Proj.1 Immunization strategies to elicit bNAbs against HIV-1 PI: Bjorkman, P.J./Nussenzweig, M.C. ! Summary AIDS is a preventable disease, however, according to UNAIDS, millions of people are newly infected every year. The design of a vaccine for HIV-1 is therefore highly desirable. To date, despite numerous efforts, no immunization regimen reproducibly elicits broadly neutralizing antibodies (bNAbs) against HIV-1. Recently available native-like Env trimers do elicit antibodies that neutralize autologous tier-2 viruses but these antibodies have only limited potency and breadth. The observation that most of the native-like Env proteins do not bind the inferred germline (iGL) antibody precursors of bNAbs suggested that rationally designed iGL targeting immunogens would be required to initiate bNAb responses. The Nussenzweig lab has confirmed this hypothesis in knock in mice that carry the iGL PGT121 bNAb which targets the base of the V3 loop and surrounding glycans (V3/N332). Immunization with iGL targeting proteins followed by a series of more native- looking Env trimers elicited bNAbs in iGL PGT121 bNAb knock-in mice. The long term goal of the proposed research is to extend these studies to other animal models that more closely resemble a human immune response and also to other types of bNAbs such as the IOMA-like bNAbs targeting the CD4bs. To accomplish these goals Dr. Nussenzweig will work with Dr. Bjorkman to design and test new immunogens and immunization strategies to elicit V3/N332 and IOMA-like bNAbs in knock-in mice, wild type mice and mice that carry un-rearranged human immunoglobulin loci. The Nussenzweig lab plans to: 1) optimize the previous immunization protocol designed to elicit PGT121-like bNAbs; 2) extend the use of this immunization regimen to other iGL bNAb knock-in mice targeting the V3/N332 site such as the BG18GL mice; 3) design a consensus series of immunogens that elicits the class of V3/N332 bNAbs; 4) design immunization strategies that elicit IOMA-like CD4bs antibodies in IOMAGL knock-in mice; 5) extend these immunization experiments to wild type mice and mice that carry un-rearranged human immunoglobulin loci; 6) evaluate the suitability of the new immunogens to isolate bNAb precursors from healthy donors. The proposed experiments will produce candidate immunogens for vaccine clinical trials. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI100148-08
Application #
10062807
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
8
Fiscal Year
2021
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Wang, Haoqing; Barnes, Christopher O; Yang, Zhi et al. (2018) Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion. Cell Host Microbe 24:579-592.e4
Stadtmueller, Beth M; Bridges, Michael D; Dam, Kim-Marie et al. (2018) DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions. Immunity 49:235-246.e4
Gautam, Rajeev; Nishimura, Yoshiaki; Gaughan, Natalie et al. (2018) A single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection. Nat Med 24:610-616
Cohn, Lillian B; da Silva, Israel T; Valieris, Renan et al. (2018) Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation. Nat Med 24:604-609
Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Fc? Receptor Function and the Design of Vaccination Strategies. Immunity 47:224-233
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:
Mayer, Christian T; Gazumyan, Anna; Kara, Ervin E et al. (2017) The microanatomic segregation of selection by apoptosis in the germinal center. Science 358:
Wang, Haoqing; Gristick, Harry B; Scharf, Louise et al. (2017) Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies. Elife 6:
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
Nishimura, Yoshiaki; Gautam, Rajeev; Chun, Tae-Wook et al. (2017) Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543:559-563

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