UNAIDS has documented millions of new HIV-1 infections every year, thus a vaccine for HIV-1 is highly desirable. To date, despite numerous efforts, no immunization regimen reproducibly elicits broadly neutralizing antibodies (bNAbs) against HIV-1. Recently available native-like HIV-1 envelope spike (Env) trimers elicit antibodies that neutralize autologous tier-2 viruses but these antibodies have only limited potency and breadth. The observations that inferred germline (iGL) antibody precursors of bNAbs do not generally bind HIV-1 Env proteins or neutralizing HIV-1 suggested that rationally designed iGL-targeting Env immunogens would be required to initiate bNAb responses. Drs. Bjorkman and Nussenzweig propose a highly collaborative project to apply this approach to target epitopes of two classes of HIV-1 bNAbs: a class related to PGT121 that binds to the base of the V3 variable loop and interacts with the N332gp120 glycan (V3/N332 bNAbs), and IOMA-like bNAbs, a new class of CD4-mimetic CD4 binding site (CD4bs) bNAbs derived from the VH1-2 germline gene segment. The V3/N332 and IOMA classes were chosen because (i) V3/N332 Abs are among the most potent of bNAbs and are commonly found in HIV-infected individuals who develop bNAbs, (ii) IOMA's relatively low number of somatic hypermutations and its normal-length CDRL3 suggest it may be more easily elicited than VRC01-class VH1-2?derived CD4bs bNAbs that are heavily somatically mutated and contain rare 5-residue CDRL3s, and (iii) immunogen design will be facilitated the crystal structure of a natively-glycosylated Env trimer bound to the V3/N332 bNAb 10-1074 and to IOMA. The Bjorkman lab will create immunogens to target iGLs and shepherd bNAb maturation, while the Nussenzweig lab develops immunization schemes to elicit bNAbs using the designed immunogens. The Nussenzweig lab specific aims are: (1) Develop and simplify immunization protocols that elicit bNAbs to V3/N332 in iGL knock-in mice, (2) Adapt immunization protocols developed for V3/N332 bNAbs in knock-in mice to wild type and AlivaMab mice that carry un-rearranged human antibody loci, (3) Develop an immunization protocol to elicit IOMA-like antibodies, and (4) Determine the frequency of IOMA and V3/N332 bNAb precursors in the nave B cell repertoire of un-infected human donors. The Bjorkman lab specific aims are: (1) Solve structures of iGL?immunogen complexes to aid in structure-based immunogen design, (2) Use structure-based design and library screening to identify Env trimers that bind V3/N332 iGLs with high affinity, (3) Use structural information to guide construction of a yeast display library to find rare variants that bind IOMA iGL, (4) Combine results to create Env trimer immunogens that bind iGLs of both bNAbs and work with Dr. Nussenzweig to evaluate double and single immunogens in mice. These efforts will be supported by Core A (Automated cell/biochemical assays) and Core B (Protein Expression). The proposed experiments will produce candidate immunogens testing in macaques by collaborator Dr. Malcolm Martin and for vaccine trials in humans.

Public Health Relevance

HIV/AIDS remains an important threat to global public health; at least 60 million people have been infected with HIV-1, of which almost half have died. A vaccine to protect against HIV-1 infection is urgently needed, especially in the developing world. Building upon our knowledge of the structural correlates of broad and potent antibody neutralization of HIV-1, we propose immunogen design, selection, and evaluation schemes to raise broad and potent neutralizing antibodies in animal models that is directly relevant to vaccine efforts in humans.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Dang, Que
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
California Institute of Technology
Schools of Arts and Sciences
United States
Zip Code
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
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
Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Anti-retroviral antibody Fc?R-mediated effector functions. Immunol Rev 275:285-295
Gristick, Harry B; Wang, Haoqing; Bjorkman, Pamela J (2017) X-ray and EM structures of a natively glycosylated HIV-1 envelope trimer. Acta Crystallogr D Struct Biol 73:822-828
Bournazos, Stylianos; Wang, Taia T; Dahan, Rony et al. (2017) Signaling by Antibodies: Recent Progress. Annu Rev Immunol 35:285-311
Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Fc? Receptor Function and the Design of Vaccination Strategies. Immunity 47:224-233

Showing the most recent 10 out of 52 publications