Designing effective strategies to combat HIV-1 requires structural knowledge of how antibodies (Abs) recognize HIV envelope proteins and how they are used by the immune system to eliminate viruses and virally-infected cells. Until recently, only a small number of broadly neutralizing antibodies (bNAbs) against HIV-1 had been characterized and the immunological basis for their breadth and potency remains poorly understood. The limited availability of bNAbs was resolved by new methods developed by Dr. Nussenzweig for HIV Ab isolation from the B cells of HIV-infected individuals. Several of these Abs, including NIH45-46, show superior potency and breadth to VRCOl, previously the best bNAb. We collaborated with Dr. Nussenzweig to solve the structure of NIH45-46 bound to gpl 20, and used structure-based design to increase its potency at least 10-fold, making NIH45-46 the best anti-HIV bNAb available as of its publication in 2011;we have now made an even more effective version (45-46m2) that neutralizes up to 97% of HIV strains. We will now collaborate with Drs. Nussenzweig to determine their mechanisms of action in animal models. The Ravetch laboratory has developed amino acid and glycan modifications of IgG Fc regions that optimize binding to activating Fc receptors, which will be introduced into designed bNAbs to increase their effector functions. In collaboration with Drs. Nussenzweig and Ravetch, we propose to determine the structural correlates of (i) broad/potent neutralization by the variable Fabs of bNAbs, and (ii) improved effector functions mediated by Fc regions. Information gleaned from these structures is directly relevant to """"""""reverse vaccination"""""""" involving gene therapy to deliver improved bNAbs and also required for immunogen design. This collaboration presents the opportunity to merge structural biology with in vitro and in vivo efficacy evaluations of new bNAbs against HIV, which will be facilitated by a set of scientific cores that will permit all three laboratories to quickly and accurately measure neutralization potencies and binding profiles of bNAbs (Core A, Automated Cell/Biochemical Assays Core), express large numbers of different bNAbs and HIV proteins (Core B, Protein Expression Core), and conduct experiments with HIV-infected humanized mice (Core C, Animal Services Core). The following specific aims will be pursued collaboratively: 1) Solve crystal structures of bNAb Fabs and bNAb Fab-gp120 complexes to define essential features of broad/potent HIV neutralization. 2) Solve crystal structures of IgG Fc regions and Fc/Fc receptor complexes to determine the structural effects of effector function-altering amino acid and glycan changes. 3) Produce natural antibody variants with enhanced activity in neutralization and mediating effector functions. 4) Use knowledge gained from these structural studies to design immunogens to elicit bNAbs.

Public Health Relevance

HIV/AIDS remains a critical threat to global public health. At least 60 million people have been infected with HIV. Although anti-retroviral drugs have been effective in the developed world, a vaccine and/or new methods to prevent infections are needed in the developing world. We will systematically analyze the structures of anti-HIV antibodies with the goal of understanding their protective mechanisms and routes of viral resistance, information that will be used to improve their efficacy and to design immunogens for vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI100148-02
Application #
8617124
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
DUNS #
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Freund, Natalia T; Wang, Haoqing; Scharf, Louise et al. (2017) Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller. Sci Transl Med 9:
Horwitz, Joshua A; Bar-On, Yotam; Lu, Ching-Lan et al. (2017) Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo. Cell 170:637-648.e10
Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Fc? Receptor Function and the Design of Vaccination Strategies. Immunity 47:224-233
Nishimura, Yoshiaki; Gautam, Rajeev; Chun, Tae-Wook et al. (2017) Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543:559-563
Mayer, Christian T; Gazumyan, Anna; Kara, Ervin E et al. (2017) The microanatomic segregation of selection by apoptosis in the germinal center. Science 358:
Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Anti-retroviral antibody Fc?R-mediated effector functions. Immunol Rev 275:285-295
Bournazos, Stylianos; Wang, Taia T; Dahan, Rony et al. (2017) Signaling by Antibodies: Recent Progress. Annu Rev Immunol 35:285-311
Halper-Stromberg, Ariel; Nussenzweig, Michel C (2016) Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest 126:415-23
McGuire, Andrew T; Gray, Matthew D; Dosenovic, Pia et al. (2016) Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice. Nat Commun 7:10618
Ahmed, Alysia A; Keremane, Sravya R; Vielmetter, Jost et al. (2016) Structural characterization of GASDALIE Fc bound to the activating Fc receptor Fc?RIIIa. J Struct Biol 194:78-89

Showing the most recent 10 out of 46 publications