Woolly monkey hepatitis B virus

A member of the Hepadnaviridae family, WMHBV has a partially double-stranded, partially single-stranded circular DNA genome.[4] Its genome is 3,179 nucleotides in length, and encodes 5 proteins: the capsid (core) protein, the large envelope protein (L glycoprotein), the external core antigen, protein P (polymerase), and protein x (multifunctional protein).[5] The polymerase open reading frame (ORF) is the largest ORF in the genome, and has significant overlap with each of the other genes, perhaps constraining its evolutionary properties.[2] Although WMHBV is considerably divergent from the human hepatitis B virus (HBV), they share the same genetic organization. The core gene of WMHBV was the most similar to human HBV with 85.8-86.9% similarity at the amino acid level, while the WHMBV X gene was most divergent from human HBV with only 64.3-65.6% similarity at the amino acid level.[2]

Woolly monkey hepatitis B virus is similar in structure to other Orthohepadnaviridae. Mature virions are enveloped, and consist of an icosahedral capsid.[4] The majority of virions consist of 240 capsid proteins and display T=4 symmetry, however, a small amount of virions consist of 180 capsid proteins and display T=3 symmetry.[5] The envelope surrounding the capsid is derived from the host membrane. L glycoproteins line the surface of the envelope and play a role in viral attachment to cell receptors.[5] The virions are small, approximately 42 nm in diameter.[4]

It has been found that sodium taurocholate cotransporting polypeptide (NTCP), a sodium/bile acid symporter found in the cellular membrane of hepatocytes, acts as a cellular receptor for WMHBV, as well as many other hepadnaviruses.[6] Following attachment to the NTCP, WMHBV enters into the cell cytoplasm via endocytosis, and the large envelope protein ensures fusion between the endosomal membrane and the viral membrane.[5]

Replication and transcription of the WMHBV has not been extensively studied, but is believed to occur very similarly to all other HBV including human HBV.[7] Once inside the cell, nuclear localization signals on the capsid protein allow the capsid to bind to importin α-importin β complexes.[8] The genome is released from the capsid at the nuclear pore complex, and enters into the nucleus. Inside, the viral polymerase protein is released and ligates the DNA so that it becomes covalently closed circular DNA, or cccDNA.[8] The cccDNA then binds nucleosomes and acts as the host DNA.

The cccDNA is then transcribed to RNA via host cell RNA polymerase.[8] Many RNAs are shipped to the cytoplasm where the proteins are assembled, including a large number of empty capsids. Reverse transcription by the viral polymerase protein re-creates the relaxed, partially double-stranded circular DNA genome.[8]

The relaxed, partially double-stranded circular DNA genome is able to diffuse into an empty capsid through large pores in the capsid.[8] The capsid is then enveloped and exported from the cell through a process that is not yet well understood.[8]

Since woolly monkeys are endangered, they cannot be used as an HBV animal model for research.[7] Therefore, they are seeking out other primates that may be able to be infected by WMHBV. The woolly monkey's close relative, the black-handed spider monkey (Ateles geoffroyi) is susceptible to infection by WMHBV, but does not display levels of viral replication as high as woolly monkeys.[2] Researchers were able to create an infectious clone of WMHBV, coined WMHBV-2, that infects and replicates in black-handed spider monkeys to the same degree that WMHBV replicates in woolly monkeys.[7] This infectious clone will allow for greater research of hepatitis B virus treatments on a primate model.