Fetal Metabolic Stress Disrupts Immune Homeostasis and Induces Proinflammatory Responses in Human Immunodeficiency Virus Type 1- and Combination Antiretroviral Therapy-Exposed Infants.

Johannes C Schoeman, Gontse P Moutloatse, Amy C Harms, Rob J Vreeken, Henriette J Scherpbier, Liesbeth Van Leeuwen, Taco W Kuijpers, Carools J Reinecke, Ruud Berger, Thomas Hankemeier, Madeleine J Bunders

Journal: The Journal of infectious diseases 2017;216(4):436-446

PMID: 28633455

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Abstract

Increased morbidity and fetal growth restriction are reported in uninfected children born to human immunodeficiency virus type 1 (HIV-1)-infected women treated with antiretroviral (ARV) therapy. Viruses and/or pharmacological interventions such as ARVs can induce metabolic stress, skewing the cell's immune response and restricting (cell) growth. Novel metabolomic techniques provided the opportunity to investigate the impact of fetal HIV-1 and combination ARV therapy (cART) exposure on the infants' immune metabolome. Peroxidized lipids, generated by reactive oxygen species, were increased in cART/HIV-1-exposed infants, indicating altered mitochondrial functioning. The lipid metabolism was further dysregulated with increased triglyceride species and a subsequent decrease in phospholipids in cART/HIV-1-exposed infants compared to control infants. Proinflammatory immune mediators, lysophospholipids as well as cytokines such as CXCL10 and CCL3, were increased whereas anti-inflammatory metabolites from the cytochrome P450 pathway were reduced in cART/HIV-1-exposed infants. Taken together, these data demonstrate that the fetal metabolism is impacted by maternal factors (cART and HIV-1) and skews physiological immune responses toward inflammation in the newborn infant.

Address: Department of Analytical Biosciences, Leiden Academic Center for Drug Research, Leiden University, The Netherlands.; Centre for Human Metabolomics, Faculty of Natural Sciences, North-West University, Potchefstroom, South Africa.; Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital.; Department of Gynecology and Obstetrics.; Department of Experimental Immunology.; Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The Netherlands.; Research Unit Virus Immunology, Heinrich-Pette-Institute, Hamburg, Germany.

DOI: 10.1093/infdis/jix291

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MeSH Terms: Adult, Anti-HIV Agents, Case-Control Studies, Chemokine CCL3, Chemokine CXCL10, Cholesterol, Female, Fetus, HIV Infections, Homeostasis, Humans, Hypertriglyceridemia, Infant, Infant, Newborn, Infectious Disease Transmission, Vertical, Inflammation, Lipid Peroxidation, Male, Metabolomics, Oxidative Stress, Phospholipids, Pregnancy, Pregnancy Complications, Infectious, Stress, Physiological, Triglycerides