HIV-1 neutralizing antibodies elicited in humans by a prefusion-stabilized envelope trimer form a reproducible class targeting fusion peptide

• Published in: Cell reports (Cambridge) Vol. 42; no. 7; p. 112755
• Main Authors: Wang, Shuishu, Matassoli, Flavio, Zhang, Baoshan, Liu, Tracy, Shen, Chen-Hsiang, Bylund, Tatsiana, Johnston, Timothy, Henry, Amy R., Teng, I-Ting, Tripathi, Prabhanshu, Becker, Jordan E., Changela, Anita, Chaudhary, Ridhi, Cheng, Cheng, Gaudinski, Martin, Gorman, Jason, Harris, Darcy R., Lee, Myungjin, Morano, Nicholas C., Novik, Laura, O’Dell, Sijy, Olia, Adam S., Parchment, Danealle K., Rawi, Reda, Roberts-Torres, Jesmine, Stephens, Tyler, Tsybovsky, Yaroslav, Wang, Danyi, Van Wazer, David J., Zhou, Tongqing, Doria-Rose, Nicole A., Koup, Richard A., Shapiro, Lawrence, Douek, Daniel C., McDermott, Adrian B., Kwong, Peter D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2023; Elsevier
• Subjects: AIDS Vaccines; Antibodies, Neutralizing; antibody-antigen binding; CP: Immunology; cryo-EM structure; env Gene Products, Human Immunodeficiency Virus; envelope trimer; fusion peptide; glycan hole; HIV Antibodies; HIV Infections; HIV Seropositivity; HIV vaccine; HIV-1; Humans; immunogen design; Peptides; reproducible antibody class; site of vulnerability; CP: Immunology; fusion peptide; antibody-antigen binding; glycan hole; immunogen design; cryo-EM structure; HIV vaccine; envelope trimer; reproducible antibody class; site of vulnerability
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112755

Elicitation of antibodies that neutralize the tier-2 neutralization-resistant isolates that typify HIV-1 transmission has been a long-sought goal. Success with prefusion-stabilized envelope trimers eliciting autologous neutralizing antibodies has been reported in multiple vaccine-test species, though not in humans. To investigate elicitation of HIV-1 neutralizing antibodies in humans, here, we analyze B cells from a phase I clinical trial of the “DS-SOSIP”-stabilized envelope trimer from strain BG505, identifying two antibodies, N751-2C06.01 and N751-2C09.01 (named for donor-lineage.clone), that neutralize the autologous tier-2 strain, BG505. Though derived from distinct lineages, these antibodies form a reproducible antibody class that targets the HIV-1 fusion peptide. Both antibodies are highly strain specific, which we attribute to their partial recognition of a BG505-specific glycan hole and to their binding requirements for a few BG505-specific residues. Prefusion-stabilized envelope trimers can thus elicit autologous tier-2 neutralizing antibodies in humans, with initially identified neutralizing antibodies recognizing the fusion-peptide site of vulnerability. [Display omitted] •HIV-1 neutralizing antibodies 2C06 and 2C09 from VRC 018 clinical trial are isolated•Cryo-EM structures of 2C06 and 2C09 in complex with HIV envelope trimer are determined•2C06 and 2C09 binding requires a glycan hole at 241 and BG505-specific residues•Antibodies 2C06 and 2C09 form a reproducible class, recognizing fusion peptide Vaccine elicitation of tier-2 HIV-1 neutralizing antibodies in humans has been a long-sought goal. Wang et al. isolate and determine structures of two antibodies from a clinical trial of a prefusion-closed HIV-1 envelope trimer. These antibodies target the fusion-peptide site of vulnerability, form a reproducible class, and neutralize the tier-2 HIV-1 strain BG505.