Human hepatitis B virus (HBV) is a global health problem, affecting more than 250 million people worldwide. HBV-like viruses, named orthohepadnaviruses, also naturally infect nonhuman primates, rodents, and bats, but their pathogenicity and evolutionary history are unclear. Here, we determined the evolutionary history of the HBV receptors NTCP and GPC5 over millions of years of primate, rodent, and bat evolution. We use this as a proxy to understand the pathogenicity of orthohepadnaviruses in mammalian hosts and to determine the implications for species specificity. We found that NTCP, but not GPC5, has evolved under positive selection in primates (27 species), rodents (18 species), and bats (21 species) although at distinct residues. Notably, the positively selected codons map to the HBV-binding sites in primate NTCP, suggesting past genetic "arms races" with pathogenic orthohepadnaviruses. In rodents, the positively selected codons fall outside and within the presumed HBV-binding sites, which may contribute to the restricted circulation of rodent orthohepadnaviruses. In contrast, the presumed HBV-binding motifs in bat NTCP are conserved, and none of the positively selected codons map to this region. This suggests that orthohepadnaviruses may bind to different surfaces in bat NTCP. Alternatively, the patterns may reflect adaptive changes associated with metabolism rather than pathogens. Overall, our findings further point to NTCP as a naturally occurring genetic barrier for cross-species transmissions in primates, which may contribute to the narrow host range of HBV. In contrast, this constraint seems less important in bats, which may correspond to greater orthohepadnavirus circulation and diversity. IMPORTANCE Chronic infection with hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. Mammalian HBV-like viruses are also found in nonhuman primates, rodents, and bats. As for most viruses, HBV requires a successful interaction with a host receptor for replication. Cellular receptors are thus key determinants of host susceptibility as well as specificity. One hallmark of pathogenic virus-host relationships is the reciprocal evolution of host receptor and viral envelope proteins, as a result of their antagonistic interaction over time. The dynamics of these so-called "evolutionary arms races" can leave signatures of adaptive selection, which in turn reveal the evolutionary history of the virus-host interaction as well as viral pathogenicity and the genetic determinants of species specificity. Here, we show how HBV-like viruses have shaped the evolutionary history of their mammalian host receptor, as a result of their ancient pathogenicity, and decipher the genetic determinants of cross-species transmissions.W ith approximately 257 million cases of chronic infections, human hepatitis B virus (HBV) infection is one of the most common viral infections and the leading cause of liver diseases worldwide. HBV is a member of the family Hepadnaviridae, which are ancient pathogens that naturally inf...

HIV-2 groups have emerged from sooty mangabey SIV and entered the human population in Africa on several separate occasions. Compared to world pandemic HIV-1 that arose from the chimpanzee SIVcpz virus, the SIVsm-derived HIV-2, largely confined to West Africa, is less replicative, less transmissible and less pathogenic. Here, we evaluated the interactions between host cellular factors, which control HIV-1 infection and target the capsid, and HIV-2 capsids obtained from primary isolates from patients with different disease progression status. We showed that, like HIV-1, all HIV-2 CA we tested exhibited a dependence on cyclophilin A. However, we observed no correlation between HIV-2 viremia and susceptibility to hu-TRIM5alpha or dependence to CypA. Finally, we found that all CA from HIV-2 primary isolates exploit Nup358 and Nup153 for nucleus transposition. Altogether, these findings indicate that the ability to use the two latter nucleoporins is essential to infection of human cells for both HIV-1 and HIV-2. This dependence provides another molecular target that could be used for antiviral strategies against both HIV-1 and 2, based on both nucleoporins.