Gibbon ape leukemia virus

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Gibbon ape leukemia virus
Virus classification OOjs UI icon edit-ltr.svg
(unranked): Virus
Realm: Riboviria
Kingdom: Pararnavirae
Phylum: Artverviricota
Class: Revtraviricetes
Order: Ortervirales
Family: Retroviridae
Genus: Gammaretrovirus
Species:
Gammaretrovirus gibleu
Synonyms
  • Gibbon sarcoma and leukemia virus

Gibbon-ape leukemia virus (GaLV) is an oncogenic, type C retrovirus that has been isolated from primate neoplasms, including the white-handed gibbon and woolly monkey. [1] The virus was identified as the etiological agent of hematopoietic neoplasms, leukemias, and immune deficiencies within gibbons in 1971, during the epidemic of the late 1960s and early 1970s. Epidemiological research into the origins of GaLV has developed two hypotheses for the virus' emergence. These include cross-species transmission of the retrovirus present within a species of East Asian rodent or bat, and the inoculation or blood transfusion of a MbRV-related virus into captured gibbons populations housed at medical research institutions. [2] The virus was subsequently identified in captive gibbon populations in Thailand, the US and Bermuda. [3]

Contents

GaLV is transmitted horizontally by contact with excretory products of infected gibbons. [4] However, it is also hypothesised to be vertically transmitted via parent-progeny transmission. [5] Phylogenetic analysis have revealed 7 strains of GaLV; GaLV-SF, GaLV-SEATO, GaLV-BR, GALV-X, GaLV-Mar, GaLV-H and SSV, which have emerged as a result of selection pressures from the host immune system. [3] Recently, full genome sequences of these strains have been made available which broadens the possibilities for GaLV's utility as a viral vector in gene transfer. [6]

Epizootiology

History

GaLV Phylogenetic trees derived from genome sequences of GaLV strains; GaLV-SEATO, GaLV-Br, GaLV-H, GaLV-X and GaLV-SF. Gibbon-ape leukemia virus Phylogenetic tree.jpg
GaLV Phylogenetic trees derived from genome sequences of GaLV strains; GaLV-SEATO, GaLV-Br, GaLV-H, GaLV-X and GaLV-SF.
Phylogenies of Gammaretrovirus
Searchtool.svg Mottaghinia et al. (2024), focusing on the clade containing G. gibleu and G. koa

Cases of malignant lymphomas and leukemias were not described in gibbons until the 1960s, when several cases of haematopoietic neoplasia were reported in a single colony of white-handed gibbons housed at the SEATO research facility in Bangkok, Thailand. [7] In 1971, phylogenetic analysis of the Leukemia-inducing retrovirus, lead to the identification of GaLV-SEATO, published within De Paoli et al. (1971). [3] Following this discovery, five other strains of GaLV was identified from animals whose associated neoplastic syndromes were exclusively recorded in captive gibbon populations, which include:

These strains exhibit high genetic similarity, demonstrated through DNA sequencing which reveals approx. 90% sequence identity and more than 93% amino acid genome identity between strains of GaLV. Differences between these strains occurs in the env gene, with divergence ranging from 85% to 99%. [4]

Origins

The discovery of a contagious oncogenic gammaretrovirus in sub-human primates stimulated a great deal of research into the pathogenesis of GaLV and its origins including the virus' intermediate host, which is currently disputed. [2] Virologist initially suggested that GaLV was related to murine leukaemia virus (MLV) detected in Southeast Asian rodents. The endogenous retroviruses with similar homology are; McERV, detected within Mus caroli , and Mus dunni endogenous virus (MDEV) isolated from the earth-coloured mouse (Lieber et al. 1975, Callahan et al. 1979). Furthermore, this hypothesis was based on results derived from low resolution serological and DNA homology methods. [3] Thus, present phylogenetic analysis of proviral sequences of GALV‐SEATO and MLV shows a 68–69% similarity for pol and 55% similarity for env, thus indicating the limited sequence similarity. [3] Therefore, there are no published proviral sequences from rodent hosts which share a sufficiently high degree of sequence identity to GALV to confirm an intermediate rodent host as the precursor for GaLV. [2]

An alternative hypothesis is based on the high sequence similarity of GaLV-SEATO and the Melomys burtoni retrovirus (MbRV), isolated from a species of rodent from Papua New Guinea. Immunological analysis highlights that MbRV shares 93% sequence homology with GaLV-SEATO which is significantly higher than McERV and MDEV. [2] However, due to the lack of geographic overlap of grassland melomys in PNG and Thailand, MbRV was initially considered ill-suited as the intermediate host of GaLV. [12] However, in 2016 the Mammal Review published "Is gibbon ape leukaemia virus still a threat?" which offered a valid hypothesis for the spread of MbRV from PNG to Thailand by divulging SEATO facility reports and reviewing geographical movement of gibbons during the 1960s and 1970's. [3] The SEATO facility report demonstrated that gibbons were frequently inoculated with biomaterial from humans, Southeast Asian rodents and other gibbons, for pathogenetic study of human diseases including malaria and dengue fever. It is therefore proposed that blood and tissue samples used at SEATO were contaminated with MbRV-related virus and later introduced into Gibbon test subjects via blood transfusion or inoculation, thereby resulting in the development of GaLV within two gibbons (S-76 and S-77). [3]

The last hypothesis is based on the sequence similarity of GaLV and retroviruses present within Southeast Asian bat species. [13] Mobile bat species are potential intermediate hosts of GALV as they can disperse rapidly over large geographical areas and have also been linked to several zoonotic diseases. [14]

In any case, an Australo-Papuan origin is likely, as the local fauna harbors several GaLV-like viruses infecting a wide range of monkeys, apes, bats, rodents, and koalas. Three of these viruses (KoRV, MelWMV-NG, cMWMV) are vertically transmitted. [11]

Replication cycle

GaLV belongs to the retrovirus family which utilises an enzyme called reverse transcriptase in viral replication. Retroviruses have single stranded genomes (ssRNA) which undergoes reverse transcription to form double-stranded DNA (dsNDA) prior to proviral integration into the genome of the host cell. The GaLV replication cycle proceeds as follows:

  1. Binding: The first step of GaLV retroviral replication is the adsorption of adsorbate particles on the surface of human cells using receptor molecules SLC20A1 (GLVR-1, PIT-1) and SLC20A2 (GLVR-2, PIT-2). [15] Both molecules are cellular proteins (phosphate transporters).
  2. Entry into host cell: Then GaLV particles use these cell-surface proteins on the cell membrane, as specific receptors to enter their host cells. [16]
  3. Reverse transcription: The viral core then enters the cytoplasm of the target cell where the enzyme, reverse transcriptase, generates a complementary DNA strand from 3' to 5'. [16]
  4. Nuclear entry: The proviral integration of GaLV into the host genome requires entry into the nucleus of the target cell. However, GaLV is incapable of infecting non-dividing cells and therefore relies on the breakdown of the nuclear membrane during mitosis cell division for nuclear entry. [16]
  5. Replication: Once the proviral DNA enters the nucleus of the host cell, replication occurs via polypeptide synthesis and becomes integrated into the host genome. [16]

Viral resistance

Research published within the Retroviruses and Insights into Cancer Journal, highlights the potential of viral resistance within gibbon-apes, due to the partial proviral transcription of an intact envelope gene. The expression of the GaLV envelope gene was exhibited within an asymptomatic gibbon despite long term exposure to another highly viremic gibbon. Therefore, the expression of the GaLV envelope in the absence of replication-competent GaLV may have rendered the animal resistant to GaLV infection. [17] Furthermore, antibodies against the retrovirus was identified in gibbons without evidence of disease which suggests a natural immunological resistance to GaLV. [18]

Transmission

GaLV is an exogenous virus that is horizontally transmitted via contact with GaLV contaminated biomaterials such as urine and feces. [19] This is confirmed within hybridization assay which evidenced the lack of proviral genome within uninfected gibbons. Furthermore, experimental research conducted at the Comparative Oncology Laboratory demonstrates the "horizontal transmission of GaLV within a 14-month-old uninfected gibbon which contracted GaLV within six weeks of exposure to viremic individuals." Furthermore, GaLV is also transmitted prenatally via parent-progeny transmission in utero, of which offspring exhibit a large quantity of proviral DNA in opposed to postnatal transmission. [5]

Signs and symptoms

Conditions associated with GALV include neoplastic syndromes leading to susceptible secondary and often fatal diseases including; malignant lymphoma, lymphoblastic leukemia, osteoporosis and granulocytic leukemia. In cases of granulocytic leukemia, increased granulocytes in the peripheral blood infiltrated bone marrow and liver lymph nodes, causing a greenish hue (chlorosis) within these tissues. [18] Pathology study published by Kawakami et al in 1980, identifies the development of chronic granulocytic leukemia within young GaLV infected gibbons after latency periods of 5–11 months. Additionally, the introduction of GaLV into 14-month-old gibbons, demonstrated the production of neutralising antibodies which enabled individuals to remain asymptomatic and free of hematopoietic disease, thereby demonstrating the host's immune response to GaLV infection. [8]

In medicine

GaLV envelope protein

GaLV Envelope Protein has biomedical significance due to its utility as a viral vector in cancer gene therapy and gene transfer. [20] Retroviral vectors are used in ex vivo gene therapy, which involves the modification of cells in vitro, to replace genes that code for dysfunctional proteins. The inserted gene undergoes transcription and translation within the nucleus and ribosome of the host cell producing "normal" secretable proteins. [21] The earliest retroviral vectors were based on the Moloney murine leukemia virus (MMLV) which when pseudotyped with GaLV envelope protein, enabled gene transfer to various host cells. [22] Furthermore, the development of "hybrid murine amphotropic viral envelope with the extracellular domains of GALV also helps to increase the cell infection rate within the host during gene therapy." [23] [24]

Gene transfer is dependent on the relationship between receptor expression and transduction efficiency. Human T-lymphocytes have two surface receptors (GLVR-1 and GLVR-2) that detect the presence of GaLV. Furthermore, Lam et al evidenced the 8 fold greater expression of GLVR-1 than GLVR-2, which demonstrates that human T lymphocyte gene transfer methods should utilise the GaLV envelope protein that binds to the GLVR-1 surface receptor. [25] However, because gammaretroviruses are incapable of infecting non-dividing cells, the utility of GaLV envelope protein in gene transfer is being superseded by lentiviral vectors. [22]

References

  1. ↑ S, Delassus; P, Sonigo; S, Wain-Hobson (November 1989). "Genetic Organization of Gibbon Ape Leukemia Virus". Virology. 173 (1): 205–13. doi:10.1016/0042-6822(89)90236-5. PMID   2683360.
  2. 1 2 3 4 5 J, McKee; N, Clark; F, Shapter; G, Simmons (April 2017). "A New Look at the Origins of Gibbon Ape Leukemia Virus". Virus Genes. 53 (2): 165–172. doi:10.1007/s11262-017-1436-0. PMID   28220345. S2CID   28786457.
  3. 1 2 3 4 5 6 7 Brown, Katherine; Tarlinton, Rachael E. (January 2017). "Is gibbon ape leukaemia virus still a threat?" (PDF). Mammal Review. 47 (1): 53–61. Bibcode:2017MamRv..47...53B. doi:10.1111/mam.12079.
  4. 1 2 3 4 Murphy, Hayley Weston; Switzer, William M. (2008-01-01), Fowler, Murray E.; Miller, R. Eric (eds.), "Chapter 31 - Occupational Exposure to Zoonotic Simian Retroviruses: Health and Safety Implications for Persons Working with Nonhuman Primates", Zoo and Wild Animal Medicine (Sixth Edition), W.B. Saunders, pp. 251–264, ISBN   978-1-4160-4047-7 , retrieved 2020-02-02
  5. 1 2 Kawakami, Thomas (1978-10-04). "Natural Transmission of Gibbon Leukemia Virus". Journal of the National Cancer Institute. 61 (4): 1113–5. PMID   212567 – via Google Booka.
  6. ↑ "Complete genome of all strains of the gibbon ape leukemia virus sequenced". ScienceDaily. Retrieved 2020-02-09.
  7. ↑ "Virologists unravel mystery of late 20th century gibbon leukaemia outbreak". ScienceDaily. Retrieved 2020-02-06.
  8. 1 2 3 Hausen, Harald zur (2007-09-24). Infections Causing Human Cancer. John Wiley & Sons. ISBN   978-3-527-60929-1.
  9. ↑ Reitz, M S; wong-Staal, F; Haseltine, W A; Kleid, D G; Trainor, C D; Gallagher, R E; Gallo, R C (January 1979). "Gibbon ape leukemia virus-Hall's Island: new strain of gibbon ape leukemia virus". Journal of Virology. 29 (1): 395–400. doi:10.1128/JVI.29.1.395-400.1979. ISSN   0022-538X. PMC   353141 . PMID   219232.
  10. ↑ Burke, Mark; Ptito, Maurice (2018-05-30). Primates. BoD – Books on Demand. ISBN   978-1-78923-216-5.
  11. 1 2 Mottaghinia, Saba; Stenzel, Saskia; Tsangaras, Kyriakos; Nikolaidis, Nikolas; Laue, Michael; Müller, Karin; Hölscher, Henriette; Löber, Ulrike; McEwen, Gayle K.; Donnellan, Stephen C.; Rowe, Kevin C.; Aplin, Ken P.; Goffinet, Christine; Greenwood, Alex D. (6 February 2024). "A recent gibbon ape leukemia virus germline integration in a rodent from New Guinea". Proceedings of the National Academy of Sciences. 121 (6). doi:10.1073/pnas.2220392121.
  12. ↑ Simmons, Greg; Clarke, Daniel; McKee, Jeff; Young, Paul; Meers, Joanne (2014-09-24). Roca, Alfred L. (ed.). "Discovery of a Novel Retrovirus Sequence in an Australian Native Rodent (Melomys burtoni): A Putative Link between Gibbon Ape Leukemia Virus and Koala Retrovirus". PLOS ONE. 9 (9): e106954. Bibcode:2014PLoSO...9j6954S. doi: 10.1371/journal.pone.0106954 . ISSN   1932-6203. PMC   4175076 . PMID   25251014.
  13. ↑ J, Denner (2016-12-20). "Transspecies Transmission of Gammaretroviruses and the Origin of the Gibbon Ape Leukaemia Virus (GaLV) and the Koala Retrovirus (KoRV)". Viruses. 8 (12): 336. doi: 10.3390/v8120336 . PMC   5192397 . PMID   27999419.
  14. ↑ Alfano, Niccolò; Michaux, Johan; Morand, Serge; Aplin, Ken; Tsangaras, Kyriakos; Löber, Ulrike; Fabre, Pierre-Henri; Fitriana, Yuli; Semiadi, Gono; Ishida, Yasuko; Helgen, Kristofer M. (2016-08-26). "Endogenous Gibbon Ape Leukemia Virus Identified in a Rodent (Melomys burtoni subsp.) from Wallacea (Indonesia)". Journal of Virology. 90 (18): 8169–8180. doi:10.1128/JVI.00723-16. ISSN   0022-538X. PMC   5008096 . PMID   27384662.
  15. ↑ Liu, Meihong; Eiden, Maribeth V. (2011-07-05). "The receptors for gibbon ape leukemia virus and amphotropic murine leukemia virus are not downregulated in productively infected cells". Retrovirology. 8 (1): 53. doi: 10.1186/1742-4690-8-53 . ISSN   1742-4690. PMC   3136417 . PMID   21729311.
  16. 1 2 3 4 Nisole, Sébastien; Saïb, Ali (2004-05-14). "Early steps of retrovirus replicative cycle". Retrovirology. 1: 9. doi: 10.1186/1742-4690-1-9 . ISSN   1742-4690. PMC   421752 . PMID   15169567.
  17. ↑ Dudley, Jaquelin (2010-10-22). Retroviruses and Insights into Cancer. Springer Science & Business Media. ISBN   978-0-387-09581-3.
  18. 1 2 Lowenstine, Linda J.; McManamon, Rita; Terio, Karen A. (2018-01-01), Terio, Karen A.; McAloose, Denise; Leger, Judy St. (eds.), "Chapter 15 - Apes", Pathology of Wildlife and Zoo Animals, Academic Press, pp. 375–412, ISBN   978-0-12-805306-5 , retrieved 2020-02-09
  19. ↑ Murphy, Hayley Weston; Switzer, William M. (2008-01-01), Fowler, Murray E.; Miller, R. Eric (eds.), "Chapter 31 - Occupational Exposure to Zoonotic Simian Retroviruses: Health and Safety Implications for Persons Working with Nonhuman Primates", Zoo and Wild Animal Medicine (Sixth Edition), W.B. Saunders, pp. 251–264, ISBN   978-1-4160-4047-7 , retrieved 2020-02-09
  20. ↑ Denner, Joachim; Young, Paul R (2013-10-23). "Koala retroviruses: characterization and impact on the life of koalas". Retrovirology. 10: 108. doi: 10.1186/1742-4690-10-108 . ISSN   1742-4690. PMC   4016316 . PMID   24148555.
  21. ↑ Hunter, Jacqueline E.; Ramos, Linnet; Wolfe, John H. (2017-01-01), "Viral Vectors in the CNS☆", Reference Module in Neuroscience and Biobehavioral Psychology, Elsevier, ISBN   978-0-12-809324-5 , retrieved 2020-02-17
  22. 1 2 Cooray, Samantha; Howe, Steven J.; Thrasher, Adrian J. (2012-01-01), "Chapter three - Retrovirus and Lentivirus Vector Design and Methods of Cell Conditioning", in Friedmann, Theodore (ed.), Gene Transfer Vectors for Clinical Application , Methods in Enzymology, vol. 507, Academic Press, pp. 29–57, doi:10.1016/B978-0-12-386509-0.00003-X, ISBN   978-0-12-386509-0, PMID   22365768 , retrieved 2020-02-17
  23. ↑ Worgall, Stefan; Crystal, Ronald G. (2014-01-01), Lanza, Robert; Langer, Robert; Vacanti, Joseph (eds.), "Chapter 34 - Gene Therapy", Principles of Tissue Engineering (Fourth Edition), Academic Press, pp. 657–686, ISBN   978-0-12-398358-9 , retrieved 2020-02-17
  24. ↑ Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina (2014-01-01), Etzioni, Amos; Ochs, Hans D. (eds.), "Chapter 26 - How Primary Immunodeficiencies Have Made Gene Therapy a Reality", Primary Immunodeficiency Disorders, Academic Press, pp. 327–339, ISBN   978-0-12-407179-7 , retrieved 2020-02-17
  25. ↑ Lam, John S.; Reeves, Mark E.; Cowherd, Robert; Rosenberg, Steven A.; Hwu, Patrick (August 1996). "Improved Gene Transfer into Human Lymphocytes Using Retroviruses with the Gibbon Ape Leukemia Virus Envelope". Human Gene Therapy. 7 (12): 1415–1422. doi:10.1089/hum.1996.7.12-1415. ISSN   1043-0342. PMID   8844200.
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