Soluble CD4 enhances the efficacy of immunotoxins directed against gp41 of the human immunodeficiency virus.
Monoclonal antibodies specific for the gp120 or gp41 portions of the human immunodeficiency virus (HIV) envelope protein gp160 were conjugated to ricin A chain, and their immunotoxic activities against HIV-infected cells were evaluated in the presence or absence of soluble CD4 (sCD4). Immunotoxin activity was measured in vitro as cytotoxicity and inhibition of secretion of infectious HIV. The efficacy of anti-gp41 immunotoxins was enhanced at least 30-fold in the presence of sCD4. This effect was specific for HIV-infected cells, but not for uninfected cells, and was seen at concentrations of sCD4 as low as 0.1 micrograms/ml. Anti-gp120 immunotoxins were marginally inhibited at higher concentrations of sCD4. Flow cytometry analyses showed that sCD4 increased the expression of gp41 on the surface of infected cells and increased internalization of gp120 and gp41. These data suggest that sCD4 alters the cellular trafficking of HIV envelope proteins. These findings also have important implications for the therapeutic use of anti-HIV immunotoxins and may be generalizable to other immunotoxins as well.
Pincus
S H
SH
Laboratory of Microbial Structure and Function, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, Hamilton, MT 59840.
McClure
J
J
D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D015704:CD4 Antigens / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006678:HIV / Q000187:drug effects* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D012276:Ricin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D000922:Immunotoxins; D012276:Ricin