Isolation of broadly neutralizing antibodies (bnAbs) has been a monumental step forward in HIV-1 antibody directed vaccine efforts. The discovery of bnAbs was predicated on two major advancements. First, development of high throughput neutralization assays allowed for the identification of HIV-1 infected individuals that had broad and potent neutralization responses, termed ?elite neutralizers.? Second, isolation of individual antibody producing cells and subsequent single cell PCR technologies made it possible to clone and produce bnAbs in an efficient manner from the elite neutralizers. At this time, no vaccine immunogens have been designed that can elicit bnAbs in uninfected at risk individuals. Nearly all bnAbs, isolated to date, have extensive level of somatic mutation, which may be one characteristic that will be especially difficult to elicit with current vaccine technologies. Human vaccine trials, correlate analysis, and animal studies all suggest that antibody dependent cellular cytotoxicity (ADCC) along with neutralization responses are also important in preventing virus acquisition. Despite the importance of ADCC responses, efforts similar to those that led to the discovery of bnAbs have not been undertaken for ADCC inducing antibodies. For instance, previous investigations have not identified individuals that possess exceptionally broad and potent anti-HIV-1 ADCC responses, termed ?elite ADCC.? Identification and subsequent isolation of antibodies from individuals that have elite ADCC activity may yield novel anti-HIV-1 antibodies. These ADCC inducing antibodies may be more amenable for elicitation with current immunogens. Individuals with broad and potent ADCC responses have not been identified primarily because of assays and reagent limitations. We have developed a novel ADCC assay which, for the first time, will allow high throughput screening of a large number of samples for ADCC breadth and potency. We propose to examine ADCC responses against a diverse panel of viruses among a large number of chronically infected treatment nave patients. Our studies will begin to identify individuals that harbor elite ADCC. Furthermore, we will examine if specific antibody characteristics, such as binding to infected cells, antibody glycosylation, and immunoglobulin subtype, confer ADCC breadth and potency. Future investigations will aim to isolate and characterize antibodies from individuals shown to have broad and potent ADCC responses. These proposed studies are the first step towards the goal of identifying novel anti-HIV-1 antibodies that can potentially both prevent virus acquisition and be elicited with current vaccine immunogens.
Discovery and isolation of anti-HIV-1 broadly neutralizing antibodies hinged on the ability to identify individuals that had exceptionally broad and potent neutralization responses. Vaccine trials, correlate analysis, and animal studies suggest that besides neutralization, antibodies that induce antibody dependent cellular cytotoxicity (ADCC) are crucial in preventing virus acquisition. We propose to use a novel assay to identify individuals that have exceptionally broad and potent anti-HIV-1 ADCC activity so that future investigations can isolate and characterize unique antibodies from these patients for antibody directed vaccine efforts.
