title: Placental Hofbauer cells assemble and sequester HIV-1 in tetraspanin-positive compartments that are accessible to broadly neutralizing antibodies.
abstract: BACKGROUND
  Within monocyte-derived macrophages, HIV-1 accumulates in intracellular virus-containing compartments (VCCs) that are inaccessible to the external environment, which implicate these cells as latently infected HIV-1 reservoirs. During mother-to-child transmission of HIV-1, human placental macrophages (Hofbauer cells (HCs)) are viral targets, and have been shown to be infected in vivo and sustain low levels of viral replication in vitro; however, the risk of in utero transmission is less than 7%. The role of these primary macrophages as viral reservoirs is largely undefined. The objective of this study is to define potential sites of viral assembly, accumulation and neutralization in HCs given the pivotal role of the placenta in preventing HIV-1 infection in the mother-infant dyad.
  
  
  METHODS
  Term placentae from 20 HIV-1 seronegative women were obtained following caesarian section. VCCs were evaluated by 3D confocal and electron microscopy. Colocalization R values (Pearson's correlation) were quantified with colocalization module of Volocity 5.2.1. Replication kinetics and neutralization studies were evaluated using p24 ELISA.
  
  
  RESULTS
  We demonstrate that primary HCs assemble and sequester HIV-1(BaL) in intracellular VCCs, which are enriched in endosomal/lysosomal markers, including CD9, CD81, CD63 and LAMP-1. Following infection, we observed HIV-1 accumulation in potentially acidic compartments, which stained intensely with Lysotracker-Red. Remarkably, these compartments are readily accessible via the cell surface and can be targeted by exogenously applied small molecules and HIV-1-specific broadly neutralizing antibodies. In addition, broadly neutralizing antibodies (4E10 and VRC01) limited viral replication by HIV-1-infected HCs, which may be mediated by FcγRI.
  
  
  CONCLUSIONS
  These findings suggest that placental HCs possess intrinsic adaptations facilitating unique sequestration of HIV-1, and may serve as a protective viral reservoir to permit viral neutralization and/or antiretroviral drug entry in utero.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Johnson
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Hin
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Pathology & Laboratory Medicine, Emory University School of Medicine Atlanta, GA, USA; Emory Vaccine Center, Emory University School of Medicine Atlanta, GA, USA.
authors.forename: Siddappa Nagadenahalli
authors.initials: SN
authors.lastname: Byrareddy
authors.affiliation: Department of Pediatrics, Emory University School of Medicine Atlanta, GA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Spearman
authors.affiliation: Department of Pediatrics, Emory University School of Medicine Atlanta, GA, USA; rchakr5@emory.edu.
authors.forename: Rana
authors.initials: R
authors.lastname: Chakraborty
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D010920:Placenta / Q000166:cytology / Q000821:virology*; D011247:Pregnancy; D059470:Tetraspanins / Q000032:analysis*; D019065:Virus Assembly; D014779:Virus Replication
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D059470:Tetraspanins
keywords: HIV-1; Hofbauer cells; MTCT; VCCs; bNAbs; placenta