Iron Deficiency is Prevalent among HIV-Infected Kenyan Adults and is Better Measured by Soluble Transferrin Receptor than Ferritin.

Iron deficiency (ID) and human immunodeficiency virus (HIV) infection frequently coexist. Little data exist on ID in HIV-infected individuals, partly because the iron marker ferritin is altered by inflammation common in HIV infection. We measured iron biomarkers (ferritin, soluble transferrin receptor [sTfR], hepcidin) and red cell indices (hemoglobin, mean corpuscular volume [MCV]) in newly diagnosed, antiretroviral therapy-naive, HIV-infected (N = 138) and uninfected (N = 52) Kenyan adults enrolled in a study of the immune response to malaria. We compared markers between infected and uninfected groups with t test and Wilcoxon Rank-Sum, used Spearman correlation to determine the association between iron and inflammatory markers, and applied logistic regression to determine which markers best predicted anemia. HIV-infected individuals had lower hemoglobin (P < 0.001), lower MCV (P < 0.001), higher sTfR (P = 0.003), and a greater prevalence of ID (sTfR > 8.3 mg/L) than uninfected individuals. Ferritin was elevated in HIV-infected individuals and was more strongly correlated with C-reactive protein (ρ = 0.43, P < 0.001) and hepcidin (ρ = 0.69, P < 0.001) than with hemoglobin. The best predictor of anemia in HIV-infected participants was sTfR, with a one log-unit increase in sTfR associated with a 6-fold increase in the odds of anemia (odds ratio = 6.3, 95% confidence interval: 1.8-21.8). These data suggest a significant burden of ID among treatment-naive HIV-infected Kenyan adults. Soluble transferrin receptor may be a reliable marker of ID in HIV-mediated inflammation.

Decrease in Numbers of Naive and Resting B Cells in HIV-Infected Kenyan Adults Leads to a Proportional Increase in Total and Plasmodium falciparum-Specific Atypical Memory B Cells.

Human immunodeficiency virus type 1 (HIV-1) infection is associated with B cell activation and exhaustion, and hypergammaglobulinemia. How these changes influence B cell responses to coinfections such as malaria is poorly understood. To address this, we compared B cell phenotypes and Abs specific for the Plasmodium falciparum vaccine candidate apical membrane Ag-1 (AMA1) in HIV-infected and uninfected adults living in Kenya. Surprisingly, HIV-1 infection was not associated with a difference in serum AMA1-specific Ab levels. HIV-infected individuals had a higher proportion of total atypical and total activated memory B cells (MBCs). Using an AMA1 tetramer to detect AMA1-specific B cells, HIV-infected individuals were also shown to have a higher proportion of AMA1-specific atypical MBCs. However, this proportional increase resulted in large part from a loss in the number of naive and resting MBCs rather than an increase in the number of atypical and activated cells. The loss of resting MBCs and naive B cells was mirrored in a population of cells specific for an Ag to which these individuals were unlikely to have been chronically exposed. Together, the data show that changes in P. falciparum Ag-specific B cell subsets in HIV-infected individuals mirror those in the overall B cell population, and suggest that the increased proportion of atypical MBC phenotypes found in HIV-1-infected individuals results from the loss of naive and resting MBCs.

Decline in childhood iron deficiency after interruption of malaria transmission in highland Kenya.

BACKGROUND: Achieving optimal iron status in children in malaria-endemic areas may increase the risk of malaria. Malaria itself may contribute to iron deficiency, but the impact of an interruption in malaria transmission on the prevalence of iron deficiency is unknown. OBJECTIVES: We aimed to determine whether 1) iron status improved in children living in 2 Kenyan villages with a documented cessation in malaria transmission and 2) changes in iron status correlated with changes in hemoglobin. DESIGN: We measured iron [hemoglobin, ferritin, soluble transferrin receptor (sTfR)] and inflammatory [C-reactive protein (CRP)] markers in paired plasma samples from 190 children aged 4-59 mo at the beginning (May 2007) and end (July 2008) of a documented 12-mo period of interruption in malaria transmission in 2 highland areas in Kenya with unstable malaria transmission and ongoing malaria surveillance. RESULTS: Between May 2007 and July 2008, mean (±SD) hemoglobin increased from 10.8 ± 1.6 to 11.6 ± 1.6 g/dL. Median (25th, 75th percentile) ferritin increased from 17.0 (9.7, 25.6) to 22.6 (13.4, 34.7) µg/L (P < 0.001), whereas median sTfR decreased from 32.4 (26.3, 43.2) to 27.7 (22.1, 36.0) nmol/L (P < 0.001). Median CRP was low (<1 mg/L in both years) and did not change significantly. Iron deficiency prevalence (ferritin <12 µg/L, or <30 µg/L if CRP ≥10 mg/L) decreased from 35.9% (95% CI: 28.9%, 43.0%) to 24.9% (18.5%, 31.2%) (P = 0.005). The prevalence of iron deficiency with anemia (hemoglobin <11.0 g/dL) declined from 27.2% (20.7%, 33.8%) to 12.2% (7.4%, 17.1%) (P < 0.001). Improvement in iron status correlated with an increase in hemoglobin and was greater than explained by physiologic changes expected with age. CONCLUSIONS: In this area of unstable malaria transmission, the prevalence of iron deficiency in children decreased significantly after the interruption of malaria transmission and was correlated with an increase in hemoglobin. These findings suggest that malaria elimination strategies themselves may be an effective way to address iron deficiency in malaria-endemic areas.

An ethnic-specific polymorphism in the catalytic subunit of glutamate-cysteine ligase impairs the production of glutathione intermediates in vitro.

Glutathione plays a crucial role in free radical scavenging, oxidative injury, and cellular homeostasis. Previously, we identified a non-synonymous polymorphism (P462S) in the gene encoding the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme in glutathione biosynthesis. This polymorphism is present only in individuals of African descent. Presently, we report that this ethnic-specific polymorphism (462S) encodes an enzyme with significantly decreased in vitro activity when expressed by either a bacterial or mammalian cell expression system. In addition, overexpression of the 462P wild-type GCLC enzyme results in higher intracellular glutathione concentrations than overexpression of the 462S isoform. We also demonstrate that apoptotically stimulated mammalian cells overexpressing the 462S enzyme have increased caspase activation and increased DNA laddering compared to cells overexpressing the wild-type 462P enzyme. Finally, we genotyped several African and African-descent populations and demonstrate that the 462S polymorphism is in Hardy-Weinberg disequilibrium, with no individuals homozygous for the 462S polymorphism identified. These findings describe a glutathione production pathway polymorphism present in individuals of African descent with significantly decreased in vitro activity.