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).

National Institute of Health (NIH)
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
United States
Zip Code
Chen, Jia; Frey, Gary; Peng, Hanqin et al. (2014) Mechanism of HIV-1 neutralization by antibodies targeting a membrane-proximal region of gp41. J Virol 88:1249-58
Hraber, Peter; Seaman, Michael S; Bailer, Robert T et al. (2014) Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection. AIDS 28:163-9
Pollara, Justin; Bonsignori, Mattia; Moody, M Anthony et al. (2014) HIV-1 vaccine-induced C1 and V2 Env-specific antibodies synergize for increased antiviral activities. J Virol 88:7715-26
Verkoczy, Laurent; Diaz, Marilyn (2014) Autoreactivity in HIV-1 broadly neutralizing antibodies: implications for their function and induction by vaccination. Curr Opin HIV AIDS 9:224-34
Hwang, Kwan-Ki; Trama, Ashley M; Kozink, Daniel M et al. (2014) IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria. PLoS One 9:e90725
Haynes, Barton F; Moody, M Anthony; Alam, Munir et al. (2014) Progress in HIV-1 vaccine development. J Allergy Clin Immunol 134:3-10; quiz 11
Holl, T Matt; Yang, Guang; Kuraoka, Masayuki et al. (2014) Enhanced antibody responses to an HIV-1 membrane-proximal external region antigen in mice reconstituted with cultured lymphocytes. J Immunol 192:3269-79
Roederer, Mario; Keele, Brandon F; Schmidt, Stephen D et al. (2014) Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV. Nature 505:502-8
Dennison, S Moses; Anasti, Kara M; Jaeger, Frederick H et al. (2014) Vaccine-induced HIV-1 envelope gp120 constant region 1-specific antibodies expose a CD4-inducible epitope and block the interaction of HIV-1 gp140 with galactosylceramide. J Virol 88:9406-17
Fera, Daniela; Schmidt, Aaron G; Haynes, Barton F et al. (2014) Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains. Proc Natl Acad Sci U S A 111:10275-80

Showing the most recent 10 out of 48 publications