HIV-specific neutralizing antibodies (Nabs) are considered a critical component of a HIV vaccine response. One of the major challenges to developing an effective Nab response through immunization is that we do not know how to elicit such Nabs. The identification of broad and potent Nabs in adults provided great encouragement for the field, as it suggested that broad and potent antibodies can be elicited in response to HIV antigens. However, the Mabs isolated to date are largely derived from individuals with a long-term HIV infection - in some cases greater than a decade - and a disappointing feature of these antibodies is the extent of affinity maturation and variation from germline, which is greater than 40% in some cases. Thus, while these Mabs helped define epitopes targeted by some notably broad HIV-specific Nabs, they raise challenging issues regarding how to elicit Nabs with these properties, as these responses have evolved after continued HIV sequence variation and stimulation over many years. We believe that because immunization may not be able to mimic this type of long-term affinity maturation process, it is critical to determine if it is possible t elicit a rapid, broad Nab response in HIV infection, and if so, to define how this occurs. We recently discovered that HIV-infected infants develop broad and potent HIV-specific Nab responses, in some cases, within the first year of their infection. Mapping studies suggest that these responses are distinct from those found in most adults with broad Nab activity. We propose here to characterize these novel responses with the following specific AIMs: 1) To isolate HIV-specific monoclonal antibodies from infants with broad Nabs and define whether the breadth of their response is due to a polyclonal response or a monoclonal response. 2) To define the epitope specificity of the Mabs that contributed to the breadth of the infant response. 3) To determine the ontogeny of the antibody gene of the Mab and define the original B cell receptor that recognized HIV to give rise to the later Mab. 4) To define and compare the binding properties of mature versus initial neutralizing antibodies. Infants who developed a rapid robust HIV-specific Nab response may hold important clues to the nature of broad and potent Nabs that can be elicited with shorter-term immunization strategies. We believe that defining the progenitor B cell receptor and the pathway and functional interactions that resulted in such bNabs will provide critical insights into how to elicit such responses with a vaccine.
A major hurdle to developing a protective HIV vaccine is our inability to define a pathway to generate protective neutralizing antibodies. A recent study by our group showed that infants make notably broad and potent HIV neutralizing antibody responses, and do so relatively quickly. We propose to study how they accomplish this so that this information can be used to help define more promising vaccine approaches.
|Dingens, Adam S; Acharya, Priyamvada; Haddox, Hugh K et al. (2018) Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV. PLoS Pathog 14:e1007159|
|DeWitt 3rd, William S; Mesin, Luka; Victora, Gabriel D et al. (2018) Using Genotype Abundance to Improve Phylogenetic Inference. Mol Biol Evol 35:1253-1265|
|Olson, Branden J; Matsen 4th, Frederick A (2018) The Bayesian optimist's guide to adaptive immune receptor repertoire analysis. Immunol Rev 284:148-166|
|Dhar, Amrit; Davidsen, Kristian; Matsen 4th, Frederick A et al. (2018) Predicting B cell receptor substitution profiles using public repertoire data. PLoS Comput Biol 14:e1006388|
|Dingens, Adam S; Haddox, Hugh K; Overbaugh, Julie et al. (2017) Comprehensive Mapping of HIV-1 Escape from a Broadly Neutralizing Antibody. Cell Host Microbe 21:777-787.e4|
|Simonich, Cassandra A; Williams, Katherine L; Verkerke, Hans P et al. (2016) HIV-1 Neutralizing Antibodies with Limited Hypermutation from an Infant. Cell 166:77-87|
|Verkerke, Hans P; Williams, James A; Guttman, Miklos et al. (2016) Epitope-Independent Purification of Native-Like Envelope Trimers from Diverse HIV-1 Isolates. J Virol 90:9471-82|