One of the major challenges of HlV-1 vaccine development is the elicitation of broadly neutralizing antibodies (bNAbs) against HIV Env. The recent isolation of several bNAbs from HIV-infected individuals demonstrates that the human B cell repertoire can generate bNAbs targeting the conserved Env region. However, there is still a tremendous knowledge gap regarding how the broad responses are elicited during chronic HIV-1 infection and, additionally, how these compare to the much more limited responses elicited by Env vaccination. To fill this information gap, we propose to define and improve the elicitation of neutralizing antibody responses toward the most functionally conserved and accessible element ofthe HIV-1 Env complex, including the receptor CD4 binding site (CD4bs). Previously, we developed a multicolor Env epitope-specific B cell sorting and RT-PCR strategy to analyze the memory B cell compartment of HIVinfected individuals, which led to the isolation of CD4bs potent and bNAb, VRCOl, which neutralizes >90% of circulating primary viruses. We adapted this epitope-specific memory B cell sorting strategy to extend our analyses to gain insight of Env B cell response during and following Env immunogen vaccination into nonhuman primates (NHPs). Accordingly, the aims of this Project 3 are summarized as follows.
In Aim 1 we will develop envelope-specific, including CD4bs-specific memory B cell isolation and monoclonal antibody cloning from Env immunogen vaccinated NHP animals and design new and novel probes specific for bNAb isolation.
In Aim 2, we will characterize the Env-specific monoclonal antibody specificities with state ofthe art binding and characterization assays.
In Aim 3, we will investigate the role, composition, and evolution pathway ofthe Env-specific IgM memory B cell compartment, a subset of memory B cells, which recently has been shown to play an important role in the long term B cell response.

Public Health Relevance

This study proposes to gain basic and high resolution insight ofthe primate B cell response to the HIV-1 envelope glycoproteins (Env) conserved and accessible structural/functional elements elicited by engineered Env immunogen. The outcomes of this study will contribute to the developement of a broadly effective HIV-1 vaccine, particularly to the improvement of antibody response, as well as increase the understanding of host/immunoaen interactions.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-KP-A (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Khan, Salar N; Sok, Devin; Tran, Karen et al. (2018) Targeting the HIV-1 Spike and Coreceptor with Bi- and Trispecific Antibodies for Single-Component Broad Inhibition of Entry. J Virol 92:
Sarkar, Anita; Bale, Shridhar; Behrens, Anna-Janina et al. (2018) Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer. Nat Commun 9:1956
Yang, Lifei; Sharma, Shailendra Kumar; Cottrell, Christopher et al. (2018) Structure-Guided Redesign Improves NFL HIV Env Trimer Integrity and Identifies an Inter-Protomer Disulfide Permitting Post-Expression Cleavage. Front Immunol 9:1631
Bale, Shridhar; Martiné, Alexandra; Wilson, Richard et al. (2018) Cleavage-Independent HIV-1 Trimers From CHO Cell Lines Elicit Robust Autologous Tier 2 Neutralizing Antibodies. Front Immunol 9:1116
Singh, Rajendra; Stoneham, Charlotte; Lim, Christopher et al. (2018) Phosphoserine acidic cluster motifs bind distinct basic regions on the ? subunits of clathrin adaptor protein complexes. J Biol Chem 293:15678-15690
Pauthner, Matthias; Havenar-Daughton, Colin; Sok, Devin et al. (2017) Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches. Immunity 46:1073-1088.e6
Guenaga, Javier; Garces, Fernando; de Val, Natalia et al. (2017) Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein. Immunity 46:792-803.e3
Cai, Hui; Orwenyo, Jared; Guenaga, Javier et al. (2017) Synthetic multivalent V3 glycopeptides display enhanced recognition by glycan-dependent HIV-1 broadly neutralizing antibodies. Chem Commun (Camb) 53:5453-5456
Soldemo, Martina; Àdori, Monika; Stark, Julian M et al. (2017) Glutaraldehyde Cross-linking of HIV-1 Env Trimers Skews the Antibody Subclass Response in Mice. Front Immunol 8:1654
Sheng, Zizhang; Schramm, Chaim A; Kong, Rui et al. (2017) Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation. Front Immunol 8:537

Showing the most recent 10 out of 44 publications