title: Coverage of primary mother-to-child HIV transmission isolates by second-generation broadly neutralizing antibodies.
abstract: OBJECTIVE
  A vaccine capable of providing cross-clade, sterilizing protection has been the holy grail of HIV-1 prevention and control since the beginning of the pandemic. A major component of this effort has been the identification and characterization of broadly neutralizing antibodies (bNAbs). Recent advances in bNAb isolation, structure-based engineering, and vector-mediated gene transfer have led to increased interest in bypassing the immune system by expressing neutralizing antibodies directly in muscle. To assess the neutralization potency and coverage of a panel of second-generation bNAbs, we cloned and phenotypically characterized 227 primary HIV-1 envelopes from 23 mother-to-child transmission (MTCT) pairs.
  
  
  METHODS
  Viral envelopes were tested for in-vitro neutralization sensitivity using a standard pseudotype assay system. A 50% inhibitory concentration (IC50) at least 10 μg/ml was used to define neutralization resistance.
  
  
  RESULTS
  The combination of antibodies PG16 and NIH45-46 had the broadest activity with the highest neutralization potency, achieving full coverage of 87% of transmission pairs (at a median sampling depth of 10 envelopes per pair) and 96% of recently infected infants in a very conservative analysis.
  
  
  CONCLUSIONS
  Our data strongly support the inclusion of NIH45-46, or a more extensively modified variant, in future proof-of-principle immunoprophylaxis or gene therapy-based trials. Furthermore, until robust sequence-based resistance detection becomes available, it will be necessary to conduct deeper phenotypic screening of primary isolates in order to determine the prevalence of minor resistant variants to help in selecting the best reagents for clinical trials.
authors.affiliation: Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, CA, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Nakamura
authors.forename: Chiara
authors.initials: C
authors.lastname: Cerini
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Sobrera
authors.forename: Laura
authors.initials: L
authors.lastname: Heath
authors.forename: Moses
authors.initials: M
authors.lastname: Sinkala
authors.forename: Chipepo
authors.initials: C
authors.lastname: Kankasa
authors.forename: Donald M
authors.initials: DM
authors.lastname: Thea
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Louise
authors.initials: L
authors.lastname: Kuhn
authors.forename: Grace M
authors.initials: GM
authors.lastname: Aldrovandi
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000302:isolation & purification; D005260:Female; D015483:HIV Antibodies / Q000276:immunology* / Q000302:isolation & purification; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000635:transmission; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D008297:Male; D008895:Milk, Human / Q000276:immunology; D009035:Mothers; D009500:Neutralization Tests; D011247:Pregnancy; D015024:Zambia; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus