an important role in antimicrobial and antitumoral defense, but may also harm the host. Low levels of such metabolites can also facilitate viral replication because of their mitogenic effects on cells. Most viruses grow better in proliferating cells, and indeed, many viruses induce in their host cell changes similar to those seen early after treatment with mitogenic lectins. Influenza and paramyxo-viruses activate in phagocytes in the generation of superoxide by a mechanism involving the interaction between the viral surface glycoproteins and the phagocyte's plasma membrane. Interestingly, viruses that activate this host defense mechanism are toxic when injected in the bloodstream of animals. Mice infected with influenza virus undergo oxidative stress. In addition, a wide array of cytokines are formed in the lung, contributing to the systemic effects of influenza. Oxidative stress is seen also in chronic viral infections, such as AIDS and viral hepatitis. Oxidant production in viral hepatitis may contribute to the emergence of hepatocellular carcinoma, a tumor seen in patients after years of chronic inflammation of the liver. Antioxidants and agents that downregulate proinflammatory cytokines and lipid mediators may be a useful complement to specific antiviral drugs in the therapy of viral diseases.

202. Dietary oxidative stress and the potentiation of viral infection.
Beck MA; Levander OA
Frank Porter Graham Child Development Center, University of North Carolina, Chapel Hill
27599-8180, USA. melinda_beck@unc.edu
Annu Rev Nutr, 1998, 18:, 93-116

Oxidative stress is implicated in the pathogenesis of several viral infections, including hepatitis, influenza, and AIDS. Dietary oxidative stress due to either selenium or vitamin E deficiency increases cardiac damage in mice infected with a myocarditic strain of coxsackievirus B3. Such dietary oxidative stress also allows a normally benign (i.e., amyocarditic) coxsackievirus B3 to convert to virulence and cause heart damage. This conversion to virulence is due to a nucleotide sequence change in the genome of the benign virus, which then resembles more closely the nucleotide sequence of virulent strains. Although it has been known for many years that poor nutrition can affect host response to infection, this is the first report of host nutrition affecting the genetic sequence of a pathogen. Further research is needed to determine whether poor host nutrition plays any role in the emergence of new viral diseases via alterations in he genotype of an infectious agent.

203. Interferon/antioxidant combination therapy for chronic hepatitis C--a controlled pilot trial.
Look MP; Gerard A; Rao GS; Sudhop T; Fischer HP; Sauerbruch T; Spengler U
Department of General Internal Medicine, University of Bonn, Germany. look@uni-bonn.de
Antiviral Res, 1999 Sep, 43:2, 113-22

The effects of two forms of antioxidative co-therapy were analyzed in 24 interferon-alpha (IFN)-naive patients with chronic hepatitis C who were randomized to either receive IFN monotherapy (3 x 4.5 million units IFN-alpha 2a per week), (group A), or IFN and N-acetylcysteine (N-acetylcysteine (NAC) 1.800 mg/day) plus sodium selenite (400 microg/day) supplementation (group B), or treatment as in group B plus vitamin E (544 IU/day) (group C), over 24 weeks. Changes in histology, normalization of ALT, reduction of viral RNA, serum levels of glutathione, selenium, vitamin E, erythrocyte glutathione peroxidase, trolox equivalent antioxidative capacity (TEAC), thiobarbituric acid reactive substances (TBARS) and protein carbonyl groups were measured. Low baseline TEAC and elevated TBARS indicated increased oxidative stress before therapy, which was not affected by antioxidant supplementation. At the end of treatment complete responses were found in 3/8, 2/8 and 6/8 patients in groups A, B and C, respectively, but liver histology had not significantly improved. Vitamin E treated patients had a 2.4 greater chance (95% CI: 1.05-5.5) of obtaining a complete response and had significantly greater reduction in viral load (P = 0.028) than patients without vitamin E. Relapses, i.e. re-appearance of detectable hepatitis C virus (HCV) RNA and/or re-elevation of ALT-activity occurred in 7 out of the 11 responders within 6 months after termination of therapy (group A: 2/3, group B: 1/2 and group C: 4/6). Thus, no overall beneficial effect of antioxidant/IFN therapy was detected. However, the apparent trend towards a more favorable outcome with vitamin E supplementation warrants to further study this substance as an adjuvant to IFN therapy in chronic hepatitis C.

204. Alcohol and cancer.
Seitz HK; Pöschl G; Simanowski UA
Laboratory of Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, Heidelberg, Germany.
Recent Dev Alcohol, 1998, 14:, 67-95

A great number of epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx, and the esophagus, and for the liver. In contrast to those organs, the risk by which alcohol consumption increases cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumors, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers are controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen, but under certain experimental conditions is a cocarcinogen and/or (especially in the liver) a tumor promoter. The metabolism of ethanol leads to the generation of acetaldehyde and free radicals. These highly reactive compounds bind rapidly to cell constituents and possibly to DNA. Acetaldehyde decreases DNA repair mechanisms and the methylation of cytosine in DNA. It also traps glutathione, an important peptide in detoxification. Furthermore, it leads to chromosomal aberrations and seems to be associated with tissue damage and secondary compensatory hyperregeneration. More recently, the finding of considerable production of acetaldehyde by gastrointestinal bacteria was reported. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P4502E1, associated with an enhanced activation of various procarcinogens present in alcoholic beverages, in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens, alterations in cell cycle behavior such as cell cycle duration leading to hyperregeneration, nutritional deficiencies such as methyl, vitamin A, folate, pyrridoxalphosphate, zinc and selenium deficiency, and alterations of the immune system, eventually resulting in an increased susceptibility to certain viral infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms in the upper gastrointestinal tract and in the rectum may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Thus, all these mechanisms, functioning in concert, actively modulate carcinogenesis, leading to its stimulation.

205. Selenium-dependent glutathione peroxidase modules encoded by RNA viruses.
Zhang W, Ramanathan CS, Nadimpalli RG, Bhat AA, Cox AG, Taylor EW
Biol Trace Elem Res 1999 Nov;70(2):97-116

Computational Center for Molecular Structure and Design, and Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens 30601-2352, USA.Glutathione peroxidase (GPx) is the prototypical eukaryotic selenoprotein, with the rare amino acid selenocysteine (Sec) at the enzyme active site, encoded by the UGA codon in RNA. A DNA virus, Molluscum contagiosum, has now been shown to encode a functional selenium-dependent Gpx enzyme. Using modifications of conventional sequence database searching techniques to locate potential viral GPx modules, combined with structurally guided comparative sequence analysis, we provide compelling evidence that Se-dependent GPx modules are encoded in a number of RNA viruses, including potentially serious human pathogens like HIV-1 and hepatitis C virus, coxsackievirus B3, HIV-2, and measles virus. Analysis of the sequences of multiple viral isolates reveals conservation of the putative GPx-related features, at least within viral subtypes or genotypes, supporting the hypothesis that these are functional GPx modules.

206. Biol Trace Elem Res 1989 Apr-May;20(1-2):15-22
Chemoprevention trial of human hepatitis with selenium supplementation
in China.
Yu SY, Li WG, Zhu YJ, Yu WP, Hou C
Cancer Institute Chinese Academy of Medical Sciences, Beijing.

A three-year study has been conducted for prevention of infectious hepatitis with supplementation of table salt fortified with 15 ppm anhydrous sodium selenite to the general population of 20,847 persons in a township M.Z. at Qidong County, Jiangsu Province, China. The results showed that the incidence of virus hepatitis infection in the test township was significantly lower than that of controls provided with normal table salt. The incidence rate of infectious hepatitis in the treated township M.Z. was 1.20 and 4.52 per 1,000, whereas the average incidence in the 6 surrounding control townships was 2.96 and 10.48 per 1,000 in 1986 and 1987, respectively. The incidence of hepatitis B surface antigen (HBsAg+) was 13.2% vs 19.23% for males and 10.42% vs 12.24% for females in the supplemented vs nonsupplemented neighboring township, respectively. Epidemiological studies have demonstrated that a low grain Se content is associated with a high regional incidence of hepatitis B virus infections.

OBJECTIVE: To determine the independent contribution of specific nutritional factors on disease progression and survival in HIV-1-infected children. POPULATION: HIV-infected children (N = 24), who were perinatally exposed to the virus and symptomatic, were recruited between October and December of 1990 from the Jackson Memorial Pediatric Immunology Clinic, Miami, Florida, and observed for 5 years. METHODS: Immune status was measured by CD4 cell count; nutritional status was determined using serum albumin and plasma trace elements including iron, zinc, and selenium. Cox proportional hazards regression models were used to evaluate the relationship of these parameters to survival. Use of antiretroviral treatment was considered in the statistical model, and age at death was considered a parameter of disease progression. RESULTS: Over the course of the study, 12 children died of HIV-related causes. The final Cox multivariate analysis indicated that, of the variables evaluated, only CD4 cell count below 200 (risk ratio [RR] = 7.05; 95% confidence interval [CI], 1.87-26.5); p = .004], and low levels of plasma selenium (RR = 5.96; 95% CI, 1.32-26.81; p = .02) were significantly and independently related to mortality. Among the children who died, those with low selenium levels (< or =85 microg/L), died at a younger age, suggesting more rapid disease progression. CONCLUSIONS: In pediatric HIV-infection, low plasma level of selenium is an independent predictor of mortality, and appears to be associated with faster disease progression.

209. High risk of HIV-related mortality is associated with selenium deficiency.
J Acquir Immune Defic Syndr Hum Retrovirol 1997 Aug
Baum MK, Shor-Posner G, Lai S, Zhang G, Lai H, Fletcher MA, Sauberlich H, Page JB
Department of Psychiatry and Behavioral Sciences, University of Miami, School of Medicine, Florida 33136, U.S.A.

To determine the independent contribution of specific immunologic and nutritional factors on survival in HIV-1 disease, CD4 cell count, antiretroviral treatment, plasma levels of vitamins A, E, B6, and B12 and minerals selenium and zinc were considered in relation to relative risk for HIV?related mortality. Immune parameters and nutrients known to affect immune function were evaluated at 6?month intervals in 125 HIV-1-seropositive drug-using men and women in Miami, FL, over 3.5 years. A total of 21 of the HIV-1-infected participants died of HIV-related causes during the 3.5-year longitudinal study. Subclinical malnutrition (i.e., overly low levels of prealbumin, relative risk [RR] = 4.01, p < 0.007), deficiency of vitamin A (RR = 3.23, p < 0.03), vitamin B12 deficiency (RR = 8.33, p < 0.009), zinc deficiency (RR = 2.29.1, p < 0.04), and selenium deficiency (RR = 19.9, p < 0.0001) over time, but not zidovudine treatment, were shown to each be associated with HIV-1-related mortality independent of CD4 cell counts <200/mm3 at baseline, and CD4 counts over time. When all factors that could affect survival, including CD4 counts <200/mm3 at baseline, CD4 levels over time, and nutrient deficiencies were considered jointly, only CD4 counts over time (RR = 0.69, p < 0.04) and selenium deficiency (RR = 10.8, p < 0.002) were significantly associated with mortality. These results indicate that selenium deficiency is an independent predictor of survival for those with HIV-1 infection.

210. Micronutrient status in relationship to mortality in HIV-1 disease.
Nutr Rev 1998 Jan;56(1 Pt 2):S135-9
Baum MK, Shor-Posner G
University of Miami School of Medicine, USA.

Selenium deficiency has been demonstrated to be a significant predictor of HIV-related mortality, independent of CD4 over time, CD4 < 200 at baseline, and antiretroviral treatment. Although selenium deficiency in healthy humans is relatively rare (Cohen et al. 1989, Lockitch, 1989), a number of studies have documented a decline in plasma selenium levels and decreased glutathione peroxidase activity in individuals with HIV/AIDS (Dworkin et al. 1988, Cirelli et al. 1991, Mantero-Atienza et al. 1991, Staal et al. 1992, Allavena et al. 1995). These findings are of particular concern in light of selenium's influence on immune function, viral replication, and survival. As recent investigations (Delmas-Beauvieux et al. 1996) indicate that supplementation with selenium may help to increase the enzymatic defense systems in HIV-infected patients, further studies to determine possible mechanisms and clinical trials to evaluate the effect of selenium supplementation on HIV disease progression are essential.