Serum Selenium and Inflammation in Individuals with Human Immunodeficiency Virus Infection

Abstract

HIV infection has been linked to selenium deficiency and chronic inflammation. Both selenium deficiency and inflammation have been associated with poor health outcomes among individuals with HIV. However, the role of serum selenium levels in inflammation has not been studied among individuals with HIV. We assessed the relationship of serum selenium levels to C-reactive protein (CRP), a marker of inflammation, in individuals with HIV in Kathmandu, Nepal. In this cross-sectional study, we measured the normal serum CRP and selenium levels of 233 individuals with HIV (109 women and 124 men) using the latex agglutination turbidimetric and atomic absorption methods, respectively. We used multiple linear regression analysis in examining the association of serum selenium levels with CRP adjusting for sociodemographic and clinical parameters, including antiretroviral therapy, CD4⁺ T cell count, chronic diseases, and body mass index. The geometric means of CRP and selenium levels were 1.43 mg/liter and 9.65 μg/dL, respectively. Overall, serum selenium levels were inversely associated with CRP levels (β for one unit change in log selenium; β = −1.01, p = .06). Mean CRP levels significantly decreased with increasing selenium across selenium tertiles (p for trend = .019). The mean serum CRP levels were 40.8% lower in the highest selenium tertile than in the lowest. Our study suggests that high serum selenium levels may reduce serum CRP levels in individuals with HIV, although a longitudinal study is warranted to establish causality.

Introduction

Chronic inflammation is associated with HIV infection.^1
–3 The chronic activation of immune systems may increase chronic inflammation in individuals with HIV due to viral replication, loss of immunoregulatory responses, and hypercoagulability.^1
–3 C-reactive protein (CRP), a proinflammatory biomarker, may mediate the systemic effects of HIV and is an independent predictor for survival among individuals with HIV.⁴ High serum CRP levels may exacerbate disease progression to develop acquired immune deficiency syndrome (AIDS) by reducing CD4⁺ T cell count and increasing HIV viral loads.⁵

Serum selenium levels are observed to be low and are associated with disease progression in individuals with HIV. A cross-sectional study reported significantly lower mean serum selenium among individuals with HIV in CDC HIV stage II and III than HIV stage I and HIV-negative subjects.⁶ Observational studies have shown an association between low serum selenium levels and advanced HIV disease stage and increased mortality in individuals with HIV.^7
–9 In a longitudinal study among Tanzanian pregnant women, baseline plasma selenium levels were associated with higher CD4⁺ T cell count during their first years of follow-up.⁸ Similarly, a systematic review of randomized controlled trials suggested that daily selenium supplementation (200 μg) can delay CD4⁺ T cell count decline among those on antiretroviral therapy (ART) and ART-naive individuals with HIV.¹⁰ However, the review did not provide quantifiable evidence that selenium supplementation reduces HIV viral load. Collectively, this evidence suggests that higher serum selenium levels may provide a protective effect on HIV disease progression.

The serum selenium levels are low, and inflammation levels are high in individuals with HIV. The low selenium levels may increase inflammation, but its association has not been adequately studied in individuals with HIV. In a cross-sectional study among children in Uganda, plasma selenium concentrations were inversely associated with lower systemic inflammation measured via interleukin-6, and soluble tumor necrosis factor-alpha (TNF-α) 1 and II.¹¹ In another study among HIV-infected men in Mexico, serum selenium levels were inversely correlated with proinflammatory cytokines such as interleukin-1β, interleukin-6, and TNF-α.¹²

Selenium plays a significant role in the modulation of immune function, inflammatory response, and oxidative stress.¹³ Selenium, the essential trace element in the form of selenoproteins, may benefit patients with inflammatory diseases and even infectious diseases such as HIV infection.¹⁴ Selenium may inhibit the activation of nuclear factor kappa-B (NF-κB), which has been associated with an enhanced inflammatory response by modulating selenoprotein gene expression.^14,15 Thus, we aimed to assess the association of serum selenium to CRP levels in individuals with HIV. We hypothesized that decreased serum selenium levels would be associated with increased serum CRP levels in individuals with HIV while accounting for important sociodemographic and clinical parameters such as CD4⁺ T cell count and ART.

Methods

Study participants

We conducted a cross-sectional study among individuals with HIV in the Kathmandu Valley, Nepal. We recruited 233 individuals using the network of 5 nongovernment organizations (NGOs) working with individuals with HIV in the Kathmandu Valley. During the fieldwork, these NGOs provided several HIV services, such as weekly HIV clinics, hospital visits for consultation, CD4⁺ cell count monitoring, community and home-based care, in-house crisis management services, and home delivery of ART to needy individuals. For recruitment, trained research assistants (RAs) provided detailed information about the study to individuals with HIV, answered their questions, and offered opportunities to participate to those aged 18–60 years, who self-reported their HIV-positive diagnosis, resided in the Kathmandu Valley, and provided written informed consent to participate in the study voluntarily.

Our study protocol was reviewed and approved by the Ethics Committees of the (1) Nepal Health Research Council, Kathmandu, Nepal, and (2) National Center for Global Health and Medicine, Japan. The Institutional Review Board of the University of Massachusetts Amherst also approved the study procedures.

Data collection

Trained RAs interviewed each participant face-to-face in a private setting using a structured pretested Nepali language questionnaire. Each interview took about 45–60 min. Before the interview, RA reassured study participants individually that the study team would not include their names in any documents containing their interview or laboratory results. Measures included sociodemographic characteristics, smoking, ART use, and history of illness in the past 12 months. ART type and adherence were collected according to the current medication use at the time of the survey. Smoking status was measured as never or ever smoked. The history of diseases was measured by asking for a history of any chronic diseases in the past 12 months.

Physical examination

Trained RAs measured body weight in kilograms using digital scales. Participants were allowed to wear light clothes without shoes. Similarly, RAs used a stadiometer to measure height in centimeters. We calculated body mass index (BMI) as weight (kg)/height (m).² They used an Omron Automatic Blood Pressure Monitor to measure the blood pressure of our participants. Participants were requested to rest for at least 10 min before measuring their blood pressure. RAs repeated measurements of weight, height, and blood pressure to estimate mean values.

Laboratory methods

We collected fasting blood samples from all participants. Immediately we centrifuged blood samples for 15 min and separated serum from other blood components. We then placed serum samples in a cooler box to transport them to a local laboratory in Kathmandu. After completion of the fieldwork, we transported serum samples to a research laboratory in Tokyo, Japan using dry ice. In this laboratory, we stored serum at −80°C until analysis.

For analysis, we used dry ice to transfer serum samples to the laboratory of Mitsubishi Chemical Medience Corporation, Tokyo, Japan. The latex agglutination nephelometry and the atomic absorption methods were used to measure high-sensitive serum CRP and selenium levels, respectively. We measured the regular serum CRP levels of those individuals whose CRP value was 5 mg/liter or more using the latex agglutination turbidimetric method. The intra-assay coefficient of variation at CRP levels on the control serum was within 10%.

We obtained CD4 cell count from the medical records of participants. CD4 cell count was measured at the local laboratory using a specific monoclonal antibody and fluorescence-activated cell sorter analysis. We did not measure viral load because of a lack of resources.

Statistical analyses

The difference in sociodemographic and clinical characteristics of participants was analyzed using chi-square tests for categorical variables and linear regression analysis for continuous variables across tertiles of serum selenium concentrations. We used multiple linear regression analysis to assess the relationship of serum selenium to CRP levels, separately for men and women.

We log-transformed serum CRP and selenium values to calculate the means and their 95% confidence intervals, then back-transformed. Different sociodemographic and clinical parameters that were associated with inflammation were adjusted in the multivariate model, including sex (men or women), BMI (kg/m², continuous), age (years, continuous), smoking (never or ever), history of any disease in the past 12 months, including minor illnesses (yes or no), CD4⁺ T cell count (cells/μL; continuous), and ART (yes or no). The serum selenium categories were assigned 0, 1, and 2 for their trend calculation. We considered that the relationship is statistically significant if the two-sided p values <.05. We analyzed the data using SAS statistical software version 9.1 (SAS Institute, Inc., Cary, NC).

Results

The geometric means of serum selenium levels in total, in men, and in women were 9.65, 9.53, and 9.78 μg/dL, respectively. The mean (SD) age of men and women was 35.4 (6.28) and 32.5 (6.54) years, respectively. The differences in sociodemographic and clinical characteristics of participants across tertiles of serum selenium levels are presented in Table 1. The lowest serum selenium levels were observed in those not using ART and with a history of chronic disease.

Table 1.

Baseline Characteristics of Participants by Tertile of Serum Selenium Concentrations

	Serum selenium concentrations			p ^a
	T1 (lowest)	T2	T3 (highest)	p ^a
Selenium (median, range; μg/dL)	7.9 (5.9–8.6)	9.7 (8.7–10.5)	11.7 (10.6–16.0)
Subjects (n)	76	81	76
Age (mean ± SD, year)	35.06 (6.86)	33.69 (6.57)	33.42 (6.17)	.122
Sex (male, %)	44 (57.89)	43 (53.09)	37 (48.68)	.256
Smoking (never, %)	36 (47.37)	36 (44.44)	30 (39.47)	.327
Antiretroviral therapy (yes, %)	54 (71.05)	54 (66.67)	63 (82.89)	.099
History of any disease in past 12 months (yes, %)	51 (67.11)	52 (64.20)	40 (52.63)	.067
Body mass index (mean ± SD, kg/m²)	21.84 (2.92)	21.75 (2.60)	22.06 (3.04)	.625
CD4⁺ T cell count (median, range; cells/μL)	328 (41–1412)	386 (113–1551)	367 (57–1031)	.405

p for trend values were based on the Mantel-Haenszel chi-square test for categorical variables and linear regression analysis for continuous variables, with ordinal numbers 0–2 assigned to tertile categories of serum selenium concentrations.

SD, standard deviation.

The serum CRP levels were lower in participants with high selenium levels (Table 2). Our result showed that the geometric mean of serum CRP levels was 40.8% lower in the highest tertile of selenium than in the lowest (p for trend = .019) in the multivariate analysis. The mean serum CRP levels 42.0% and 44.6% lower in men and women, respectively, in the highest selenium tertile than in the lowest (p for trend = .118 and .142, respectively).

Table 2.

Serum C-Reactive Concentrations According to the Tertile of Serum Selenium Concentrations in Individuals with HIV (n = 233)

	Serum selenium concentrations			p for trend^a
	T1 (lowest)	T2	T3 (highest)	p for trend^a
All participants
Univariate model	1.77 (1.41–2.13)	1.64 (1.29–1.98)	1.01 (0.66–1.37)	.028
Multivariate model^b	1.75 (1.41–2.09)	1.73 (1.41–2.05)	1.04 (0.70–1.38)	.019
Men
Univariate model	1.52 (1.06–1.98)	1.67 (1.23–2.11)	1.01 (0.57–1.45)	.208
Multivariate model^b	1.57 (1.10–2.04)	1.78 (1.33–2.23)	0.91 (0.44–1.38)	.118
Women
Univariate model	2.05 (1.49–2.61)	1.50 (0.95–2.05)	1.13 (0.56–1.70)	.139
Multivariate model^b	2.04 (1.50–2.58)	1.50 (0.96–2.04)	1.13 (0.56–1.70)	.142

p for trend values were based on the multiple linear regression analysis, with ordinal numbers 0–2 assigned to tertile categories of serum selenium concentrations.

All multivariate models adjusted for age (years, continuous), sex (men or women), smoking (never or ever), body mass index (kg/m², continuous), history of any disease in past 12 months (yes or no), CD4⁺ T cell count (≤200 or >200; cells/μL), and anti-retroviral therapy (yes or no).

We found an inverse association between log serum selenium and CRP levels after adjustment for sociodemographic and clinical parameters (β for 1 U change in log selenium; β = −1.01, p = .066), although the relationship was insignificant in men (β = −0.92, p = .198) and women (β = −1.31, p = .141). Moreover, this inverse relationship did not remain significant among participants with or without a history of ART. But the inverse relationship tends to remain significant in participants with a history of chronic diseases (β = −0.92, p = .078) and with a CD4⁺ T cell count >200 μL (β = −0.94, p = .044). However, the inverse relationship was not significant among participants with a CD4⁺ T cell count ≤200 μL (β = −0.13, p = .912), perhaps due to the small size (n = 46) (data not shown).

Discussion

Serum selenium levels were inversely associated with serum CRP levels in individuals with HIV living in resource-poor settings. The serum CRP levels were significantly lower in individuals with HIV in the highest selenium tertile compared to the lowest. This association was independent of potential sociodemographic and clinical parameters such as CD4⁺ T cell count and ART. Ours is the first study examining the relationship of serum selenium to serum CRP levels in individuals with HIV infection, to our knowledge.

We are unaware of similar studies reporting serum selenium's relationship to CRP levels in individuals with HIV infection. Still, our findings are consistent with observational and experimental studies that reported an inverse association of serum selenium to CRP levels in other populations. For instance, in a study among older individuals living in aged-care facilities in New Zealand, plasma selenium levels were significantly lower across deciles of CRP.¹⁶ Serum selenium levels were inversely associated with acute and chronic inflammation in other observational studies.¹⁷ Several clinical trials explored the anti-inflammatory effects of selenium supplementation on serum CRP levels. Significant reductions in high sensitive C-reactive protein were observed in a 12-week trial among diabetic nephropathy patients supplemented with 200 μg/day selenium yeast¹⁸ and a 10-week trial among pregnant women with increased risk for intrauterine growth restriction, supplemented with 100 μg/day selenium.¹⁹

A meta-analysis and systematic review of randomized controlled clinical trials assessing the effect of selenium supplementation on serum CRP levels suggested that selenium supplementation can significantly reduce serum CRP levels in patients with elevated CRP levels (>3 mg/liter).²⁰ Selenium has also shown therapeutic benefits in reducing mortality in patients with inflammatory disorders after administering high doses of selenium.^21,22

Selenium may have anti-inflammatory effects due to its effect on NF-κB and the macrophage signal transduction pathways.¹⁴ The stress response, free radicals, oxidative stress, and bacterial and virus infections all activate proinflammatory processes via the activation of the NF-κB pathway.²³ NF-κB has been associated with enhanced inflammatory response, and its activation has been significantly correlated with interleukin-6 and TNF-α production.²⁴ Thus, the production of proinflammatory cytokines activated by NF-κB may mediate the acute phase reaction that is epitomized by increased production of CRP secretion from the liver.²⁵ Selenium may inhibit the activation of NF-κB by modulating selenoprotein gene expression. Thus, adequate selenium supplementation in chronic inflammation restores the depleted hepatic and serum selenium levels by increasing selenoprotein biosynthesis leading to suppression of CRP production to reduce inflammation.¹⁴

Moreover, selenium reduces oxidative stress induced by inflammatory or viral infectious diseases.²⁶ In an in vitro study, selenium in the form of sodium selenite inhibits TNF-α-induced expression of adhesion molecules,²⁷ which are required to promote endothelial cell proinflammation by recruiting leukocytes across the endothelium.²⁸ Thus, selenium may attenuate inflammation by inhibiting NF-κB via cellular glutathione peroxidase, an enzyme that catalyzes redox reactions.²⁹ In vivo, selenium regulates cellular glutathione peroxidase that decreases the production of reactive oxygen species by inhibiting 1kB-alpha phosphorylation and consequently translocates NF-κB. A study has reported that cellular glutathione peroxidase can double the half-life of 1kB-alpha phosphorylation and preserve its degradation.³⁰ Therefore, increased selenium levels inhibit acute protein release by impeding the transactivation of genes that encode inflammatory cytokines.³¹

Selenium has a fundamental role in the modulation of immune function, inflammatory response, and oxidative stress,^13,32 which are needed for the proper functioning of the immune system and in counteracting the development of virulence and inhibiting HIV progression to AIDS.³³ In a randomized controlled trial of selenium supplementation among 174 individuals with HIV (200 μg/day),³⁴ and 400 HIV-infected pregnant women (micronutrients +200 μg/day)³⁵ showed that the selenium supplemented group had higher CD4⁺ T cell count levels than the placebo group. In prospective studies among individuals with HIV^9,36 and children,³⁷ authors observed that patients who died had significantly lower selenium concentrations. Selenium supplementation has also shown a protective effect in reducing hospital admissions³⁸ and developing cardiac dysfunction.³⁹

Our study has two limitations. First, our cross-sectional study design cannot rule out the possibility of reverse causality that the serum levels may be influenced by inflammation. However, our hypothesis is supported by clinical trials²⁰ that suggested that inflammation may be increased due to selenium deficiency. Next, we selected participants using the purposive sampling method; thus, our study findings cannot be generalized to all individuals with HIV living in the country.

In conclusion, our study suggests that high serum selenium levels may be associated with low inflammation in individuals with HIV after considering important clinical parameters such as ART and CD4⁺ T cell count. This finding is crucial as it suggests the importance of monitoring selenium in individuals with HIV living in resource-poor settings. It also supports the need for intervention to reduce inflammation to improve the quality of life of individuals with HIV. Further prospective studies and/or clinical trials are needed to verify the benefit of serum selenium in serum CRP levels in individuals with HIV.

Footnotes

Acknowledgments

The authors thank all the participants for their time and participation in the study. The authors also thank five nongovernment organizations (Sneha Samaj, Shakti Milan Samaj, Srijansil Mahila Samuha, SPARSHA Nepal, and Youth Vision) working with HIV-positive individuals in Kathmandu, Nepal, for their assistance in selecting study participants and providing space for data collection.

Authors' Contributions

K.P.-T. contributed to the conception and design of the study. K.P.-T. and K.C.P. prepared study materials, supervised the fieldwork, and analyzed data. E.R.B.-J. provided statistical expertise and contributed to analyzing and interpreting data. K.P.-T. wrote the first draft of the article. K.C.P. and E.R.B.-J. reviewed and edited the article. All authors reviewed and approved the final article.

Data Availability

The dataset generated for analyses is available from the corresponding author upon reasonable request.

Ethics Approval

The procedures of this study were reviewed and approved by the (1) Ethics Committee of the Nepal Health Research Council, (2) Ethics Committee of the National Center for Global Health and Medicine, Japan, and (3) Institutional Review Board of the University of Massachusetts Amherst, MA.

Consent to Participate

All participants provided written informed consent before participating in the study.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

Grant-in-Aid for Young Scientists, JSPS, The Ministry of Education, Culture, Sports, Science and Technology, Japan (B22790581), and Grant for Research on Global Health and Medicine from the National Center for Global Health and Medicine, Japan (No. 21A-2), partially supported this study. The authors were responsible for designing the study, analyzing and interpreting the data, and preparing the article for publication.

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