Monoclonal antibodies to the V2 domain of MN-rgp120: fine mapping of epitopes and inhibition of α4β7 binding.
BACKGROUND
Recombinant gp120 (MN-rgp120) was a major component of the AIDSVAX B/E vaccine used in the RV144 trial. This was the first clinical trial to show that vaccination could prevent HIV infection in humans. A recent RV144 correlates of protection study found that protection correlated with the presence of antibodies to the V2 domain. It has been proposed that antibodies to the α4β7 binding site in the V2 domain might prevent HIV-1 infection by blocking the ability of virions to recognize α4β7 on activated T-cells. In this study we investigated the specificity of monoclonal antibodies (MAbs) to the V2 domain of MN-rgp120 and examined the possibility that these antibodies could inhibit the binding of MN-rgp120 to the α4β7 integrin.


RESULTS
Nine MAbs to the V2 domain were isolated from mice immunized with recombinant envelope proteins. The ability of these MAbs to inhibit HIV infection, block the binding of gp120 to CD4, and block the binding of MN-rgp120 to the α4β7 integrin was measured. Mutational analysis showed that eight of the MAbs recognized two immunodominant clusters of amino acids (166-168 and 178-183) located at either end of the C strand within the four-strand anti-parallel sheet structure comprising the V1/V2 domain.


CONCLUSIONS
These studies showed that the antigenic structure of the V2 domain is exceedingly complex and that MAbs isolated from mice immunized with MN-rgp120 exhibited a high level of strain specificity compared to MAbs to the V2 domain isolated from HIV-infected humans. We found that immunization with MN-rgp120 readily elicits antibodies to the V2 domain and some of these were able to block the binding of MN-rgp120 to the α4β7 integrin.
Antibody Engineering Department, Genentech, Incorporated, South San Francisco, California, United States of America.
Gerald R
GR
Nakamura
Dora P A J
DP
Fonseca
Sara M
SM
O'Rourke
Aaron L
AL
Vollrath
Phillip W
PW
Berman
D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity; D018604:Epitope Mapping; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009500:Neutralization Tests; D011485:Protein Binding
D000911:Antibodies, Monoclonal; D015699:HIV Envelope Protein gp120; D016023:Integrins; C071777:integrin alpha4beta7