The Structural and Lineage-Based Immunogen Design Scientific Research Support Component (SRSC) has the following roles within the overall B cell immunogen development effort: (a) to acquire a detailed structural picture of the stages of affinity maturation in clonal lineages of HlV-1 protective antibodies derived and analyzed as part of the B Cell Focus and (b) to develop approaches for design of immunogens that can elicit vaccine-induced responses similar to those that have matured in chronically infected subjects with broad neutralizing antibodies. This SRSC will receive BnAb and other protective antibody unmutated ancestor (UA) and intermediate antibodies (IA) from the B Cell Focus and other SRSCs and use UAs and IAs as template for new immunogen design.
Specific Aims :
Aim 1. Determine crystal structures of critical mAb Fabs from informative clonal antibody lineages from Aims 1 and 4 of the B Cell Focus and the Computational Biology SRSC.
Aim 2. Determine crystal structures (when feasible) of selected BnAb or other protective antibody Fabs from B Cell Focus Aims 1 and 4 in complex with gp120 (or a suitable gp120 fragment) or with a gp41 peptide or similar construct.
Aim 3. Vary selected positions on gp120 (or gp41) by random mutagenesis and use the library of variants, expressed on the surfaces of individual cells, in integrative screens for antigens that bind with enhanced affinity to UAs or lineage intermediate antibodies.
Aim 4. Express Envs or their fragments that result from the screens in Aim 3.

Public Health Relevance

The detailed information about antibody affinity maturation afforded by a combination of high-throughput sequence analysis and targeted 3D molecular structure determination opens up new possibilities for designing immunogens that can direct the immune system to respond in desired directions (e.g., toward broad, rather than narrow, neutralization of HIV-1 variants).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
4UM1AI100645-05
Application #
9088311
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Bonsignori, Mattia; Scott, Eric; Wiehe, Kevin et al. (2018) Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier. Immunity 49:1162-1174.e8
Blasi, Maria; Negri, Donatella; LaBranche, Celia et al. (2018) IDLV-HIV-1 Env vaccination in non-human primates induces affinity maturation of antigen-specific memory B cells. Commun Biol 1:134
Song, Hongshuo; Giorgi, Elena E; Ganusov, Vitaly V et al. (2018) Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection. Nat Commun 9:1928
Hurwitz, Julia L; Bonsignori, Mattia (2018) Multi-Envelope HIV-1 Vaccine Development: Two Targeted Immune Pathways, One Desired Protective Outcome. Viral Immunol 31:124-132
Yates, Nicole L; deCamp, Allan C; Korber, Bette T et al. (2018) HIV-1 Envelope Glycoproteins from Diverse Clades Differentiate Antibody Responses and Durability among Vaccinees. J Virol 92:
Castillo-Menendez, Luis R; Nguyen, Hanh T; Sodroski, Joseph (2018) Conformational Differences Between Functional Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Trimers and Stabilized Soluble Trimers. J Virol :
Finney, Joel; Kelsoe, Garnett (2018) Poly- and autoreactivity of HIV-1 bNAbs: implications for vaccine design. Retrovirology 15:53
Bradley, Todd; Peppa, Dimitra; Pedroza-Pacheco, Isabela et al. (2018) RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses. Cell 175:387-399.e17
Richard, Jonathan; Prévost, Jérémie; Baxter, Amy E et al. (2018) Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses. MBio 9:
Pardi, Norbert; Hogan, Michael J; Porter, Frederick W et al. (2018) mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov 17:261-279

Showing the most recent 10 out of 261 publications