Old World monkeys highlight new targets for Hepatitis B
Cryo-electron microscopy reveals the structural basis for the restriction of hepatitis B virus (HBV) entry in macaques, enhancing our understanding of viral dynamics.
A team of researchers from the Tokyo University of Science (Japan), led by Koichi Watashi, has discovered why Old World monkeys, such as the crab-eating macaque, naturally display HBV resistance, while humans and chimpanzees do not. The study identified differences in critical amino acid residues involved in HBV binding and entry into liver cells, shedding light on potential avenues to neutralize HBV’s infectivity in humans.
HBV is a leading cause of chronic liver disease that affects a narrow host range. While monkeys and chimpanzees can be infected, their phylogenetic outgroup, Old World monkeys, show little or no infectivity. Previous research has revealed that this difference in infectivity is related to differences in the liver cell-membrane receptor sodium taurocholate co-translating polypeptide (NTCP), which is known to play a role in the viral entry of HBV into humans, and Watashi’s group has previously solved the structure of human NTCP (hNTCP). HBV binds to human hNTCP using its preS1 region, however, it cannot bind to macaque NTCP (mNTCP), despite 96% sequence identity to hNTCP.
To understand the differences between viral transmission in these species Watashi and his team used cryo-electron microscopy to solve the structure of macaque NTCP (mNTCP) and compare its structure to hNTCP and mNTCP. The team identified differences in critical amino acid residues for HBV binding and entry into liver cells. One of the key differences was the replacement of glycine with arginine at position 158, distal to the bile acid binding site which introduces arginine’s bulky side chain into this position in mNTCP, preventing the binding of preS1 into the NTCP bile acid pocket. An amino acid with a smaller sidechain at position 158, such as glycine found in hNTCP, is necessary for viral entry into liver cells.
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Describing these findings, Watashi explained that the team “… identified a binding mode for NTCP-preS1 where two functional sites are involved in human NTCP (hNTCP). In contrast, macaque NTCP (mNTCP) loses both binding functions due to steric hindrance and instability in the preS1 binding state.”
Watashi continued “These animals probably evolved to acquire escape mechanisms from HBV infections without altering their bile acid transport capacity. Consistently, phylogenetic analysis showed strong positive selection at position 158 of NTCP, probably due to pressure from HBV. Such molecular evolution driven to escape virus infection has been reported for other virus receptors.”
The team performed further lab experiments and simulations, revealing that lysine at position 86 is also critical for stabilizing the binding of NTCP-preS1 and enabling infection. Macaques have asparagine at this position, further contributing to HBV resistance.
This study contributes to our understanding of viral dynamics, shedding light on how natural evolution can defend certain species against diseases and open doorways for anti-HBV compounds.
“Development of bile acid-based anti-HBV compounds is underway and our results will be useful for the design of such anti-HBV entry inhibitors,” concluded Watashi.
