Neutralization of zoonotic retroviruses by human antibodies: Genotype-specific epitopes within the receptor-binding domain from simian foamy virus

• Published in: PLoS pathogens Vol. 19; no. 4; p. e1011339
• Main Authors: Dynesen, Lasse Toftdal, Fernandez, Ignacio, Coquin, Youna, Delaplace, Manon, Montange, Thomas, Njouom, Richard, Bilounga-Ndongo, Chanceline, Rey, Félix A, Gessain, Antoine, Backovic, Marija, Buseyne, Florence
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2023; Public Library of Science (PLoS)
• Subjects: Adaptive immunology; Analysis; Animals; Antibodies; Antibodies, Neutralizing; Antigenic determinants; Antigens; Binding sites; Biology and Life Sciences; Chronic infection; Competition; Control; Disease transmission; Domains; Epitopes; Epitopes, B-Lymphocyte - genetics; Genetic aspects; Genotype & phenotype; Genotypes; Glycan; Glycosylation; Health aspects; Heparan sulfate; HIV Antibodies; Hominidae; Human populations; Humans; Identification and classification; Immune system; Immunology; Infection; Infections; Life Sciences; Lymphocytes B; Medicine and Health Sciences; Microbiology and Parasitology; Monkeys & apes; Neutralization; Peptides; Plasma; Prevention; Proteins; Receptors; Retroviridae; Retroviruses; Simian foamy virus - genetics; Simian viruses; Testing; Trimers; Variable region; Vectors (Biology); Viral antibodies; Virology; Viruses; Zoonoses; Cameroon; Central Africa
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011339

Infection with viruses of animal origin pose a significant threat to human populations. Simian foamy viruses (SFVs) are frequently transmitted to humans, in which they establish a life-long infection, with the persistence of replication-competent virus. However, zoonotic SFVs do not induce severe disease nor are they transmitted between humans. Thus, SFVs represent a model of zoonotic retroviruses that lead to a chronic infection successfully controlled by the human immune system. We previously showed that infected humans develop potent neutralizing antibodies (nAbs). Within the viral envelope (Env), the surface protein (SU) carries a variable region that defines two genotypes, overlaps with the receptor binding domain (RBD), and is the exclusive target of nAbs. However, its antigenic determinants are not understood. Here, we characterized nAbs present in plasma samples from SFV-infected individuals living in Central Africa. Neutralization assays were carried out in the presence of recombinant SU that compete with SU at the surface of viral vector particles. We defined the regions targeted by the nAbs using mutant SU proteins modified at the glycosylation sites, RBD functional subregions, and genotype-specific sequences that present properties of B-cell epitopes. We observed that nAbs target conformational epitopes. We identified three major epitopic regions: the loops at the apex of the RBD, which likely mediate interactions between Env protomers to form Env trimers, a loop located in the vicinity of the heparan binding site, and a region proximal to the highly conserved glycosylation site N8. We provide information on how nAbs specific for each of the two viral genotypes target different epitopes. Two common immune escape mechanisms, sequence variation and glycan shielding, were not observed. We propose a model according to which the neutralization mechanisms rely on the nAbs to block the Env conformational change and/or interfere with binding to susceptible cells. As the SFV RBD is structurally different from known retroviral RBDs, our data provide fundamental knowledge on the structural basis for the inhibition of viruses by nAbs. Trial registration: The study was registered at www.clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT03225794/.