An understanding of the serum responses of both HIV-1-infected individuals and vaccines is necessary for the development of an effective HIV-1 vaccine. Perhaps the most important biological aspect of a serum response is its neutralizing activity, with a close second being a compendium of its antigenic recognition. We will utilize the tools of structural and computational biology to develop probes to assist in the evaluation of the neutralizing activity of sera, and to decipher the HIV-1 elements recognized by both binding and neutralizing antibodies. Further, these probes will be used for the selection and isolation of B-cells so that their antibody gene loci can be sequenced, enabling the in-depth characterization of secreted antibodies. These capabilities are expected to enhance our understanding of how a broadly neutralizing antibody response develops during the course of infection and also of how the humoral immune system targets vulnerable regions on the HIV-1 Env glycoprotein. The tools of computational design allow for the manipulation of both the surface of a protein as well as its interior. Surface manipulation allows for a precise control of antigenicity, whereas interior manipulation allows for physical properties of flexibility and stability to be altered, thereby modulating surface antigenicity. Together these tools should allow for a precise understanding of elicited serum responses. Such an understanding should facilitate the iterative structure-based improvement of immunogens. The next-generation sequencing technique, 454 pyrosequencing, allows hundreds of thousands of antibody sequences to be obtained directly from patient sera, thus enabling quantitative analysis of serum response, better understanding of antibody maturation process, and identification of broadly neutralizing antibodies. Due to the natural variation of antibody sequences and inherent sequencing errors, novel bioinformatics techniques have to be developed for antibodyome analysis. These techniques will play a critical role in sera analysis and antibody identification. Identified antibodies can represent natural solutions to antibody optimization, which has potential implications for therapeutic and/or passive transfer studies.

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Soto, Cinque; Ofek, Gilad; Joyce, M Gordon et al. (2016) Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. PLoS One 11:e0157409
Bonsignori, Mattia; Zhou, Tongqing; Sheng, Zizhang et al. (2016) Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody. Cell 165:449-63
Gorman, Jason; Soto, Cinque; Yang, Max M et al. (2016) Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design. Nat Struct Mol Biol 23:81-90
Doria-Rose, Nicole A; Bhiman, Jinal N; Roark, Ryan S et al. (2016) New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency. J Virol 90:76-91
Joyce, M Gordon; Wheatley, Adam K; Thomas, Paul V et al. (2016) Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses. Cell 166:609-23
Kong, Rui; Xu, Kai; Zhou, Tongqing et al. (2016) Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody. Science 352:828-33
Wu, Xueling; Zhang, Zhenhai; Schramm, Chaim A et al. (2015) Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection. Cell 161:470-85
Crooks, Ema T; Tong, Tommy; Chakrabarti, Bimal et al. (2015) Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. PLoS Pathog 11:e1004932
Kwon, Young Do; Pancera, Marie; Acharya, Priyamvada et al. (2015) Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. Nat Struct Mol Biol 22:522-31
Georgiev, Ivelin S; Joyce, M Gordon; Yang, Yongping et al. (2015) Single-Chain Soluble BG505.SOSIP gp140 Trimers as Structural and Antigenic Mimics of Mature Closed HIV-1 Env. J Virol 89:5318-29

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