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

Date Published: October 8, 2018

Publisher: Public Library of Science

Author(s): Caroline Lambert, Mathilde Couteaudier, Julie Gouzil, Léa Richard, Thomas Montange, Edouard Betsem, Réjane Rua, Joelle Tobaly-Tapiero, Dirk Lindemann, Richard Njouom, Augustin Mouinga-Ondémé, Antoine Gessain, Florence Buseyne, Katie J. Doores.

http://doi.org/10.1371/journal.ppat.1007293

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.

Partial Text

Simian foamy viruses (SFVs) are complex retroviruses that are widely prevalent in nonhuman primates (NHPs) [1]. In animals, SFV replicate in the superficial cell layers of the buccal cavity [2] and are mostly transmitted through bites and licking [3]. Humans are not natural hosts of SFV, but can be persistently infected over several decades after a cross-species transmission event [4–7]. Most SFV-infected people were bitten by a NHP and are thus the first hosts of a zoonotic virus [6, 8]. Human infection with zoonotic SFV is thus a natural model to study the key steps of the emergence of retroviruses. Several NHP species live in the tropical forests of Central Africa, and people from rural areas are frequently exposed to their body fluids through hunting, butchering, and meat consumption. Several new zoonotic agents have emerged from simian reservoirs populating this region, including human immunodeficiency virus-1 (HIV-1), human T-cell leukemia virus-1 (HTLV-1), and Ebola and Monkeypox viruses [9]. We have established that the prevalence rates of SFV in South Cameroon are approximately 0.3% of the general population and greater than 20% for people who have been bitten by a NHP [8, 10, 11]. Our work and other studies on people infected with SFV from African NHP species have consistently reported the persistence of replication-competent virus and the presence of SFV DNA in blood cells [12–18]. Blood gorilla SFV DNA loads vary between 1 and 1000 copies/105 cells [8, 18]. This is the range observed for blood HIV-1 DNA levels in HIV-1 infected humans [19].

We report the presence of high titers of neutralizing antibodies in the plasma of most SFV-infected individuals. Ape SFV species comprise two genotypes that cocirculate in humans and NHPs from Central-Africa [33]. We detected predominantly genotype-specific neutralization. We constructed vectors with chimeric Env, based on naturally occurring sequence variations, and used them to map dominant viral susceptibility sites to the dimorphic portion of the surface domain that overlaps the receptor-binding domain. The frequent cross-neutralization of gorilla and chimpanzee SFVs supports the recognition of highly conserved epitopes. Our description of the neutralization patterns of SFV-infected humans provides two key pieces of information concerning their virological status: gorilla SFVs appear to continuously or sporadically express their viral proteins and the coinfection rate is over 30%. Several hematological markers differ between SFV-infected individuals and uninfected controls [32]. We found that a larger neutralization breadth is statistically associated with smaller hematological changes, supporting the beneficial impact of the humoral response on the clinical outcome of infected hosts. SFV has a high capacity to cross the host-species barrier and persistently infect humans. Overall, our data demonstrate potent neutralization, targeting mostly conserved and immunodominant epitopes located in the receptor binding domain, produced by approximatively 90% of gorilla SFV-infected humans. These properties may have helped to block the spread of SFV in the human population.

 

Source:

http://doi.org/10.1371/journal.ppat.1007293