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Presentation of HIV V3 loop epitopes for enhanced antigenicity, immunogenicity and diagnostic potential.

Fontenot, J. Darrell; VanCott, Tom. C.; Parekh, Bharat S.; Pau, Chou-Pong; George, J. Richard; Birx, Debra L.; Zolla-Pazner, Susan; Gorny, Miroslaw K.; Gatewood, Joe M.

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Abstract

Objective: To evaluate the immunological properties of a panel of human mucin MUC1/HIV V3 loop chimeras.

Design: The immunodominant epitope of MUC1 (APDTR) was found to be structurally isomorphous with the tip of the principle neutralizing determinant (PND) of HIV-1 (MN) (GPGRA). A panel of 120 residue, six tandem repeat (TR) and 60 residue, three TR chimeric antigens were constructed in which the repeating MUC1 epitope is replaced by HIV-1 PND. Each 20 residue TR contains one PND epitope. The PND of HIV-1 is presented in the native [beta]-turn conformation at the crest of each repeating knob structure of the mucin-like protein.

Methods: The antigenicity of the chimeric antigens were compared using enzyme-linked immunosorbent assay (ELISA) and HIV-infected patient sera. Structural effects of antibody-antigen interactions were determined using surface plasmon resonance, with human monoclonal antibodies, chimeric antigens and the cyclic and linear V3 loops. Immunogenicity of three versus six TR was measured in mice.

Results: Nine residues of the HIV PND substituted into the mucin backbone were equivalent to the 36 residue cyclic V3 loop in ELISA. The 120 residue antigens induced high liter, immunoglobulin (Ig) M and IgG, and HIV-specific antibodies in mice.

Conclusions: MUC1/V3 chimeras efficiently detect HIV-specific antibodies in patient sera. Multivalent presentation of the PND is advantageous for higher affinity antibody-antigen interactions and for inducing HIV-specific IgM and IgG antibodies.

(C) Lippincott-Raven Publishers.

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