title: The Interplay Between Host Genetic Variation, Viral Replication, and Microbial Translocation in Untreated HIV-Infected Individuals.
abstract: Systemic immune activation, a major determinant of human immunodeficiency virus (HIV) disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. Although human genetic variants influencing HIV load have been identified, it is unknown how much the host genetic background contributes to interindividual differences in other determinants of HIV pathogenesis such as gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty acid-binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble CD14 (sCD14), a marker of lipopolysaccharide bioactivity and microbial translocation. We also assessed the correlations between HIV load, sCD14, and I-FABP. Although we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infection.
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: Molly R
authors.initials: MR
authors.lastname: Perkins
authors.affiliation: Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne Swiss Institute of Bioinformatics, Lausanne Institute of Microbiology, University Hospital and University of Lausanne.
authors.forename: Istvan
authors.initials: I
authors.lastname: Bartha
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: J Katherina
authors.initials: JK
authors.lastname: Timmer
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Liebner
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Wolinsky
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Wollinsky
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich and University of Zurich.
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: University Clinic of Infectious Diseases, University Hospital Bern and University of Bern.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hauser
authors.affiliation: Division of Infectious Diseases, Regional Hospital Lugano.
authors.forename: Enos
authors.initials: E
authors.lastname: Bernasconi
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St Gallen.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: HIV Unit, Department of Internal Medicine, Geneva University Hospital.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Calmy
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, Departments of Clinical and Biomedical Research, University Hospital Basel, University of Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.affiliation: Institute of Microbiology, University Hospital and University of Lausanne.
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.affiliation: Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne Swiss Institute of Bioinformatics, Lausanne.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D050556:Fatty Acid-Binding Proteins / Q000097:blood / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000097:blood / Q000378:metabolism; D008297:Male; D013557:Switzerland / Q000453:epidemiology; D014178:Translocation, Genetic; D019562:Viral Load; D014779:Virus Replication / Q000502:physiology*
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D050556:Fatty Acid-Binding Proteins; D018950:Lipopolysaccharide Receptors
keywords: HIV; I-FABP; genome-wide association study; host genomics; immune activation; microbial translocation; sCD14