Abstract
The hepatic Na+/taurocholate co-transporting polypeptide (NTCP in man, Ntcp in animals) is the high-affinity receptor for the hepatitis B (HBV) and hepatitis D (HDV) viruses. Species barriers for human HBV/HDV within the order Primates were previously attributed to Ntcp sequence variations that disable virus-receptor interaction. However, only a limited number of primate Ntcps have been analysed so far. In the present study, a total of 11 Ntcps from apes, Old and New World monkeys were cloned and expressed in vitro to characterise their interaction with HBV and HDV. All Ntcps showed intact bile salt transport. Human NTCP as well as the Ntcps from the great apes chimpanzee and orangutan showed transport-competing binding of HBV derived myr-preS1-peptides. In contrast, all six Ntcps from the group of Old World monkeys were insensitive to HBV myr-preS1-peptide binding and HBV/HDV infection. This is basically predetermined by the amino acid arginine at position 158 of all studied Old World monkey Ntcps. An exchange from arginine to glycine (as present in humans and great apes) at this position (R158G) alone was sufficient to achieve full transport-competing HBV myr-preS1-peptide binding and susceptibility for HBV/HDV infection. New World monkey Ntcps showed higher sequence heterogeneity, but in two cases with 158G showed transport-competing HBV myr-preS1-peptide binding, and in one case (Saimiri sciureus) even susceptibility for HBV/HDV infection. In conclusion, amino acid position 158 of NTCP/Ntcp is sufficient to discriminate between the HBV/HDV susceptible group of humans and great apes (158G) and the non-susceptible group of Old World monkeys (158R). In the case of the phylogenetically more distant New World monkey Ntcps amino acid 158 plays a significant, but not exclusive role.
Highlights
The hepatic Na+/taurocholate co-transporting peptide (NTCP in man, Ntcp in animals, gene name: SLC10A1/Slc10a1) together with the closely related intestinal apical sodium-dependent bile acid transporter ASBT/Asbt are essential drivers of the enterohepatic circulation of bile salts in mammals [1]
Amino acid position 158 of NTCP/Ntcp is sufficient to discriminate between the HBV/HDV susceptible group of humans and great apes (158G) and the non-susceptible group of Old World monkeys (158R)
Ntcp transcripts were de novo cloned from a series of liver samples, derived from six species with habitats in the Old World
Summary
The hepatic Na+/taurocholate co-transporting peptide (NTCP in man, Ntcp in animals, gene name: SLC10A1/Slc10a1) together with the closely related intestinal apical sodium-dependent bile acid transporter ASBT/Asbt are essential drivers of the enterohepatic circulation of bile salts in mammals [1]. Only NTCP is exploited by the human hepatitis B (HBV) and hepatitis D (HDV) viruses as high-affinity binding and entry receptor for productive infection of hepatocytes [2,3,4]. Since NTCP/Ntcp is mainly expressed in hepatocytes [5], the strict liver tropism of HBV and HDV can mainly be explained by organ-specific expression of this receptor protein. Whereas in the closely related primate family of Cercopithecidae (Old World monkeys, OWM, i.e. macaques and baboons) a specific endogenous hepadnavirus has not been identified so far (despite the sporadic finding of HBV in a Macaca fascicularis colony from Mauritius, see below), two hepadnavirus species have been detected in more distantly related families of Platyrrhini, representing New World monkeys (NWM). Monkey HBV (WMHBV) was originally isolated from a captive woolly monkey (Lagothrix lagotricha, family Atelidae) with fulminant hepatitis [8] and very recently capuchin monkey HBV (CMHBV) was identified in Sapajus xanthosternos (family Cebidae) during systematic screening of NWM for novel hepadnaviruses in Brasil [9]
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