title: Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins.
abstract: The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fc-mediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs). In the course of screening monoclonal antibodies (MAbs) for their ability to deliver cytotoxic agents to infected or Env-transfected cells, we noted disparities in their functional activities. Different MAbs showed diverse functions that did not correlate with each other. For example, MAbs against the external loop region of gp41 made the most effective ITs against infected cells but did not neutralize virus and bound only moderately to the same cells that they killed so effectively when they were used in ITs. There were also differences in IT-mediated killing among transfected and infected cell lines that were unrelated to the binding of the MAb to the target cells. Our studies of a well-characterized antigen demonstrate that MAbs against different epitopes have different functional activities and that the binding of one MAb can influence the interaction of other MAbs that bind elsewhere on the antigen. These results have implications for the use of MAbs and ITs to kill HIV-infected cells and eradicate persistent reservoirs of HIV infection.
  
  
  OBJECTIVE
  There is increased interest in using antibodies to treat and cure HIV infection. Antibodies can neutralize free virus and kill cells already carrying the virus. The virus envelope (Env) is the only HIV protein expressed on the surfaces of virions and infected cells. In this study, we examined a panel of human anti-Env antibodies for their ability to deliver cell-killing toxins to HIV-infected cells and to perform other antiviral functions. The ability of an antibody to make an effective immunotoxin could not be predicted from its other functional characteristics, such as its neutralizing activity. Anti-HIV immunotoxins could be used to eliminate virus reservoirs that persist despite effective antiretroviral therapy.
authors.affiliation: Research Institute for Children, Children's Hospital, New Orleans, Louisiana, USA spincu@lsuhsc.edu.|Department of Pediatrics and Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Seth H
authors.initials: SH
authors.lastname: Pincus
authors.affiliation: Research Institute for Children, Children's Hospital, New Orleans, Louisiana, USA.
authors.forename: Kejing
authors.initials: K
authors.lastname: Song
authors.affiliation: Research Institute for Children, Children's Hospital, New Orleans, Louisiana, USA.
authors.forename: Grace A
authors.initials: GA
authors.lastname: Maresh
authors.affiliation: Laboratory of Biochemistry, Center for Cancer Research, NCI, Bethesda, Maryland, USA.
authors.forename: Dean H
authors.initials: DH
authors.lastname: Hamer
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, NCI, Frederick, Maryland, USA.
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, NCI, Frederick, Maryland, USA.
authors.forename: Weizao
authors.initials: W
authors.lastname: Chen
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, NCI, Frederick, Maryland, USA.
authors.forename: Mei-Yun
authors.initials: MY
authors.lastname: Zhang
authors.affiliation: Departments of Immunology and Microbiology, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Victor F
authors.initials: VF
authors.lastname: Ghetie
authors.affiliation: Theraclone Sciences, Seattle, Washington, USA.
authors.forename: Po-Ying
authors.initials: PY
authors.lastname: Chan-Hui
authors.affiliation: Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Departments of Immunology and Microbiology, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Vitetta
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D009500:Neutralization Tests; D011485:Protein Binding; D055503:Protein Multimerization
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D019302:HIV Envelope Protein gp160; D000922:Immunotoxins
keywords: HIV envelope; epitope; gp160; immunotoxin; monoclonal antibody