This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neutralizing antibodies may form an important component of a vaccine against HIV-1. Passive antibody transfer studies have shown that neutralizing antibodies, at high concentrations, protect against HIV-1 challenge in animal models. Significantly, non-human primates have been protected from vaginal challenge with pathogenic SHIVs bearing the envelope glycoprotein of HIV-1 primary isolates. The mechanisms of protection by neutralizing antibody and, in particular, the role of Fc-mediated effector function have not been defined. The role of secretory (mucosal) IgA and the interplay between mucosal and systemic neutralizing antibodies is often suggested to be important but, for HIV-1, has not been formally studied. In the past years experiments were carried out to elucidate the role of Fc portion of the antibody in protection against SHIV using a panel of Fc antibody mutants of the neutralizing antibody b12. Protection was reduced when monkeys were treated with IgG1 b12 mutants deficient in antibody dependent cell cytolysis (ADCC) but protection was not reduced when the complement fixation mutant was used. These preliminary results pointed to ADCC as playing the most significant role in vivo. Although results were promising, the number of animals in the original study was too small to reach a definitive conclusion. In the past year 17 monkeys were added to the study. Two were treated with control antibody, and 3 groups of 5 each were treated with wild-type antibody, the ADCC mutant and the complement fixation mutant. 1 of 5 ADCC mutant treated monkeys became infected. All others treated monkeys were protected. Both controls were infected as well. Therefore, knocking out the ADCC function in the antibody significantly lessened protection pointing to a role in vivo. It is hypothesized that understanding the role of antibody isotype in HIV-1 immunity may guide the knowledge-based design of an effective vaccine against HIV-1.
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