Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization

• Published in: Cell Vol. 178; no. 3; pp. 567 - 584.e19
• Main Authors: Kong, Rui, Duan, Hongying, Sheng, Zizhang, Xu, Kai, Acharya, Priyamvada, Chen, Xuejun, Cheng, Cheng, Dingens, Adam S., Gorman, Jason, Sastry, Mallika, Shen, Chen-Hsiang, Zhang, Baoshan, Zhou, Tongqing, Chuang, Gwo-Yu, Chao, Cara W., Gu, Ying, Jafari, Alexander J., Louder, Mark K., O’Dell, Sijy, Rowshan, Ariana P., Viox, Elise G., Wang, Yiran, Choi, Chang W., Corcoran, Martin M., Corrigan, Angela R., Dandey, Venkata P., Eng, Edward T., Geng, Hui, Foulds, Kathryn E., Guo, Yicheng, Kwon, Young D., Lin, Bob, Liu, Kevin, Mason, Rosemarie D., Nason, Martha C., Ohr, Tiffany Y., Ou, Li, Rawi, Reda, Sarfo, Edward K., Schön, Arne, Todd, John P., Wang, Shuishu, Wei, Hui, Wu, Winston, Mullikin, James C., Bailer, Robert T., Doria-Rose, Nicole A., Karlsson Hedestam, Gunilla B., Scorpio, Diana G., Overbaugh, Julie, Bloom, Jesse D., Carragher, Bridget, Potter, Clinton S., Shapiro, Lawrence, Kwong, Peter D., Mascola, John R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-07-2019; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; AIDS Vaccines - immunology; Amino Acid Sequence; Animals; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - classification; Antibodies, Neutralizing - immunology; B cell ontogeny; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; broadly neutralizing antibody; Crystallography, X-Ray; env Gene Products, Human Immunodeficiency Virus - chemistry; env Gene Products, Human Immunodeficiency Virus - immunology; env Gene Products, Human Immunodeficiency Virus - metabolism; Female; fusion peptide; HEK293 Cells; HIV Antibodies - chemistry; HIV Antibodies - classification; HIV Antibodies - immunology; HIV-1 - metabolism; HIV-1 vaccine; Humans; immune monitoring; Immunologi inom det medicinska området; Infektionsmedicin; interaction hotspot; Klinisk medicin; Macaca mulatta; Male; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; multidonor antibody class; Peptides - chemistry; Peptides - immunology; Protein Structure, Tertiary; fusion peptide; broadly neutralizing antibody; multidonor antibody class; HIV-1 vaccine; immune monitoring; B cell ontogeny; interaction hotspot
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.06.030

The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.
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•Vaccine elicitation of FP-directed antibody that neutralizes up to 59% of HIV•Development for five NHP lineages of vaccine-induced broadly neutralizing antibodies•FP-carrier effective at priming and Env-trimer effective at maturing•Priming with a target subregion induces antibodies with target-interaction hotspots
A cross-clade, cross-reactive HIV-1 neutralizing antibody with ∼59% neutralization breadth is elicited in macaques using a fusion-peptide-primed vaccine regimen, which focuses antibody-binding energy on a conserved viral epitope. Further phylogenetic antibody analysis provides insight into the eclipse phase of B cell development.