Our laboratory is studying the relationships among antibody specificity, effector functions, and protective immunity in both HIV-1 infected humans and in a rhesus macaque vaccine model. We have developed methods to quantify memory B cell responses (BMem) at the clonal level that allow the capture of desired specificities as molecularly cloned monoclonal antibodies (mAbs). Using these methods we recently reported discordance between BMem and circulating antibodies for the HIV-1 envelope glycoprotein (Env) (1) in a population of HIV-1 infected people who control viremia to undetectable levels in the absence of anti-retroviral therapy(2, 3). Monoclonal antibody analysis confirmed the presence of bona fide BMem specific for Env epitopes for which circulating antibodies were absent. These data illustrate the lack of persistent serological memory to HIV-1 Env in the absence of continuous antigenic stimulation, which is a serious problem in exploiting Env immuogens as HIV-1 vaccines. Studies are underway in our group to understand the mechanism of this defect with the long-term goal of increasing persistence of anti-Env antibody responses after vaccination.
In a related series of studies to probe the relationships between specificity and function, we are isolating Env-specific mAbs from HIV-1 infected people who have circulating antibodies that neutralize a broad array of HIV-1 isolates. We are also carrying out similar studies using non-human primates that control a SHIV challenge consequent to immunization with the conformationally constrained gp120 immunogen (FLSC) developed in collaboration with IHV colleagues (4, 5). These studies are ongoing, however, in addition to conventional neutralizing mAbs, we have also found a new category of non-neutralizing mAbs that mediate potent Fc-mediated effector function. A subset of these mAbs recognize epitopes that are selectively exposed during viral entry. We are evaluating these mAbs for specificity by epitope mapping and x-ray crystallography and ultimately by passive immunization in non-human primates to determine their protective efficacy. These studies will help delineate the relationships among specificity, effector function, and protective immunity to HIV-1.