title: Monoclonal and Single Domain Antibodies Targeting β-Integrin Subunits Block Sexual Transmission of HIV-1 in In Vitro and In Vivo Model Systems.
abstract: BACKGROUND
  Poor adherence to prevention regimens for gel-based anti-HIV-1 microbicides has been a major obstacle to more effective pre-exposure prophylaxis. Concern persists that the antiretroviral drug containing microbicides might promote development of antiretroviral resistance.
  
  
  METHODS
  Using in vitro transwell systems and a humanized mouse model of HIV-1 sexual transmission, we examined, as candidate microbicides, antibodies targeting the heterodimeric leukocyte function-associated antigen 1 (LFA-1), a non-virally encoded protein acquired by the virus that also plays a critical role cell movement across endothelial and epithelial barriers. LFA-1-specific single domain variable regions from alpaca heavy-chain only antibodies (VHH) were identified and evaluated for their ability to inhibit HIV-1 transmission in the in vitro transwell system.
  
  
  RESULTS
  Monoclonal antibodies targeting the CD11a and CD18 components of LFA-1 significantly reduced cell-free and cell-associated HIV-1 transmission in the in vitro transwell culture system and prevented virus transmission in the humanized mouse model of vaginal transmission. The broadly neutralizing monoclonal antibody b12 was unable to block transmission of cell-free virus. CD11a-specific VHH were isolated and expressed and the purified variable region protein domains reduced in vitro transepithelial transmission with an efficacy comparable with that of the CD11a monoclonal antibody.
  
  
  CONCLUSIONS
  Targeting integrins acquired by HIV-1 during budding and which are critical to interactions between epithelial cells and lymphocytes can reduce viral movement across epithelial barriers and prevent transmission in a humanized mouse model of sexual transmission. VHH capable of being produced by transformed bacteria can significantly reduce transepithelial virus transmission in in vitro model systems.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Janet Tai
authors.initials: JT
authors.lastname: Guedon
authors.forename: Kun
authors.initials: K
authors.lastname: Luo
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Richard B
authors.initials: RB
authors.lastname: Markham
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D000918:Antibody Specificity; D040881:CD11a Antigen / Q000276:immunology; D018821:CD18 Antigens / Q000276:immunology; D002161:Camelids, New World; D002460:Cell Line; D004847:Epithelial Cells / Q000821:virology; D015658:HIV Infections / Q000517:prevention & control / Q000635:transmission*; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D039641:Integrin beta Chains / Q000276:immunology*; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear; D051379:Mice; D016513:Mice, SCID; D019151:Peptide Library
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D040881:CD11a Antigen; D018821:CD18 Antigens; D039641:Integrin beta Chains; D019151:Peptide Library
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