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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/09/07 19:57:51」(JST)

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Lentivirus (lente-, Latin for "slow") is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in the human and other mammalian species.^[1] The best known lentivirus is the Human Immunodeficiency Virus HIV, which causes AIDS. Lentiviruses are also hosted in apes, cows, goats, horses, cats, and sheep.^[1] Recently, lentiviruses have been found in monkeys, lemurs, Malayan flying lemur (not a true lemur nor a primate), rabbits, and ferrets. Lentiviruses and their hosts have worldwide distribution. Lentiviruses can integrate a significant amount of viral RNA into the DNA of the host cell and can efficiently infect nondividing cells, so they are one of the most efficient methods of gene delivery.^[2] Lentiviruses can become endogenous (ERV), integrating their genome into the host germline genome, so that the virus is henceforth inherited by the host's descendants.

Classification

Five serogroups of lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, domestic cats, and cattle).^[3] The primate lentiviruses are distinguished by the use of CD4 protein as a receptor and the absence of dUTPase.^[4] Some groups have cross-reactive gag antigens (e.g., the ovine, caprine, and feline lentiviruses). Antibodies to gag antigens in lions and other large felids indicate the existence of other as yet unidentified viruses related to feline lentivirus and the ovine/caprine lentiviruses.

Morphology

The virions are enveloped, slightly pleomorphic, spherical and measure 80–100 nm in diameter. Projections of envelope make the surface appear rough, or tiny spikes (about 8 nm) may be dispersed evenly over the surface. The nucleocapsids (cores) are isometric. The nucleoids are concentric and rod-shaped, or shaped like a truncated cone.^[5]

Genome organization and replication

Features of the genome: infectious viruses have three main genes coding for the viral proteins in the order: 5´-gag-pol-env-3´. There are two regulatory genes, tat and rev. There are 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. The Long terminal repeat (LTR) is about 600 nt long, of which the U3 region is 450, the R sequence 100 and the U5 region some 70 nt long.

Viral proteins involved in early stages of replication include reverse transcriptase and integrase. 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 also has RNaseH activity for destruction of the RNA-template. Integrase binds both the viral cDNA generated by reverse transcriptase and the host DNA. Integrase processes the LTR 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.^[6]

Proteome

The lentiviral proteome consists of five major structural proteins and 3-4 non-structural proteins (3 in the primate lentiviruses).

Structural proteins listed by size:

Gp120 surface envelope protein SU, encoded by the viral gene env. 120000 Da (Daltons).
Gp41 transmembrane envelope protein TM, also encoded by the viral gene env. 41000 Da.
P24 capsid protein CA, encoded by the viral gene gag. 24000 Da.
P17 matrix protein MA, also encoded by gag. 17000 Da.
P9 capsid protein NC, also encoded by gag. 7000-11000 Da.

The envelope proteins SU and TM are glycosylated in 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:

Reverse transcriptase RT encoded by the pol gene. Protein size 66000 Da.
Integrase IN also encoded by the pol gene. Protein size 32000 Da.
Protease PR encoded by the pro gene.
dUTPase DU encoded by the pro gene (part of pol gene in some viruses), the role of which is still unknown. Protein size 14000 Da.

Gene regulatory proteins:

Tat
Rev

Accessory proteins:

Nef
Vpr
Vif
Vpu/Vpx
p6

Antigenic properties

Serological Relationships: Antigen determinants 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 the glycoproteins. Cross-reactivity has been found among some species of the same serotype, but not between members of different genera. Classification of members of this taxon is infrequently based on their antigenic properties.

Epidemiology

Symptoms and host range: The virus' hosts are found in the orders Primates (humans, apes and monkeys), Carnivora (cats, dogs and other carnivores), Perissodactyla and Artiodactyla (single and double-toed hooved mammals).
Transmission: Transmitted by means not involving a vector.
Geographic distribution: Worldwide.

Physicochemical and physical properties

General
- Buoyant density 1.16–1.18 g cm⁻³ in sucrose
- Virions sensitive to heat, detergents, and formaldehyde
- Infectivity not affected by UV irradiation

Classed as having class C morphology

Nucleic Acid
- Virions contain 2% nucleic acid
- Genome consists of a dimer
- Virions contain one molecule of (each) linear positive-sense single stranded RNA.
- Total genome length is of one monomer 9200 nt
- 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; 3'-terminus has a tRNA-like structure (and accepts lysin)
- Encapsidated nucleic acid are solely genomic
- 2 copies packed per particle (held together by hydrogen bonds 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

Lentiviral Delivery of designed shRNA's and the mechanism of RNA interference in mammalian cells.

Lentivirus is primarily a research tool used to introduce a gene product into in vitro systems or animal models. Large-scale collaborative efforts are underway to use lentiviruses to block the expression of a specific gene using RNA interference technology in high-throughput formats.^[7] The expression of short-hairpin RNA (shRNA) reduces the expression of a specific gene, thus allowing researchers to examine the necessity and effects of a given gene in a model system. These studies can be a precursor to the development of novel drugs which aim to block a gene-product to treat diseases. 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 mouse hemophilia is corrected by expressing wild-type platelet-factor VIII, the gene that is mutated in human hemophilia.^[8] Lentiviral infection has advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of a transgene, and low immunogenicity. Lentiviruses have also been successfully used for transfection of diabetic mice with the gene encoding PDGF (platelet-derived growth factor),^[9] a therapy being considered for use in humans. These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studies. Gammaretroviral and lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases.^[10]

Notes

^ ^a ^b "What is Lentivirus?". News-Medical.net. Retrieved 2015-11-30.
^ Cockrell, Adam S.; Kafri, Tal (2007-07-01). "Gene delivery by lentivirus vectors". Molecular Biotechnology. 36 (3): 184–204. ISSN 1073-6085. PMID 17873406. doi:10.1007/s12033-007-0010-8.
^ Mahy, Brian W. J. (2009-02-26). The Dictionary of Virology. Academic Press. ISBN 9780080920368.
^ 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. ISSN 0105-2896. PMID 10399064. doi:10.1111/j.1600-065x.1999.tb01282.x.
^ "ViralZone: Lentivirus". viralzone.expasy.org. Retrieved 2015-11-30.
^ Gilbert, James R., and Flossie Wong-Staal. "HIV-2 and SIV Vector Systems." Lentiviral Vector Systems for Gene Transfer. Ed. Gary L. Buchschacher. Georgetown, TX: Eurekah.com, 2003. https://books.google.com/books?id=59FuGsgsI5wC&printsec=frontcover&source=gbs_ge_summary_r&cad=0#v=onepage&q&f=false
^ shRNA – short hairpin RNA
^ 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. PMID 17269937. doi:10.1111/j.1538-7836.2007.02346.x.
^ 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. PMID 16079687. doi:10.1097/01.prs.0000172892.78964.49.
^ Kurth, R; Bannert, N, eds. (2010). Retroviruses: Molecular Biology, Genomics and Pathogenesis. Caister Academic Press. ISBN 978-1-904455-55-4.

References

Ryan KJ, Ray CG, eds. (2004). Sherris Medical Microbiology: An Introduction to Infectious Diseases (4th ed.). New York: McGraw Hill. ISBN 0-8385-8529-9.
Desport, M, ed. (2010). Lentiviruses and Macrophages: Molecular and Cellular Interactions. Caister Academic Press. ISBN 978-1-904455-60-8.

External links

Viralzone: Lentivirus

English Journal

All-in-One inducible lentiviral vector systems based on drug controlled FLP recombinase.

Maetzig T1, Kuehle J1, Schwarzer A1, Turan S1, Rothe M1, Chaturvedi A2, Morgan M1, Ha TC1, Heuser M2, Hammerschmidt W3, Baum C1, Schambach A4.Author information 1Institute of Experimental Hematology, Hannover Medical School, Germany.2Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany.3Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Centre for Infection Research (DZIF), Partner Site Munich, Germany.4Institute of Experimental Hematology, Hannover Medical School, Germany; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, USA. Electronic address: schambach.axel@mh-hannover.de.AbstractSite specific recombinases are frequently used as gene switches in transgenic animals where recombination is induced by drug treatment or by tissue specific recombinase expression. Alternatively, lentiviral gene transfer can be utilized for the genetic modification of a wide variety of cell types, albeit systems for tight control of transcriptional activity are scarce. Here, we combined lentiviral gene transfer and the development of a tightly drug-controlled FLP recombinase for the construction of "All-in-One" inducible gene expression systems. Tight control of FLP activity was achieved through N-terminal fusion with a FKBP12-derived conditional destruction domain and a C-terminal estrogen receptor binding domain making recombination dependent on the presence of Shield-1 and 4-hydroxytamoxifen. Exploiting the capacity of FLP to mediate excision and inversion, "All-in-One" lentiviral gene switch vector systems were generated where drug-induced recombination resulted in abrogation of FLP expression and subsequent overexpression or knockdown of the prototypical tumor suppressor phosphatase and tensin homolog PTEN. "All-in-One" vectors proved their functionality in a variety of hematopoietic cell lines, and primary murine bone marrow cells. Our new vector system thus combines the ease of lentiviral gene transfer and the power of site specific recombinases for analysis of gene function.
Biomaterials.Biomaterials.2014 May;35(14):4345-56. doi: 10.1016/j.biomaterials.2014.01.057. Epub 2014 Feb 14.
Site specific recombinases are frequently used as gene switches in transgenic animals where recombination is induced by drug treatment or by tissue specific recombinase expression. Alternatively, lentiviral gene transfer can be utilized for the genetic modification of a wide variety of cell types, a
PMID 24529624

Sirt1 Activation Ameliorates Renal Fibrosis by Inhibiting the TGF-β/Smad3 Pathway.

Huang XZ1, Wen D, Zhang M, Xie Q, Ma L, Guan Y, Ren Y, Chen J, Hao CM.Author information 1Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, 200040, China; Division of Nephrology, Affiliated Hospital of Nantong University, Nantong, 226001, China.AbstractTGF-β signaling plays an important role in the pathogenesis and progression of chronic kidney disease (CKD). Smad3, a transcription factor, is a critical fibrogenic mediator of TGF-β. Sirt1 is a NAD(+) -dependent deacetylase that has been reported to modify a number of transcription factors to exert certain beneficial health effects. This study examined the effect of Sirt1 on Smad3 and its role in CKD. Resveratrol attenuated the expression of extracelluar matrix proteins in both the remnant kidney of 5/6th nephrectomized rats and cultured mesangial cells (MMCs) exposed to TGF-β1. The effect of resveratrol was substantially attenuated in cultured MMCs for which Sirt1 had been knocked down by an shRNA lentivirus. Overexpression of Sirt1 attenuated TGF-β1-induced extracelluar matrix expression in cultured cells. Co-immunoprecipitation studies suggested that Sirt1 could bind with Smad3. Resveratrol treatment enhanced this binding and reduced acetylation levels of Smad3. Resveratrol inhibited the transcription activity of Smad3. Knockdown of Sirt1 increased acetylated Smad3 and substantially enhanced the transcriptional activity following TGF-β1. Finally, Sirt1 deficiency aggravated renal function damage and markedly enhanced fibrosis in the remnant kidney of 5/6 nephrectomized mice. Taken together, these results identify Sirt1 as an important protective factor for renal fibrosis in a CKD rodent model, and the protective function of Sirt1 is attributable to its action on TGF-β/Smad3 signaling. Therefore, we suggest that Sirt1 may be a potential therapeutic target for the treatment of CKD. J. Cell. Biochem. 115: 996-1005, 2014. © 2014 Wiley Periodicals, Inc.
Journal of cellular biochemistry.J Cell Biochem.2014 May;115(5):996-1005. doi: 10.1002/jcb.24748.
TGF-β signaling plays an important role in the pathogenesis and progression of chronic kidney disease (CKD). Smad3, a transcription factor, is a critical fibrogenic mediator of TGF-β. Sirt1 is a NAD(+) -dependent deacetylase that has been reported to modify a number of transcription factors to exe
PMID 24356887

Deletion variant near ZNF389 is associated with control of ovine lentivirus in multiple sheep flocks.

White SN1, Mousel MR, Reynolds JO, Herrmann-Hoesing LM, Knowles DP.Author information 1Animal Disease Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Pullman, WA, 99164, USA; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, 99164, USA.AbstractOvine lentivirus (OvLV) is a macrophage-tropic lentivirus found in many countries that causes interstitial pneumonia, mastitis, arthritis and cachexia in sheep. There is no preventive vaccine and no cure, but breed differences suggest marker-assisted selective breeding might improve odds of infection and control of OvLV post-infection. Although variants in TMEM154 have consistent association with odds of infection, no variant in any gene has been associated with host control of OvLV post-infection in multiple animal sets. Proviral concentration is a live-animal diagnostic measure of OvLV control post-infection related to severity of OvLV-induced lesions. A recent genome-wide association study identified a region including four zinc finger genes associated with proviral concentration in one Rambouillet flock. To refine this region, we tested additional variants and identified a small insertion/deletion variant near ZNF389 that showed consistent association with proviral concentration in three animal sets (P < 0.05). These animal sets contained Rambouillet, Polypay and crossbred sheep from multiple locations and management conditions. Strikingly, one flock had exceptionally high prevalence (>87%, including yearlings) and mean proviral concentration (>950 copies/μg), possibly due to needle sharing. The best estimate of proviral concentration by genotype, obtained from all 1310 OvLV-positive animals tested, showed insertion homozygotes had less than half the proviral concentration of other genotypes (P < 0.0001). Future work will test additional breeds, management conditions and viral subtypes, and identify functional properties of the haplotype this deletion variant tracks. To our knowledge, this is the first genetic variant consistently associated with host control of OvLV post-infection in multiple sheep flocks.
Animal genetics.Anim Genet.2014 Apr;45(2):297-300. doi: 10.1111/age.12107. Epub 2013 Dec 5.
Ovine lentivirus (OvLV) is a macrophage-tropic lentivirus found in many countries that causes interstitial pneumonia, mastitis, arthritis and cachexia in sheep. There is no preventive vaccine and no cure, but breed differences suggest marker-assisted selective breeding might improve odds of infectio
PMID 24303974

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リンク元	「lentivirus」「レンチウイルス亜科」

「lentivirus」

lentivirus
Virus classification
Group:	Group VI (ssRNA-RT)
Order:	Unassigned
Family:	Retroviridae
Subfamily:	Orthoretrovirinae
Genus:	Lentivirus
Type species
	Human immunodeficiency virus 1;
Species
	Bovine lentivirus group; Bovine immunodeficiency virus Jembrana disease virus Equine lentivirus group; Equine infectious anemia virus Feline lentivirus group; Feline immunodeficiency virus Puma lentivirus Lion lentivirus (FIV-PLe) Colugo lentivirus group; Malayan colugo endogenous lentivirus (ELVgv) Weasel lentivirus group; Ferret endogenous lentivirus (MELVmpf) Rabbit lentivirus group; Rabbit endogenous lentivirus type K (RELIK) Ovine/caprine lentivirus group; Caprine arthritis encephalitis virus Visna/maedi virus Primate lentivirus group; Human immunodeficiency virus 1 Human immunodeficiency virus 2 Simian immunodeficiency virus Gray mouse lemur prosimian immunodeficiency virus (pSIVgml)

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レンチウイルス

関: lentiviral、Lentivirinae

「レンチウイルス亜科」

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ラ: Lentivirinae
関: レンチウイルス

[:0-1] "What is Lentivirus?". News-Medical.net. Retrieved 2015-11-30.

[2] Cockrell, Adam S.; Kafri, Tal (2007-07-01). "Gene delivery by lentivirus vectors". Molecular Biotechnology. 36 (3): 184–204. ISSN 1073-6085. PMID 17873406. doi:10.1007/s12033-007-0010-8.

[3] Mahy, Brian W. J. (2009-02-26). The Dictionary of Virology. Academic Press. ISBN 9780080920368.

[4] 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. ISSN 0105-2896. PMID 10399064. doi:10.1111/j.1600-065x.1999.tb01282.x.

[5] "ViralZone: Lentivirus". viralzone.expasy.org. Retrieved 2015-11-30.

[6] Gilbert, James R., and Flossie Wong-Staal. "HIV-2 and SIV Vector Systems." Lentiviral Vector Systems for Gene Transfer. Ed. Gary L. Buchschacher. Georgetown, TX: Eurekah.com, 2003. https://books.google.com/books?id=59FuGsgsI5wC&printsec=frontcover&source=gbs_ge_summary_r&cad=0#v=onepage&q&f=false

[7] shRNA – short hairpin RNA

[8] 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. PMID 17269937. doi:10.1111/j.1538-7836.2007.02346.x.

[9] 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. PMID 16079687. doi:10.1097/01.prs.0000172892.78964.49.

[KurthBannert-10] Kurth, R; Bannert, N, eds. (2010). Retroviruses: Molecular Biology, Genomics and Pathogenesis. Caister Academic Press. ISBN 978-1-904455-55-4.

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Lentivirinae