10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 22
S.-H. Xiang¹ , M. Abreu¹, J. Robinson², J. Sodroski^1
1Dana-Farber Cancer Inst, Boston, MA and ²Tulane Univ Med Ctr, New Orleans, LA

BACKGROUND: The binding site of CD4-induced (CD4i) antibodies on the gp120 envelope glycoprotein of HIV-1 is known to overlap with the binding site for co-receptors. Most CD4i antibodies exhibit only weak neutralizing activity against HIV-1 isolates, which have evolved mechanisms to resist these antibodies. Additional CD4i antibodies were derived from acutely HIV-1-infected individuals undergoing early structured treatment interruptions (STI). A newly isolated monoclonal antibody, named E51, was found to be CD4-inducible and exhibited more potent neutralizing activity against HIV-1 primary strains.

METHODS: The E51 antibody was isolated from a cell line established from an early STI patient. The epitope mapping of the E51 epitope on the HIV-1 gp120 glycoprotein was carried out by site-directed mutagenesis and radio-immunoprecipitation. Neutralizing activity was measured by a single-round infection assay using recombinant HIV-1 expressing luciferase.

RESULTS: A panel of about 50 mutants of YU2 gp120 was used for E51 epitope mapping. The results clearly revealed that 2 neighboring residues, K421 and Q422, within the 4th conserved (C4) region of gp120, were critical for E51 antibody binding. These 2 residues of gp120 are also known to be required for CCR5 coreceptor binding. The neutralization assay demonstrated that E51 has higher neutralizing activities than the prototype CD4i antibody 17b. We also showed that the E51 antibody could neutralize viruses that had already attached to the cells prior to entry. This property is unusual for CD4i antibodies. It is suggested that the long CDR3 loop of the E51 heavy chain may allow the antibody to access the virion-cell complex.

CONCLUSIONS: The E51 antibody is a broadly neutralizing antibody and its epitope is located in a conserved gp120 region important for chemokine receptor binding. This finding may have important implications for targeting inhibitors and vaccine development.

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