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  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 . 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 . 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 .
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 . 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 . 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 , 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 . The trial did not report changes in biological markers of HIV-1 disease progression or the effect on HIV-1-related mortality.