Potent neutralizing antibodies in humans infected with zoonotic simian foamy viruses target conserved epitopes located in the dimorphic domain of the surface envelope protein

Abstract

Human diseases of zoonotic origin are a major public health problem. Simian foamy viruses (SFVs) are complex retroviruses which are currently spilling over to humans. Replication-competent SFVs persist over the lifetime of their human hosts, without spreading to secondary hosts, suggesting the presence of efficient immune control. Accordingly, we aimed to perform an in-depth characterization of neutralizing antibodies raised by humans infected with a zoonotic SFV. We quantified the neutralizing capacity of plasma samples from 58 SFV-infected hunters against primary zoonotic gorilla and chimpanzee SFV strains, and laboratory-adapted chimpanzee SFV. The genotype of the strain infecting each hunter was identified by direct sequencing of the env gene amplified from the buffy coat with genotype-specific primers. Foamy virus vector particles (FVV) enveloped by wild-type and chimeric gorilla SFV were used to map the envelope region targeted by antibodies. Here, we showed high titers of neutralizing antibodies in the plasma of most SFV-infected individuals. Neutralizing antibodies target the dimorphic portion of the envelope protein surface domain. Epitopes recognized by neutralizing antibodies have been conserved during the cospeciation of SFV with their nonhuman primate host. Greater neutralization breadth in plasma samples of SFV-infected humans was statistically associated with smaller SFV-related hematological changes. The neutralization patterns provide evidence for persistent expression of viral proteins and a high prevalence of coinfection. In conclusion, neutralizing antibodies raised against zoonotic SFV target immunodominant and conserved epitopes located in the receptor binding domain. These properties support their potential role in restricting the spread of SFV in the human population.

An Immunodominant and Conserved B-Cell Epitope in the Envelope of Simian Foamy Virus Recognized by Humans Infected with Zoonotic Strains from Apes

“…8A and B). Two gorilla SFV genotypes that differ mostly in the central region of the env gene infect humans and NHPs (20), and we recently described coinfection by strains from the two genotypes (15). Binding magnitude to peptide N 96 -V 110 did not differ between individuals found to be infected with one or two SFV genotypes (Fig.…”

“…8D to F). We previously performed neutralization assays against each of the two genotypes from gorilla and chimpanzee SFV (SFVggo_huBAD468, SFVggo_huBAK74, SFVpsc_huHSRV.13 (prototype foamy virus [PFV]), and SFVpve_Pan2 [SFV7]) using a BHK-21-derived indicator cell line (15). Binding magnitude to peptide N 96 -V 110 strongly correlated with neutralization titers and breadth quantified on the same plasma samples ( Fig.…”

“…SFV-specific seropositivity is defined by a Gag-specific doublet in Western blots, with associated Bet-specific antibodies in some individuals (13,14). We recently described the presence of high titers of SFV-specific neutralizing antibodies in most individuals infected with a zoonotic gorilla SFV (15). The three subunits of the SFV envelope (leader peptide, gp18 LP ; surface, gp80 SU ; and transmembrane, gp48™) are generated by cleavage of a precursor.…”

“…They form heterotrimers assembled into trimeric spikes (16,17). A 250-amino-acid genotypespecific region located in gp80 SU is targeted by neutralizing antibodies (15).…”

“…Here, we report the presence of an immunodominant epitope located in the extracellular portion of the SFV envelope gp18 LP , recognized in ELISAs by plasma samples from Central African hunters infected with SFV. We precisely defined the amino acids involved in such recognition, quantified the titer and breadth of the antibodies, and searched for associations with major characteristics of SFV infection in humans such as SFV DNA levels and duration of infection (6,15).…”