Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

• Published in: Nature medicine Vol. 24; no. 6; pp. 857 - 867
• Main Authors: Xu, Kai, Acharya, Priyamvada, Kong, Rui, Cheng, Cheng, Chuang, Gwo-Yu, Liu, Kevin, Louder, Mark K., O’Dell, Sijy, Rawi, Reda, Sastry, Mallika, Shen, Chen-Hsiang, Zhang, Baoshan, Zhou, Tongqing, Asokan, Mangaiarkarasi, Bailer, Robert T., Chambers, Michael, Chen, Xuejun, Choi, Chang W., Dandey, Venkata P., Doria-Rose, Nicole A., Druz, Aliaksandr, Eng, Edward T., Farney, S. Katie, Foulds, Kathryn E., Geng, Hui, Georgiev, Ivelin S., Gorman, Jason, Hill, Kurt R., Jafari, Alexander J., Kwon, Young D., Lai, Yen-Ting, Lemmin, Thomas, McKee, Krisha, Ohr, Tiffany Y., Ou, Li, Peng, Dongjun, Rowshan, Ariana P., Sheng, Zizhang, Todd, John-Paul, Tsybovsky, Yaroslav, Viox, Elise G., Wang, Yiran, Wei, Hui, Yang, Yongping, Zhou, Amy F., Chen, Rui, Yang, Lu, Scorpio, Diana G., McDermott, Adrian B., Shapiro, Lawrence, Carragher, Bridget, Potter, Clinton S., Mascola, John R., Kwong, Peter D.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2018; Nature Publishing Group
• Subjects: 60 APPLIED LIFE SCIENCES; 631/250/255/2514; 631/250/590; 692/699/255/1901; AIDS vaccines; AIDS Vaccines - immunology; Amino Acid Sequence; Animals; Antibodies; Antibodies, Neutralizing - immunology; Antigenic determinants; Aqueous solutions; B cells; Biomedical and Life Sciences; Biomedicine; Cancer Research; Critical components; Crystal structure; env Gene Products, Human Immunodeficiency Virus - chemistry; env Gene Products, Human Immunodeficiency Virus - metabolism; Epitopes; Epitopes - immunology; Female; Guinea Pigs; Health aspects; HIV; HIV Antibodies - immunology; HIV infections; HIV-1 - drug effects; HIV-1 - immunology; Human immunodeficiency virus; Immune response; Immune system; Immunization; Immunoglobulins; Infection; Infectious Diseases; Inhibitor drugs; Macaca mulatta; Medical research; Metabolic Diseases; Mice, Inbred C57BL; Microscopy; Models, Molecular; Molecular chains; Molecular Medicine; Monoclonal antibodies; Neurosciences; Neutralization; Neutralization Tests; Neutralizing; Peptides; Peptides - pharmacology; Physiological aspects; Primates; Recombinant Fusion Proteins - pharmacology; Rodents; Trimers; Vaccines; viral infection
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-018-0042-6

A central goal of HIV-1 vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryoelectron microscopy structures of these antibodies revealed fusion peptide conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses, suggesting translatability. The N terminus of the HIV-1 fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies. An alternative HIV vaccine design facilitates generation of HIV-1-antibodies, with promising neutralization breadth in rodents and nonhuman primates.