title: A fully human antibody to gp41 selectively eliminates HIV-infected cells that transmigrated across a model human blood brain barrier.
abstract: OBJECTIVE
  Many HIV patients on combined antiretroviral therapy exhibit HIV-associated neurocognitive disorders because the brain becomes a viral reservoir. There is a need for therapeutics that can enter the central nervous system (CNS) and eradicate the virus.
  
  
  METHODS
  Radiolabeled human mAb 2556 to HIV gp41 selectively kills HIV-infected cells in vivo and in vitro. Here we tested the ability of 213Bi-2556 to cross a tissue culture model of the human blood brain barrier and kill HIV-infected peripheral blood mononuclear cells (PBMCs) and monocytes on the CNS side of the barrier.
  
  
  METHODS
  2556 mAb isoelectric point was determined with isoelectric focusing. The ability of radiolabeled 2556 to penetrate through the barrier was studied by adding it to the upper chamber of the barriers and its penetration into the CNS side was followed for 5 h. To assess the ability of Bi-2556 to kill the HIV-infected cells on the CNS side of barrier, the HIV-infected and uninfected PBMCs and monocytes were allowed to transmigrate across the barriers overnight followed by application of Bi-2556 or control mAb Bi-1418 to the top of the barrier. Killing of cells was measured by TUNEL and Trypan blue assays. The barriers were examined by confocal microscopy for overt damage.
  
  
  RESULTS
  The isoelectric point of Bi-2556 was 9.6 enabling its penetration through the barrier by transcytosis. Bi-2556 killed significantly more transmigrated HIV-infected cells in comparison to Bi-1418 and uninfected cells. No overt damage to barriers was observed.
  
  
  CONCLUSIONS
  We demonstrated that Bi-2556 mAb crossed an in-vitro human blood brain barrier and specifically killed transmigrated HIV-infected PBMCs and monocytes without overt damage to the barrier.
authors.affiliation: aAlbert Einstein College of Medicine, Bronx, New York, USA bEuropean Commission, Joint Resaerch Centre, Institute for Transuranium Elements, Karlsruhe, Germany cNew York University School of Medicine dNew York Veterans Affairs Harbor Healthcare System, New York ePublic Health Research Institute, Newark fDepartment of Microbiology and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers The State University of New Jersey, Newark, New Jersey, USA. *Currently at Children's Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: McFarren
authors.forename: Lillie
authors.initials: L
authors.lastname: Lopez
authors.forename: Dionna W
authors.initials: DW
authors.lastname: Williams
authors.forename: Mike
authors.initials: M
authors.lastname: Veenstra
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Bryan
authors.forename: Aliza
authors.initials: A
authors.lastname: Goldsmith
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.forename: Miroslaw K
authors.initials: MK
authors.lastname: Gorny
authors.forename: Eliseo A
authors.initials: EA
authors.lastname: Eugenin
authors.forename: Joan W
authors.initials: JW
authors.lastname: Berman
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Dadachova
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D001812:Blood-Brain Barrier; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015658:HIV Infections / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology* / Q000821:virology; D008954:Models, Biological
chemical_list: D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; C514787:gp41 protein, Human immunodeficiency virus 1