title: Uterine epithelial cell regulation of DC-SIGN expression inhibits transmitted/founder HIV-1 trans infection by immature dendritic cells.
abstract: BACKGROUND
  Sexual transmission accounts for the majority of HIV-1 infections. In over 75% of cases, infection is initiated by a single variant (transmitted/founder virus). However, the determinants of virus selection during transmission are unknown. Host cell-cell interactions in the mucosa may be critical in regulating susceptibility to infection. We hypothesized in this study that specific immune modulators secreted by uterine epithelial cells modulate susceptibility of dendritic cells (DC) to infection with HIV-1.
  
  
  RESULTS
  Here we report that uterine epithelial cell secretions (i.e. conditioned medium, CM) decreased DC-SIGN expression on immature dendritic cells via a transforming growth factor beta (TGF-β) mechanism. Further, CM inhibited dendritic cell-mediated trans infection of HIV-1 expressing envelope proteins of prototypic reference. Similarly, CM inhibited trans infection of HIV-1 constructs expressing envelopes of transmitted/founder viruses, variants that are selected during sexual transmission. In contrast, whereas recombinant TGF- β1 inhibited trans infection of prototypic reference HIV-1 by dendritic cells, TGF-β1 had a minimal effect on trans infection of transmitted/founder variants irrespective of the reporter system used to measure trans infection.
  
  
  CONCLUSIONS
  Our results provide the first direct evidence for uterine epithelial cell regulation of dendritic cell transmission of infection with reference and transmitted/founder HIV-1 variants. These findings have immediate implications for designing strategies to prevent sexual transmission of HIV-1.
authors.affiliation: Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire, United States of America. Daniel.O.Ochiel@Dartmouth.edu
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Ochiel
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.forename: Mimi
authors.initials: M
authors.lastname: Ghosh
authors.forename: John V
authors.initials: JV
authors.lastname: Fahey
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wira
mesh_terms: D001681:Biological Assay; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003713:Dendritic Cells / Q000378:metabolism* / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000096:biosynthesis*; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014599:Uterus / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin