ABSTRACT
The three-dimensional structure of the binding domain of the CD4 molecule has been determined and extensive mutational analyses of the respective binding sites on gp120 and CD4 have been completed. The consequences of gp120-CD4 binding with respect to secondary changes in the virion, or the cell, that may be required for infection or that may interfere with cellular function are current active areas of investigation.
Subject(s)
Antigen-Antibody Reactions , CD4 Antigens/immunology , HIV Envelope Protein gp120/immunology , Acquired Immunodeficiency Syndrome/immunology , Amino Acid Sequence , CD4 Antigens/genetics , CD4-Positive T-Lymphocytes/immunology , Epitopes/genetics , HIV Envelope Protein gp120/genetics , Humans , Molecular Sequence Data , Molecular StructureABSTRACT
CD4 (T4), a glycoprotein expressed largely on the surface of cells in the immune system, serves as the receptor for the human immunodeficiency virus, HIV. The isolation of the CD4 gene has permitted an analysis of the structure of CD4 and its role in both HIV infection and the immune response. Recently, new classes of CD4-based therapeutics have been generated that interfere with HIV attachment to target cells. Soluble CD4 proteins and CD4-based chimeric molecules are currently undergoing clinical evaluation in HIV-infected individuals.
Subject(s)
CD4 Antigens/physiology , HIV Infections/immunology , Binding Sites , CD4 Antigens/analysis , CD4 Antigens/genetics , CD4-Positive T-Lymphocytes/microbiology , HIV/physiology , Humans , Signal Transduction , T-Lymphocytes/immunologyABSTRACT
A chimeric toxin made by a genetic fusion between the DNA encoding the 389 N-terminal amino acids of diphtheria toxin and that coding for the V1 and V2 domains of human CD4 (amino acids 1-178) was produced, purified and examined for ADP ribosylation activity, gp120 binding and effects on acutely and chronically HIV infected cells. The fusion toxin DAB389CD4 possesses enzymatic activity and binds to gp120. DAB389CD4 was found to kill CEM and U937 cells infected by HIV selectively and efficiently in a dose dependent manner, however, fusion toxin treatment did not eliminate the virus from acutely infected cell cultures. In addition, treatment of chronically infected cells with DAB389CD4 rapidly led to the appearance of HIV infected cells which were resistant to the chimeric toxin. The experimental results reported here suggest that the potential use of gp120 targeted cytotoxic agents for the treatment of HIV infection should be viewed with caution.