title: Breast milk and in utero transmission of HIV-1 select for envelope variants with unique molecular signatures.
abstract: Mother-to-child transmission of human immunodeficiency virus-type 1 (HIV-1) poses a serious health threat in developing countries, and adequate interventions are as yet unrealized. HIV-1 infection is frequently initiated by a single founder viral variant, but the factors that influence particular variant selection are poorly understood.
  
  
  
  Our analysis of 647 full-length HIV-1 subtype C and G viral envelope sequences from 22 mother-infant pairs reveals unique genotypic and phenotypic signatures that depend upon transmission route. Relative to maternal strains, intrauterine HIV transmission selects infant variants that have shorter, less-glycosylated V1 loops that are more resistant to soluble CD4 (sCD4) neutralization. Transmission through breastfeeding selects for variants with fewer potential glycosylation sites in gp41, are more sensitive to the broadly neutralizing antibodies PG9 and PG16, and that bind sCD4 with reduced cooperativity. Furthermore, experiments with Affinofile cells indicate that infant viruses, regardless of transmission route, require increased levels of surface CD4 receptor for productive infection.
  
  
  
  These data provide the first evidence for transmission route-specific selection of HIV-1 variants, potentially informing therapeutic strategies and vaccine designs that can be tailored to specific modes of vertical HIV transmission.
authors.affiliation: Division of Infectious Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA.|Systems Biology and Disease Program, USC Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Nakamura
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Heath
authors.affiliation: Division of Infectious Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Sobrera
authors.affiliation: Division of Infectious Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wilkinson
authors.affiliation: Division of Global Health Equity, Brigham and Women's Hospital, Harvard Medical School, and Ariadne Labs, Boston, MA, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Semrau
authors.affiliation: University Teaching Hospital, University of Zambia, Lusaka, Zambia.
authors.forename: Chipepo
authors.initials: C
authors.lastname: Kankasa
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Tobin
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Webb
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.affiliation: Division of Global Health Equity, Brigham and Women's Hospital, Harvard Medical School, and Ariadne Labs, Boston, MA, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Thea
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Kuhn
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA, USA. GAldrovandi@mednet.ucla.edu.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Aldrovandi
mesh_terms: D001942:Breast Feeding; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000635:transmission* / Q000821:virology*; D015497:HIV-1 / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D054299:env Gene Products, Human Immunodeficiency Virus
keywords: Broadly neutralizing antibodies; CD4; Envelope; Glycosylation; HIV-1; Mother-to-child transmission