Vaccine-elicited and naturally elicited antibodies differ in their recognition of the HIV-1 fusion peptide

• Published in: Frontiers in immunology Vol. 15; p. 1484029
• Main Authors: Reveiz, Mateo, Xu, Kai, Lee, Myungjin, Wang, Shuishu, Olia, Adam S., Harris, Darcy R., Liu, Kevin, Liu, Tracy, Schaub, Andrew J., Stephens, Tyler, Wang, Yiran, Zhang, Baoshan, Huang, Rick, Tsybovsky, Yaroslav, Kwong, Peter D., Rawi, Reda
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 14.11.2024
• Subjects: AIDS Vaccines - immunology; Amino Acid Sequence; Antibodies, Neutralizing - immunology; env Gene Products, Human Immunodeficiency Virus - chemistry; env Gene Products, Human Immunodeficiency Virus - immunology; fusion peptide; HIV Antibodies - immunology; HIV Envelope Protein gp41 - chemistry; HIV Envelope Protein gp41 - immunology; HIV Infections - immunology; HIV Infections - virology; HIV-1 - immunology; HIV-1 vaccine; Humans; Immunology; Molecular Dynamics Simulation; naturally elicited; neutralizing antibody; Protein Binding; vaccine elicited; fusion peptide; neutralizing antibody; HIV-1 vaccine; vaccine elicited; naturally elicited
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1484029

Broadly neutralizing antibodies have been proposed as templates for HIV-1 vaccine design, but it has been unclear how similar vaccine-elicited antibodies are to their naturally elicited templates. To provide insight, here we compare the recognition of naturally elicited and vaccine-elicited antibodies targeting the HIV-1 fusion peptide, which comprises envelope (Env) residues 512–526, with the most common sequence being AVGIGAVFLGFLGAA. Naturally elicited antibodies bound peptides with substitutions to negatively charged amino acids at residue positions 517–520 substantially better than the most common sequence, despite these substitutions rarely appearing in HIV-1; by contrast, vaccine-elicited antibodies were less tolerant of sequence variation, with no substitution of residues 512–516 showing increased binding. Molecular dynamics analysis and cryo-EM structural analysis of the naturally elicited ACS202 antibody in complex with the HIV-1 Env trimer with an alanine 517 to glutamine substitution suggested enhanced binding to result from electrostatic interactions with positively charged antibody residues. Overall, vaccine-elicited antibodies appeared to be more fully optimized to bind the most common fusion peptide sequence, perhaps reflecting the immunization with fusion peptide of the vaccine-elicited antibodies.