Ground squirrel hepatitis virus

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Ground squirrel hepatitis virus
Virus classification Edit this classification
(unranked): Virus
Realm: Riboviria
Kingdom: Pararnavirae
Phylum: Artverviricota
Class: Revtraviricetes
Order: Blubervirales
Family: Hepadnaviridae
Genus: Orthohepadnavirus
Ground squirrel hepatitis virus

Ground squirrel hepatitis virus, abbreviated GSHV, is a partially double-stranded DNA virus that is closely related to human Hepatitis B virus (HBV) and Woodchuck hepatitis virus (WHV).[1] It is a member of the family of viruses Hepadnaviridae and the genus Orthohepadnavirus.[2] Like the other members of its family, GSHV has high degree of species and tissue specificity.[3] It was discovered in Beechey ground squirrels, Spermophilus beecheyi, but also infects Arctic ground squirrels, Spermophilus parryi.[1][2] Commonalities between GSHV and HBV include morphology, DNA polymerase activity in genome repair, cross-reacting viral antigens, and the resulting persistent infection with viral antigen in the blood (antigenemia).[4] As a result, GSHV is used as an experimental model for HBV.[5]

The species GSHV was originally isolated from, Spermophilus beecheyi, commonly known as California ground squirrel.



Ground squirrel hepatitis virus consists of a DNA genome is primarily double-stranded. Like other hepadnaviruses, it consists of a single-stranded region of variable length that is converted to double-stranded DNA by virion DNA polymerase.[4][6] A protein is covalently bound to the 5' end of the minus strand which may be used as a primer for DNA synthesis.[7]

There are four evident open reading frames within the genome, all on the same strand. Two are for the genes encoding the structural proteins (surface antigens and core antigens), and the other two are unassigned. The larger of the unassigned frames, which is called gene A and covers 80% of the genome, is predicted to encode the viral DNA polymerase. The shorter one, gene B, does not correspond to a known viral protein.[citation needed]

Inside a host cell, the GSHV genome can exist in two forms: a circular duplex and heterogenous partially single-stranded DNA.[6] Circular DNA can be either covalently closed or open.[7]

The GSHV genome is very similar to the related hepadnaviruses. Ground squirrel hepatitis is 3311 base pairs in length, making the size indistinguishable from HBV. GSHV has greater nucleotide and amino acid homology with WHV than HBV, with 82% nucleotide and 78% amino acid homology between GSHV and WHV and 55% nucleotide and 46% amino acid homology between GSHV and HBV.[6][8] The open reading frames of GSHV are similar to HBV and WHV, but the viruses differ in their EcoRI restriction enzyme recognition sites.[4]


Ground squirrel hepatitis virus is a spherical, enveloped virus. The core particle, or nucleocapsid, contains e antigen, viral DNA, and an endogenous DNA polymerase.[9] The virus particles contain two major structural proteins, surface antigens (sAg) and core antigens (cAg). Both proteins were identified based on homology with analogous proteins in other hepadnaviruses. Mature ground squirrel hepatitis sAg (GSHsAg) had 90% amino acid homology with woodchuck hepatitis sAg and is believed to be glycosylated. The ground squirrel hepatitis cAg (GSHcAg) is the most highly conserved protein sequence between GSHV, WHV, and HBV.[6]

Replication Cycle[edit]

Viral Entry[edit]

It is thought that hepadnaviruses enter host cells through receptor-mediated endocytosis.[2]

Replication and Transcription[edit]

The intracellular predomination of the long minus strand of DNA over the short plus strand suggests DNA replication proceeds from an RNA template, like other hepadnaviruses.[6] It is predicted that synthesis of the minus strand utilizes an RNA intermediate that is degraded as it is copied, and the plus strand is synthesized using the complete minus strand DNA. Viral DNA polymerase synthesizes both the plus and minus DNA strands. The production of an RNA intermediate, called the pregenome, during replication involves a reverse transcription step resembling that of retroviruses. Hepadnaviruses differ from retroviruses in that the intermediate form of the genome is RNA instead of DNA. Also, integration into the host genome is not necessary for replication in hepadnaviruses.[2] This process was first shown in Duck Hepatitis B virus, a related virus in the Hepadnaviridae family in which the minus DNA strands also outnumber the plus strands. This similarity suggests the replication mechanism is similar in GSHV.[10]

Following entry, the partial DNA duplex genome is repaired by the viral DNA polymerase and circularized to serve as the template for transcription. The four transcripts are made in the nucleus and are generally transported to the cytoplasm.[2]


It is predicted that viral DNA is packaged before synthesis of the plus strand is complete. This would explain the excess minus strand DNA compared to plus strand DNA.[7]

Infection and Disease[edit]

Ground squirrel hepatitis virus is distinguished from related viruses by its lack of pathogenic effect, even though it is common for infected hosts to have high titers of circulating virions.[3][6] The viral particles detected in the sera of wild Beechey ground squirrels are molecularly and structurally similar, but not identical to HBV. In general, GSHV particles in sera are larger than HBV particles. A filamentous virus particle was the most abundant form in ground squirrel sera much like human sera infected with HBV. The next most abundant particle in sera was spherical with an outer shell or envelope, resembling the Dane particles found in humans.[4]


Ground squirrel hepatitis virus infects liver cells and is considered highly hepatotropic.[1][6] Infection with GSHV can cause persistent infection.[8] The virus causes chronic infection and longer antigenemia (antigen in the blood) when it is injected directly into the liver compared to injection into the portal vein. GSHsAg (viral surface antigen) can be detected in the serum several weeks post infection.[5]

Associated disease[edit]

Hepatocellular carcinoma cells stained pink
Hepatocellular carcinoma cells

Illness or death in GSHV bearing animals due to liver disease has not been shown. In many infected squirrels with high GSHsAg and virion DNA polymerase levels, there are no signs of cirrhosis or hepatocellular carcinoma.[1] It is possible for ground squirrels persistently infected with GSHV to exhibit signs of mild, nonprogressive hepatitis.[2] No modulation of host processes as a result of GSHV infection is known.

Persistent infection with HBV and WHV often results in hepatocellular carcinoma (HCC). The same association has not been observed with GSHV, but it is possible that persistent infection over a time period longer than required of the other two viruses may contribute to the development of HCC.[8] Persistent infection with GSHV for up to three years only results in slight inflammation, so the development of HCC would presumably take longer in most cases.[6]


Ground squirrel hepatitis virus can be transmitted both horizontally and vertically.

Horizontal transmission can result from inoculation with viremic serum. However, the concentration of serum necessary to transmit infection is much higher than what would be predicted using the assumption that one viral particle is sufficient to initiate infection. One potential explanation for this may be that not every particle detected by physical methods is biologically active, and another explanation is that multiple virions are required to initiate infection.[3]

Vertical transmission of GSHV from mother to newborn is also possible but has not been studied extensively.[1]


Geographic distribution can be measured by testing the sera of ground squirrels for viral surface antigen, virion DNA polymerase, and virus antibodies at different locations. It is thought that the distribution of GSHV is very localized.[1] It was found in a radius smaller than eight miles in northern California, but it is likely that it exists in undetected places. Additional evidence suggests that the geographic distribution is uneven, which is the case for HBV. There are no indications of factors that may influence geographic distribution of GSHV.[4]

No differences in sex distributions of GSHV have been observed.[1] This is unlike HBV in which persistent HBV infections in males outnumbers infections in females.[4]


  1. ^ a b c d e f g Marion, Patricia L.; Knight, Susan S.; Salazar, Felix H.; Popper, Hans; Robinson, William S. (1983-01-01). "Ground Squirrel Hepatitis Virus Infection". Hepatology. 3 (4): 519–527. doi:10.1002/hep.1840030408. ISSN 1527-3350. PMID 6862363. S2CID 34164820.
  2. ^ a b c d e f "Ground Squirrel Hepatitis Virus - an overview | ScienceDirect Topics". Retrieved 2019-11-24.
  3. ^ a b c Trueba, Daniel; Phelan, Michael; Nelson, John; Beck, Fred; Pecha, Brian S.; Brown, R. James; Varmus, Harold E.; Ganem, Don (1985-05-01). "Transmission of ground squirrel hepatitis virus to homologous and heterologous hosts". Hepatology. 5 (3): 435–439. doi:10.1002/hep.1840050316. ISSN 1527-3350. PMID 3997073. S2CID 31754671.
  4. ^ a b c d e f Marion, P L; Oshiro, L S; Regnery, D C; Scullard, G H; Robinson, W S (May 1980). "A virus in Beechey ground squirrels that is related to hepatitis B virus of humans". Proceedings of the National Academy of Sciences of the United States of America. 77 (5): 2941–2945. Bibcode:1980PNAS...77.2941M. doi:10.1073/pnas.77.5.2941. ISSN 0027-8424. PMC 349522. PMID 6930677.
  5. ^ a b Seeger, C.; Ganem, D.; Varmus, H. E. (September 1984). "The cloned genome of ground squirrel hepatitis virus is infectious in the animal". Proceedings of the National Academy of Sciences of the United States of America. 81 (18): 5849–5852. Bibcode:1984PNAS...81.5849S. doi:10.1073/pnas.81.18.5849. ISSN 0027-8424. PMC 391809. PMID 6091114.
  6. ^ a b c d e f g h Seeger, C.; Ganem, D.; Varmus, H. E. (August 1984). "Nucleotide sequence of an infectious molecularly cloned genome of ground squirrel hepatitis virus". Journal of Virology. 51 (2): 367–375. doi:10.1128/JVI.51.2.367-375.1984. ISSN 0022-538X. PMC 254447. PMID 6086950.
  7. ^ a b c Weiser, B; Ganem, D; Seeger, C; Varmus, H E (October 1983). "Closed circular viral DNA and asymmetrical heterogeneous forms in livers from animals infected with ground squirrel hepatitis virus". Journal of Virology. 48 (1): 1–9. doi:10.1128/JVI.48.1.1-9.1983. ISSN 0022-538X. PMC 255316. PMID 6887347.
  8. ^ a b c Marion, P. L.; Van Davelaar, M. J.; Knight, S. S.; Salazar, F. H.; Garcia, G.; Popper, H.; Robinson, W. S. (June 1986). "Hepatocellular carcinoma in ground squirrels persistently infected with ground squirrel hepatitis virus". Proceedings of the National Academy of Sciences of the United States of America. 83 (12): 4543–4546. Bibcode:1986PNAS...83.4543M. doi:10.1073/pnas.83.12.4543. ISSN 0027-8424. PMC 323770. PMID 3012572.
  9. ^ Feitelson, M A; Marion, P L; Robinson, W S (August 1982). "Core particles of hepatitis B virus and ground squirrel hepatitis virus. II. Characterization of the protein kinase reaction associated with ground squirrel hepatitis virus and hepatitis B virus". Journal of Virology. 43 (2): 741–748. doi:10.1128/JVI.43.2.741-748.1982. ISSN 0022-538X. PMC 256178. PMID 7109041.
  10. ^ Summers, J.; Mason, W. S. (June 1982). "Replication of the genome of a hepatitis B--like virus by reverse transcription of an RNA intermediate". Cell. 29 (2): 403–415. doi:10.1016/0092-8674(82)90157-x. ISSN 0092-8674. PMID 6180831. S2CID 20205800.