Human infection with zoonotic simian foamy retroviruses: role of virological and immunological factors in restricting viral emergence – REEMFOAMY

The public health relevance of retroviruses of zoonotic origin is illustrated by the human immunodeficiency virus (HIV) epidemic, the worldwide distribution of human T-lymphotropic viruses (HTLVs), and the morbidity and mortality associated with both sets of viruses. Both HIVs and HTLVs emerged in the human population after several cross-species transmission events involving retroviruses (SIVs and STLVs) endemic in non-human primates (NHPs). Moreover, a third genus of complex retroviruses, the foamy viruses, some of which are of simian origin, can also establish persistent infections in humans. Simian foamy viruses (SFVs) are widespread and highly prevalent in many NHP species. These viruses can be readily isolated from the saliva and oropharyngeal secretions of infected NHPs. Penetrating bite wounds therefore constitute a potential route of transmission to humans, leading to the establishment of life-long persistent infection. Human infection with zoonotic SFVs constitutes a unique, natural model for studies of the restriction of retrovirus emergence in humans.
Antoine Gessain’s research group has recently confirmed the frequent occurrence of SFV infection in two large cohorts of exposed Cameroonian individuals. We demonstrated persistent SFV infection in 57 individuals bitten by apes or monkeys while hunting in rainforest areas. This study population constitutes the largest cohort of SFV–infected individuals described to date. Our preliminary results indicate that SFV-infected individuals have significantly lower hemoglobin concentrations and hematocrits, and tended to have lower CD4 T-cell percentages and higher plasma interleukin-6 concentrations than people not infected with SFV from the same villages, matched for age, ethnicity, and sex.
In collaboration with Ali Saïb and Olivier Schwartz, we propose a multidisciplinary project focusing on the cross-species transmission of retroviruses from NHPs to humans. Our research program focuses on the ex vivo study of human samples and the primary viral strains isolated from these samples. It includes six specific aims, broken down into appropriate tasks.
Aim 1 is to constitute a cohort of humans exposed to body fluids (saliva and/or blood) from NHPs, mostly through bites. SFV infection status will be determined. We will include approximatively 200 individuals, one third of whom will have persistent SFV infection. We will collect biological specimens from each individual.
Aim 2 is to set up a case-control study of 66 cases and 132 controls recruited during task 1. For each case and each control, we will perform a clinical examination, medical biology analyses, and detailed investigations of any hematologic changes identified. We will perform a transcriptome study of blood cells from 10 cases and 10 controls. Annual follow-up will be offered to 20 SFV-infected individuals.
Aim 3 is to isolate zoonotic SFV from the peripheral blood cells of at least 20 individuals, and to sequence the genomes of these viruses. These primary strains will be characterized (aim 4), and used in the immune studies for aims 5 and 6.
Aim 4 is to characterize the molecular patterns associated with viral replication and infectivity in functional in vitro assays.
Aim 5 is to study innate immune sensing in humans, TLR7-dependent and TLR7-independent sensing, downstream signaling cascades and the virus components involved in type I interferon induction.
Aim 6 is to study SFV-specific antibodies, and to perform the first study of SFV-specific CD4 and CD8 T lymphocytes, with the biological specimens collected for aim 1.

This will be a pioneering study on a large series of SFV-infected humans, involving many ex vivo biological investigations. We expect this multidisciplinary project to provide new insight into the initial steps of retrovirus emergence in humans, its restriction by the immune system, and the hematologic changes observed in infected people.