Background
Nutritional deficiencies have long been recognized as an important problem among HIV-1-seropositive individuals, particularly in resource-limited settings [
1]. Micronutrient deficiencies have been associated with more rapid HIV-disease progression and higher HIV-1 related mortality [
2,
3]. In some studies, micronutrient supplementation has delayed time to AIDS and improved survival, suggesting that supplementation could offer a simple and relatively inexpensive strategy to slow HIV-1 progression [
4,
5].
Selenium is an antioxidant micronutrient that is an essential element of selenoproteins, including selenoprotein P and glutathione peroxidase. Among HIV-1-seropositive individuals, lower serum selenium concentrations have been associated with lower CD4 counts, more advanced HIV-1 disease, and greater HIV-1 related mortality [
6‐
10]. However, most studies have not controlled for low serum albumin, which binds non-specifically to selenium in serum, or for the presence of an acute phase response, which alters hepatic production of albumin and other serum proteins [
11,
12]. We sought to determine whether serum selenium was independently associated with CD4 count or plasma viral load after adjusting for serum albumin and the presence of an acute phase response.
Discussion
In this cross-sectional study of HIV-1-seropositive women, low serum selenium was independently associated with serum albumin and with the acute phase response, but not with CD4 count or plasma viral load. Further prospective studies may help determine whether associations between low serum selenium and low CD4 count [
6,
9] and more advanced HIV-1 disease [
10] could be related to the frequent occurrence of hypoalbuminemia and the acute phase response in people with advanced HIV-1 infection.
Several ingested forms of selenium, including selenomethionine, bind non-specifically to albumin for transport to the liver [
11,
18‐
21]. The liver converts these compounds into selenocysteine, which is used to form various selenoproteins. In total, approximately 55% of selenium in human serum exists in selenoprotein P, another 17–32% exists bound to albumin, mostly in the form of selenomethionine, and only 10% of serum selenium is not protein bound [
11,
18,
21]. Since low serum albumin has been independently associated with faster HIV-1 disease progression and higher mortality, low serum selenium may simply reflect a decline in serum albumin among people with more active or advanced HIV-1 disease [
6,
23].
The presence of an acute phase response is typically associated with a decrease of serum albumin and other plasma proteins [
12]. Among HIV-1-seropositive individuals, the acute phase response has also been associated with low serum selenium and with HIV-1 disease progression and mortality [
6,
24]. One study found that CRP predicts mortality in HIV-1-infected women independent of serum albumin [
25]. Our results suggest that the observed univariate associations between serum selenium and the acute phase response may have been due, at least in part, to decreased hepatic production of albumin and other plasma proteins in HIV-1-seropositive individuals with an acute phase response [
18,
22]. There may also be a redistribution of selenium from serum and liver to muscle tissue during an acute phase response [
22].
Our study builds on previous analyses by examining the relationship between serum selenium concentrations, CD4 count, and plasma HIV-1 viral load in a large cohort of untreated HIV-1-seropositive adults. The size of this study enhanced our ability to conduct detailed multivariate analyses, which demonstrate the lack of a significant independent association between selenium and CD4 cell count or plasma viral load.
We have previously published the results of the micronutrient supplementation trial in which these women received six weeks of either a supplement containing B vitamins, vitamin C, vitamin E, and selenium or an identical placebo [
13]. Following supplementation, women who received the supplement had slightly higher CD4 counts compared to those who received placebo, an effect that was also observed in a trial of an otherwise identical supplement that did not contain selenium [
5]. It is not possible to disentangle the independent effects of selenium from the known effects of those other micronutrients that were provided in the same supplement. Thus, we were unable to use those longitudinal data to evaluate the associations between selenium supplementation and albumin, CD4 count, and plasma viral load.
The findings presented here should be interpreted in the context of the limitations of this study. Although cross-sectional studies are useful to define associations, it is not possible to infer with certainty that low albumin or the acute phase response were the cause of low measured serum selenium, although this relationship seems plausible because a large proportion of serum selenium is protein bound [
18,
22]. Regardless of the mechanism, the confounding bias demonstrated by our analyses was strong enough to nullify highly significant univariate associations between serum selenium and CD4 count and plasma viral load. However, these data cannot rule out the possibility that low serum selenium or a low antioxidant status was the cause of low serum albumin. Furthermore, because hypoalbuminemia may influence the relationship between serum selenium and total body selenium status, the measured serum selenium may not accurately reflect total body selenium in advanced HIV-1 infection. Data on dietary selenium intake were not collected in this population. Finally, because this study included only women, these results may not be generalizable to HIV-1-seropositive men.
The finding that serum selenium is not independently associated with CD4 count or plasma viral load may help to explain the results of small randomized and non-randomized trials of selenium supplementation among HIV-1-seropositive individuals. While one study found an increase in CD4/CD8 ratio after 12 weeks [
26], none have demonstrated significant effects on the absolute CD4 cell count or plasma viral load [
10,
26,
27]. However, a beneficial effect of selenium supplementation that is independent of CD4 count and plasma viral load is possible. In one randomized trial, selenium supplementation decreased hospital admissions due to infections among HIV-1 infected adults [
28]. The trial did not report changes in biological markers of HIV-1 disease progression or the effect on HIV-1-related mortality.
Acknowledgements
This research was supported by National Institutes of Health grants AI43844 and AI39996, and University of Washington Clinical Nutrition Research Unit grant DK35816. JM Baeten was supported by the Fogarty International Center (FIC) grant D43-TW00007. RS McClelland was supported by FIC D43-TW00007 and by K23-AI52480. PK Drain was supported by the David E. Rogers Fellowship of The New York Academy of Medicine.
The authors wish to acknowledge the excellent work and valuable contributions made to this study by our clinic (Mary Wamugunda, Virginia Njuki, and Florence Murigi) and laboratory staff (Bhavna Chohan, Khamis Mwinyikai, Amina Abdalla, Gladwell Maina, Sandra Emery, and Dana Panteleeff). Del Landicho provided assistance with nutritional testing performed at the University of Washington's Clinical Nutrition Research Unit. We thank Coast Provincial General Hospital for allowing us to use their clinical facilities. Finally, we would like to express our gratitude to the women who participated in this study, without whose time and effort this research would not have been possible.
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
PKD, JMB, KM, JON, and RSM designed the study. LL, JMB, KM and RSM collected data and provided study oversight. PKD and RSM analyzed data. PKD, JMB, JO, MHW, DDB, and RSM interpreted the results. PKD and RSM primarily wrote the manuscript. JMB, JO, MHW, DDH provided valuable insight for revising the manuscript. All authors read and approved the final manuscript.