Peripheral blood mononuclear cell transcriptomes reveal an over-representation of down-regulated genes associated with immunity in HIV-exposed uninfected infants

Zaneta D Musimbi,Nelson Kibinge,Etienne Pierre De Villiers,Lynette Isabella Ochola-Oyier,Eunice W Nduati,James R Otieno,Martin K Rono

doi:10.1038/s41598-019-54083-4

Abstract

HIV-exposed uninfected (HEU) infants are disproportionately at a higher risk of morbidity and mortality, as compared to HIV-unexposed uninfected (HUU) infants. Here, we used transcriptional profiling of peripheral blood mononuclear cells to determine immunological signatures of in utero HIV exposure. We identified 262 differentially expressed genes (DEGs) in HEU compared to HUU infants. Weighted gene co-expression network analysis (WGCNA) identified six modules that had significant associations with clinical traits. Functional enrichment analysis on both DEGs and the six significantly associated modules revealed an enrichment of G-protein coupled receptors and the immune system, specifically affecting neutrophil function and antibacterial responses. Additionally, malaria pathogenicity genes (thrombospondin 1-(THBS 1), interleukin 6 (IL6), and arginine decarboxylase 2 (ADC2)) were down-regulated. Of interest, the down-regulated immunity genes were positively correlated to the expression of epigenetic factors of the histone family and high-mobility group protein B2 (HMGB2), suggesting their role in the dysregulation of the HEU transcriptional landscape. Overall, we show that genes primarily associated with neutrophil mediated immunity were repressed in the HEU infants. Our results suggest that this could be a contributing factor to the increased susceptibility to bacterial infections associated with higher morbidity and mortality commonly reported in HEU infants.

Highlights

Active antiretroviral therapy (HAART), is currently the most promising intervention for HIV control, in the prevention of mother to child transmission (PMTCT)
The transcriptome analysis draws attention to a specific immune system process that is downregulated in HIV-exposed uninfected (HEU) infants, neutrophil mediated immunity, that could be a potential marker of increased susceptibility to infection and resulting morbidity and mortality
We observed the upregulation of non-coding RNA ATP1B3-AS1, in HEU infants

Summary

Introduction

Active antiretroviral therapy (HAART), is currently the most promising intervention for HIV control, in the prevention of mother to child transmission (PMTCT). HEU’s have higher numbers of CD3+ cells[16], an intricate pattern of defects in CD4+ and CD8+ T-lymphocyte subpopulations, (which show a shift from naïve to memory phenotypes and an increase in peripheral immature T-lymphocytes17,18), altered dendritic cells[19], a reduction in the proportion of circulating follicular helper T-cells[20] and impaired progenitor T-cell function that leads to reduced thymic output and results in lower naïve CD4 counts[15,21]. Some studies have reported an increase in cord blood B-lymphocytes marked by higher numbers of CD19+/CD5+ cells[16], a reduction in the resting memory B-cells (primarily due to changes in the unswitched memory B-cell subset22) and poorer humoral responses to a wide range of vaccines[15,17] These phenotypic, functional and clinical observations highlight a compromised immune system in HEU infants. We uncovered several HEU transcriptome markers and showed that the down-regulated genes in HEU infants are functionally related to diverse biological pathways with an over-representation of pathways associated with immunity

Methods

Results

Conclusion