Project 1, entitled Immunogen Design and Selection, plays the major role of generating the HIV envelope glycoprotein-based candidate vaccine immunogens to be analyzed in this HIVRAD.
In Aim 1, we will design novel trimeric immunogens based upon three distinct strategies. Initially, we will utilize recent mapping data performed in our collaborative group on CD4 binding-site (CD4bs) directed neutralizing antibodies (nAbs) isolated from non-human primates (NHPs) immunized with HIV Env trimeric immunogens. We compared the NHP CD4bs nAbs to the known, more broadly nAbs isolated from HIV-1-infected human subjects t)y alanine scanning mutagenesis ofthe HlV-1 gpl 20. Using the alanine scan information, we generated divergent mAb footprint patterns between the NHP CD4bs Mabs and the structurally defined footprint ofthe human bNabs. Armed with this information, we will design stabilized trimers that preferentially present neutralizing epitopes to activate VH genes associated with the infection-elicited bNabs and to elicit neutralizing antibody responses by vaccination. In the 2nd approach, we will assess the ability of loop-deleted, conformationally stabilized trimers, which more rapidly elicit CD4bs-directed in rabbits, to do so in NHPs. Improved versions will be assessed for their capacity to elicit CD4bs Mabs or to synergize with full-length trimers to elicit CD4bs-directed B cell responses.
In Aim 2, we will generate sFVs of our isolated NHP CD4bs Abs (GE148 or GE136) and perform yeast cell-surface display, random mutagenesis and selection with conformationally stabilized Env core antigens to determine if we can evolve these non-broadly neutralizing CD4bs mAbs to become more broadly neutralizing and the levels of mutation required to achieve such a capacity. Finally, in Aim 3, we will select novel Env trimeric immunogens using directed evolution as a complementary approach to rational Env design. Env trimers, stabilized in the context of infectious virus using selection criteria established by Dr. Michael Zwick, will be assessed for their ability to elicit B cell responses in NHPs. In addition, HIV-1 Env trimers will be selected in the Zwick laboratory for recognition by NHP germline equivalents of CD4bs bNabs (e.g. VH1-02) or PG9 or PGT128 by iterative affinity-selection of viral mutants.

Public Health Relevance

The major objective of Project 1 is to generate novel HIV Env immunogens, an undertaking which is essential forthe overall goal ofthe HIVRAD to elicit broadly neutralizing antibodies to the human pathogen HIV-1. The successful elicitation of such antibodies would be a large step forward toward the goal of generating a broadly effective HlV-1 vaccine and would have a substantial impact on improving human public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI104722-01A1
Application #
8680622
Study Section
Special Emphasis Panel (ZAI1-KP-A (J1))
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$822,960
Indirect Cost
$238,410
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Sheng, Zizhang; Schramm, Chaim A; Connors, Mark et al. (2016) Effects of Darwinian Selection and Mutability on Rate of Broadly Neutralizing Antibody Evolution during HIV-1 Infection. PLoS Comput Biol 12:e1004940
Guenaga, Javier; Dubrovskaya, Viktoriya; de Val, Natalia et al. (2016) Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J Virol 90:2806-17
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
Tian, Ming; Cheng, Cheng; Chen, Xuejun et al. (2016) Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires. Cell 166:1471-1484.e18
Ingale, Jidnyasa; Stano, Armando; Guenaga, Javier et al. (2016) High-Density Array of Well-Ordered HIV-1 Spikes on Synthetic Liposomal Nanoparticles Efficiently Activate B Cells. Cell Rep 15:1986-99
Chen, Yajing; Wilson, Richard; O'Dell, Sijy et al. (2016) An HIV-1 Env-Antibody Complex Focuses Antibody Responses to Conserved Neutralizing Epitopes. J Immunol 197:3982-3998
Wang, Yimeng; Sundling, Christopher; Wilson, Richard et al. (2016) High-Resolution Longitudinal Study of HIV-1 Env Vaccine-Elicited B Cell Responses to the Virus Primary Receptor Binding Site Reveals Affinity Maturation and Clonal Persistence. J Immunol 196:3729-43
Schramm, Chaim A; Sheng, Zizhang; Zhang, Zhenhai et al. (2016) SONAR: A High-Throughput Pipeline for Inferring Antibody Ontogenies from Longitudinal Sequencing of B Cell Transcripts. Front Immunol 7:372
Dai, Kaifan; Khan, Salar N; Wang, Yimeng et al. (2016) HIV-1 Vaccine-elicited Antibodies Reverted to Their Inferred Naive Germline Reveal Associations between Binding Affinity and in vivo Activation. Sci Rep 6:20987
Phad, Ganesh E; Vázquez Bernat, Néstor; Feng, Yu et al. (2015) Diverse antibody genetic and recognition properties revealed following HIV-1 envelope glycoprotein immunization. J Immunol 194:5903-14

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