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Lentivirus

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Lentivirus
Virus classificationEdit this classification
(unranked): Virus
Realm: Riboviria
Kingdom: Pararnavirae
Phylum: Artverviricota
Class: Revtraviricetes
Order: Ortervirales
Family: Retroviridae
Subfamily: Orthoretrovirinae
Genus: Lentivirus
Species

Lentivirusis agenusofretrovirusesthat cause chronic and deadly diseases characterized by longincubation periods,in humans and other mammalian species.[2]The genus includes thehuman immunodeficiency virus(HIV), which causesAIDS.Lentiviruses are distributed worldwide, and are known to be hosted in apes,cows,goats, horses, cats, and sheep as well as several other mammals.[2]

Lentiviruses can integrate a significant amount ofviralcomplementary DNAinto theDNAof thehost celland can efficiently infect nondividing cells, so they are one of the most efficient methods ofgene delivery.[3]They can becomeendogenous,integrating their genome into the hostgermlinegenome, so that the virus is henceforth inherited by the host's descendants.[1]

Classification

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Fiveserogroupsof lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, domestic cats, and cattle).[4]Theprimatelentiviruses are distinguished by the use ofCD4protein as areceptorand the absence ofdUTPase.[5]Some groups have cross-reactive gags (group-specific antigens) (e.g., theovine,caprine,andfelinelentiviruses).Antibodiesto gags in lions and other large felines indicate the existence of another yet-to-be identified virus related to feline lentivirus and the ovine/caprine lentiviruses.[citation needed]

Morphology

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Structure ofHIV,a lentivirus.

Thevirionsare enveloped viruses 80–100 nm in diameter.[6]They are spherical orpleomorphic,with capsid cores that mature to a cylindrical or conical shape.[6][7]Projections ofenvelopemake the surface appear rough, or tinyspikes(about 8 nm) may be dispersed evenly over the surface.[6]

Genome

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Lentiviruses contain 2 sense, single-strand RNAs that are bound by nucleocapsid proteins.[8]As with all retroviruses, lentiviruses havegag,polandenvgenes, coding for viral proteins in the order: 5´-gag-pol-env-3´. Unlike other retroviruses, however, lentiviruses have tworegulatory genes,tatandrev.They may also have additional accessory genes depending on the virus (e.g., for HIV-1:vif,vpr,vpu,nef) whose products are involved in regulation of synthesis and processing viral RNA and other replicative functions. Thelong terminal repeat(LTR) is about 600ntlong, of which the U3 region is 450, the R sequence 100 and the U5 region some 70 nt long.

Replication

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Retroviruses carry proteins within theircapsids,which bind the RNA genome. These proteins are typically involved in the early stages of genome replication, and includereverse transcriptaseandintegrase.Reverse transcriptase is the virally encoded RNA-dependent DNA polymerase. The enzyme uses the viral RNA genome as a template for the synthesis of a complementary DNA copy. Reverse transcriptase possesses [RNase H] activity for destruction of the RNA-template. Integrase binds both the viral cDNA generated by reverse transcriptase and the host DNA. It then processes the LTRs before inserting the viral genome into the host DNA. Tat acts as a trans-activator during transcription to enhance initiation and elongation. The Rev responsive element acts post-transcriptionally, regulating mRNA splicing and transport to the cytoplasm.[9]

Proteome

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Further information:Structure and genome of HIV § Genome organization

The lentiviral proteome consists of five major structural proteins and three or four non-structural proteins (three in the primate lentiviruses).[which?]

Structural proteins listed by size:

  1. Gp120surface envelope protein SU, encoded by the viral geneenv.120000 Da (daltons).
  2. Gp41transmembrane envelope protein TM, also encoded by the viral geneenv.41000 Da.
  3. P24capsidprotein CA, encoded by the viral genegag.24000 Da.
  4. P17matrixprotein MA, also encoded bygag.17000 Da.
  5. P7/P9 capsid protein NC, also encoded bygag.7000–11000 Da.

Theenvelope proteinsSU and TM areglycosylatedin at least some lentiviruses (HIV, SIV), if not all of them. Glycosylation seems to play a structural role in the concealment and variation of antigenic sites necessary for the host to mount an immune system response.

Enzymes:

  1. Reverse transcriptaseRT encoded by thepolgene. Protein size 66000 Da.
  2. IntegraseIN also encoded by thepolgene. Protein size 32000 Da.
  3. ProteasePR encoded by theprogene (part ofpolgene in some viruses).
  4. dUTPaseDU encoded by theprogene (part ofpolgene in some viruses), the role of which is still unknown. Protein size 14000 Da.

Gene regulatory proteins:

  1. Tat:main trans-activator
  2. Rev:important for synthesis of major viral proteins

Accessory proteins:

  1. Nef:negative factor
  2. Vpr:regulatory protein
  3. Vif:APOBEC3 inhibitor
  4. Vpu/Vpx:unique to each type of HIV
  5. p6: part of gag

Antigenic properties

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Serological relationships:Antigendeterminants are type specific and group specific. Antigen determinants that possess type-specific reactivity are found on the envelope. Antigen determinants that possess type-specific reactivity and are involved in antibody mediated neutralization are found on theglycoproteins.Cross-reactivity has been found among some species of the same serotype, but not between members of different genera. Classification of members of thistaxonis infrequently based on their antigenic properties.

Epidemiology

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Physicochemical and physical properties

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Classed as havingclass Cmorphology

Lentiviral delivery of designedshRNA's and the mechanism ofRNA interferenceinmammaliancells.
  • Nucleic acid
    • Virions contain 2%nucleic acid
    • Genomeconsists of adimer
    • Virions contain one molecule of (each) linear positive-sense single strandedRNA.
    • Total genome length is of onemonomerranges from 8k-10k nt (depending on the virus).
    • Genome sequence has terminal repeated sequences;long terminal repeats(LTR) (of about 600 nt)
    • The 5' end of the genome has a cap
    • Cap sequence of type 1 m7G5ppp5'GmpNp
    • 3' end of each monomer has a poly (A) tract.
    • 2 copies packed per particle (held together by Watson-Crick baseparing to form a dimer).
  • There are 11 proteins
    • Virions contain 60% protein
    • Five (major)structural virion proteins have been found so far
  • Lipids:Virions contain 35%lipid.
  • Carbohydrates:Other compounds detected in the particles 3% carbohydrates.

Use as gene delivery vectors

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Main article:Lentiviral vector in gene therapy

Lentivirus is primarily a research tool used to introduce a gene product intoin vitrosystems or animal models. Large-scale collaborative efforts are underway to use lentiviruses to block the expression of a specific gene usingRNA interferencetechnology in high-throughput formats.[10]Conversely, lentivirus are also used to stably over-express certain genes, thus allowing researchers to examine the effect of increased gene expression in a model system.

Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For example, a model of mousehemophiliais corrected by expressing wild-type platelet-factor VIII,the gene that is mutated in human hemophilia.[11]Lentiviral infection has advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of atransgene,and low immunogenicity. Lentiviruses have also been successfully used fortransductionof diabetic mice with thegeneencodingPDGF(platelet-derived growth factor),[12]a therapy being considered for use in humans. Finally, lentiviruses have been also used to elicit an immune response against tumor antigens.[13]These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studies. Gammaretroviraland lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases.[14]

See also

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Notes

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  1. ^abKambol, R; Gatseva, A; Gifford, RJ (20 December 2022)."An endogenous lentivirus in the germline of a rodent".Retrovirology.19(1): 30.doi:10.1186/s12977-022-00615-2.PMC9768972.PMID36539757.
  2. ^ab"What is Lentivirus?".News-Medical.net.2010-05-19.Retrieved2015-11-30.
  3. ^Cockrell, Adam S.; Kafri, Tal (2007-07-01)."Gene delivery by lentivirus vectors".Molecular Biotechnology.36(3): 184–204.doi:10.1007/s12033-007-0010-8.ISSN1073-6085.PMID17873406.S2CID25410405.
  4. ^Mahy, Brian W. J. (2009-02-26).The Dictionary of Virology.Academic Press.ISBN9780080920368.
  5. ^Piguet, V.; Schwartz, O.; Le Gall, S.; Trono, D. (1999-04-01). "The downregulation of CD4 and MHC-I by primate lentiviruses: a paradigm for the modulation of cell surface receptors".Immunological Reviews.168:51–63.doi:10.1111/j.1600-065x.1999.tb01282.x.ISSN0105-2896.PMID10399064.S2CID19409388.
  6. ^abc"ViralZone: Lentivirus".viralzone.expasy.org.Retrieved2015-11-30.
  7. ^Goff SP (2013). "Retroviridae". In Knipe DM, Howley PM (eds.).Fields Virology(6 ed.). Lippincott Williams & Wilkins. pp. 1424–1472.ISBN978-1-4511-0563-6.
  8. ^Bulcha, Jote T.; Wang, Yi; Ma, Hong; Tai, Phillip W. L.; Gao, Guangping (2021-02-08)."Viral vector platforms within the gene therapy landscape".Signal Transduction and Targeted Therapy.6(1): 53.doi:10.1038/s41392-021-00487-6.ISSN2059-3635.PMC7868676.PMID33558455.
  9. ^Buchschacher, Gary L. (2003-01-31).Lentiviral Vector Systems for Gene Transfer.Springer US.ISBN978-0-306-47702-7.
  10. ^shRNA – short hairpin RNA
  11. ^Shi Q, Wilcox DA, Fahs SA, et al. (February 2007)."Lentivirus-mediated platelet-derived factor VIII gene therapy in murine haemophilia A".J. Thromb. Haemost.5(2): 352–61.doi:10.1111/j.1538-7836.2007.02346.x.PMID17269937.
  12. ^Lee JA, Conejero JA, Mason JM, et al. (August 2005). "Lentiviral transfection with the PDGF-B gene improves diabetic wound healing".Plast. Reconstr. Surg.116(2): 532–8.doi:10.1097/01.prs.0000172892.78964.49.PMID16079687.S2CID8628077.
  13. ^Casado, Javier Garcia; Janda, Jozef; Wei, Joe; Chapatte, Laurence; Colombetti, Sara; Alves, Pedro; Ritter, Gerd; Ayyoub, Maha; Valmori, Danila; Chen, Weisan; Lévy, Frédéric (2008)."Lentivector immunization induces tumor antigen-specific B and T cell responses in vivo".European Journal of Immunology.38(7): 1867–1876.doi:10.1002/eji.200737923.ISSN1521-4141.PMID18546142.
  14. ^Kurth, R; Bannert, N, eds. (2010).Retroviruses: Molecular Biology, Genomics and Pathogenesis.Caister Academic Press.ISBN978-1-904455-55-4.

References

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  • Ryan KJ, Ray CG, eds. (2004).Sherris Medical Microbiology: An Introduction to Infectious Diseases(4th ed.). New York: McGraw Hill.ISBN978-0-8385-8529-0.
  • Desport, M, ed. (2010).Lentiviruses and Macrophages: Molecular and Cellular Interactions.Caister Academic Press.ISBN978-1-904455-60-8.
  • Knipe DM, Howley PM, eds. (2013).Fields Virology(6 ed.). Lippincott Williams & Wilkins.ISBN978-1-4511-0563-6.

Further reading

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