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

ABSTRACT: 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.

SUBMITTER: Kong R

PROVIDER: S-EPMC6755680 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Kong Rui R Duan Hongying H Sheng Zizhang Z Xu Kai K Acharya Priyamvada P Chen Xuejun X Cheng Cheng C Dingens Adam S AS Gorman Jason J Sastry Mallika M Shen Chen-Hsiang CH Zhang Baoshan B Zhou Tongqing T Chuang Gwo-Yu GY Chao Cara W CW Gu Ying Y Jafari Alexander J AJ Louder Mark K MK O'Dell Sijy S Rowshan Ariana P AP Viox Elise G EG Wang Yiran Y Choi Chang W CW Corcoran Martin M MM Corrigan Angela R AR Dandey Venkata P VP Eng Edward T ET Geng Hui H Foulds Kathryn E KE Guo Yicheng Y Kwon Young D YD Lin Bob B Liu Kevin K Mason Rosemarie D RD Nason Martha C MC Ohr Tiffany Y TY Ou Li L Rawi Reda R Sarfo Edward K EK Schön Arne A Todd John P JP Wang Shuishu S Wei Hui H Wu Winston W Mullikin James C JC Bailer Robert T RT Doria-Rose Nicole A NA Karlsson Hedestam Gunilla B GB Scorpio Diana G DG Overbaugh Julie J Bloom Jesse D JD Carragher Bridget B Potter Clinton S CS Shapiro Lawrence L Kwong Peter D PD Mascola John R JR

Cell 20190701 3

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 vir ...[more]

PMID: 31348886

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Project description:Human astroviruses are recognized as a leading cause of viral diarrhea worldwide in children, immunocompromised patients, and the elderly. There are currently no vaccines available to prevent astrovirus infection; however, antibodies developed by healthy individuals during previous infection correlate with protection from reinfection, suggesting that an effective vaccine could be developed. In this study, we investigated the molecular mechanism by which several strains of human astrovirus serotype 2 (HAstV-2) are resistant to the potent HAstV-2-neutralizing monoclonal antibody PL-2 (MAb PL-2). Sequencing of the HAstV-2 capsid genes reveals mutations in the PL-2 epitope within the capsid's spike domain. To understand the molecular basis for resistance from MAb PL-2 neutralization, we determined the 1.35-Å-resolution crystal structure of the capsid spike from one of these HAstV-2 strains. Our structure reveals a dramatic conformational change in a loop within the PL-2 epitope due to a serine-to-proline mutation, locking the loop in a conformation that sterically blocks binding and neutralization by MAb PL-2. We show that mutation to serine permits loop flexibility and recovers MAb PL-2 binding. Importantly, we find that HAstV-2 capsid spike containing a serine in this loop is immunogenic and elicits antibodies that neutralize all HAstV-2 strains. Taken together, our results have broad implications for rational selection of vaccine strains that do not contain prolines in antigenic loops, so as to elicit antibodies against diverse loop conformations.IMPORTANCE Human astroviruses (HAstVs) infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. In this study, we investigated how several strains of HAstV are resistant to a virus-neutralizing monoclonal antibody. We determined the crystal structure of the capsid protein spike domain from one of these HAstV strains and found that a single amino acid mutation induces a structural change in a loop that is responsible for antibody binding. Our findings reveal how viruses can escape antibody neutralization and provide insight for the rational design of vaccines to elicit diverse antibodies that provide broader protection from infection.

Dataset Information

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

Publications

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

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