HIV/AIDS is the world's foremost human epidemic. Historically, preventive vaccines that elicit neutralizing antibodies have achieved the greatest impact in curtailing epidemics. HIV-1 has thwarted modern vaccine technology by both eluding and destroying the host immune system. Critical viral epitopes are masked by glycosylation, exposed only fleetingly, or mutagenized beyond recognition. However, amidst this human immune system failure there have emerged rare but effective antibodies that broadly neutralize HIV-1 by targeting its juxtamembrane fusion apparatus. Thus, despite the historical failure to generate immunogens that elicit clinically effective anti-HIV-1 antibodies, we know from those relatively rare humans who naturally produce them that this goal is mechanistically and immunologically achievable. Several naturally-occurring anti-HIV antibodies specifically recognize structured amino acid sequences of gp41, a dynamic fusion protein that adopts a continuum of conformational changes during the process of HIV-1 infection. Fueled by fresh insights from the structural biology of these epitopes and their antibody interactions, the present challenge is to recreate the virulent face of HIV-1 and transform it into an Achilles'heel. This proposal aims to apply a novel chemical technology, termed hydrocarbon stapling, which both reinforces the bioactive structure of natural peptides and confers unprecedented protease resistance, to develop Stabilized Antigenic Structures of gp41 (SAS-gp41) for HIV-1 vaccination. Once synthesized, the stapled antigens, modeled after the membrane proximal external region of gp41, will be rigorously tested and optimized for neutralization-competent structure, functional binding activity, in vitro and in vivo stability, immunogenicity, and HIV-1 neutralizing antibody response. By operating at the interface of chemistry, structural biology, pharmacology, and HIV immunology, we hope to transform HIV-1 from virion to immunogen.

Public Health Relevance

As we pass the quarter-century mark of the HIV-1 pandemic, developing an HIV-1 vaccine remains an intractable challenge. We propose that proper education of the immune system will require the development of sturdy and structured immunogens that faithfully reconstitute the virulent conformation of HIV polypeptides. To initiate a new path toward a human HIV-1 vaccine, we will deploy a multidisciplinary strategy to synthesize, characterize, and optimize structurally-reinforced antigens for HIV-1 vaccination using our new hydrocarbon stapling technology that endows natural peptides with bioactive shape and unprecedented stability.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-CCH-A (M2))
Program Officer
Pullen, Jeffrey K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Bird, Gregory H; Boyapalle, Sandhya; Wong, Terianne et al. (2014) Mucosal delivery of a double-stapled RSV peptide prevents nasopulmonary infection. J Clin Invest 124:2113-24
Bird, Gregory H; Irimia, Adriana; Ofek, Gilad et al. (2014) Stapled HIV-1 peptides recapitulate antigenic structures and engage broadly neutralizing antibodies. Nat Struct Mol Biol 21:1058-67
Walensky, Loren D; Bird, Gregory H (2014) Hydrocarbon-stapled peptides: principles, practice, and progress. J Med Chem 57:6275-88
Bird, Gregory H; Crannell, W Christian; Walensky, Loren D (2011) Chemical synthesis of hydrocarbon-stapled peptides for protein interaction research and therapeutic targeting. Curr Protoc Chem Biol 3:99-117
Kar, Alak K; Mao, Youdong; Bird, Gregory et al. (2011) Characterization of a core fragment of the rhesus monkey TRIM5α protein. BMC Biochem 12:1
Bird, Gregory H; Madani, Navid; Perry, Alisa F et al. (2010) Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic. Proc Natl Acad Sci U S A 107:14093-8