Identification of Significant Genomic Changes and Compartmentalization of Simian Foamy Virus in a Human Zoonotically Infected by a Chimpanzee (Pan troglodytes troglodytes).

Despite increasing reports of zoonotic simian foamy virus (SFV) infections globally, knowledge of its genetic adaptation in humans and impact on viral transmission and pathogenicity remains limited. We obtained complete SFV genomes using metagenomics analysis of viral isolates from peripheral blood lymphocytes (PBLs) and throat specimens from a worker (Case 6) and source chimpanzee (B1) that bit him. We analyzed viral diversity in three genomic regions (LTR, tas, and bet) involved in replication and latency using longitudinal specimens (PBLs, throat, saliva, urine, and semen) from Case 6 over five years, and PBLs from B1 and five additional chimpanzees over three years. Proviral loads were measured using a validated qPCR assay. Phylogenetic analysis revealed nearly identical SFV genomes in Case 6 and B1. Overall, bet sequences exhibited high genetic stability across body compartments and over time, with evidence of compartmentalization in Case 6 urine and semen specimens. G→A substitutions in GG and GA motifs in bet indicated heterogeneous APOBEC-associated editing across hosts and anatomical compartments following zoonotic transmission. Case 6 had significant deletions in the LTR region that were absent in B1 and other chimpanzees. Length variation in tas, including truncated forms, was observed across longitudinal specimens from Case 6, B1, and other chimpanzees. Proviral loads were consistently low and undetectable in most Case 6 urine specimens. Together, analysis of this SFV transmission pair identifies genomic changes likely to affect viral replication and persistence, highlighting mechanisms that may limit secondary transmission and pathogenicity of SFV in humans.