Lentivirus

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Lentivirus
Hiv virion image (1).jpg
Virus classification e
(unranked): Virus
Realm: Riboviria
Kingdom: Pararnavirae
Phylum: Artverviricota
Class: Revtraviricetes
Order: Ortervirales
Family: Retroviridae
Subfamily: Orthoretrovirinae
Genus: Lentivirus
Species

Lentivirus is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species.[2] The genus includes the human immunodeficiency virus (HIV), which causes AIDS. 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 of viral complementary DNA 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.[3][4] They can become endogenous, integrating their genome into the host germline genome, so that the virus is henceforth inherited by the host's descendants.[1]

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).[5] The primate lentiviruses are distinguished by the use of CD4 protein as a receptor and the absence of dUTPase,[6] some groups have cross-reactive gag antigens.

Morphology

Structure of HIV, a lentivirus.

The virions are enveloped viruses 80–100 nm in diameter.[7]

They are spherical or pleomorphic, with capsid cores that mature to a cylindrical or conical shape.[7][8]

Projections of envelope make the surface appear rough, or tiny spikes (about 8 nm) may be dispersed evenly over the surface.[7]

Genome organization and replication

As with all retroviruses, lentiviruses have gag, pol and env genes, coding for viral proteins in the order: 5´-gag-pol-env-3´. Unlike other retroviruses, however, lentiviruses have two regulatory genes, tat and rev. They may also have additional accessory genes depending on the virus 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.[9][7][10][11]

Retroviruses carry specific proteins within their capsids, which typically associate with the RNA genome. These proteins are typically involved in the early stages of genome replication, and 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 possesses 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.[12][11]

Proteome

Structure of the RNA genome of HIV-1

The lentiviral proteome consists of five major structural proteins and three/four non-structural proteins.[13][14]

Structural proteins listed by size:

  1. Gp120 surface envelope protein SU, encoded by the viral gene env. 120000 Da (daltons).[15][13]
  2. Gp41 transmembrane envelope protein TM, also encoded by the viral gene env. 41000 Da.[16]
  3. P24 capsid protein CA, encoded by the viral gene gag. 24000 Da.[17][18]
  4. P17 matrix protein MA, also encoded by gag. 17000 Da.[19]
  5. P7/P9 capsid protein NC, also encoded by gag. 7000–11000 Da.[20][13]

The envelope proteins SU and TM are glycosylated in at least some lentiviruses , 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.[21][22]

Enzymes:

  1. Reverse transcriptase RT encoded by the pol gene.[23]
  2. Integrase IN also encoded by the pol gene.[10][24]
  3. Protease PR encoded by the pro gene [10]
  4. dUTPase DU encoded by the pro gene [10]

Gene regulatory proteins:[25][26]

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

Accessory proteins:[27]

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

Antigenic properties

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[28][29][30]

Physicochemical and physical properties

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

In terms of the physicochemical and physical properties of Lentiviruses we find the following:

Classed as having class C morphology

  • There are 11 proteins
    • Virions contain 60% protein[39]
    • Five (major)structural virion proteins have been found [13][14]
  • Lipids: Virions contain 35% lipid.[40]
  • Carbohydrates: Other compounds detected in the particles 3% carbohydrates.[35]

Use as gene delivery vectors

a-c)Key clinical uses of lentiviral vectors[41]

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. 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.[42] [43][44][45] Though there are many challenges with Lentiviruses[46]

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.[47]

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 transduction of diabetic mice with the gene encoding PDGF (platelet-derived growth factor),[48] a therapy being considered for use in humans. Finally, lentiviruses have been also used to elicit an immune response against tumor antigens.[49]

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.[50]

Human illness

Main symptoms of acute HIV infection
Africa AIDS prevalence 2001

The human immunodeficiency viruses are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome ,[51][52] a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive.[53] Without treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype.[54]

Signs and symptoms

In terms of the symptoms one sees, it can start with:[55]

And after some time lead to or become:[55]

Or even progress to:[55]

Diagnosis

In terms of the diagnosis used to ascertain HIV we find the following:[55]

Treatment

Management of HIV/AIDS is based on a combination of medications that are termed antiretrovirals to combat the infections[55]

Epidemiology

The geographic distribution of this infection is found to be worldwide.[56]

See also

Notes

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References

  • Ryan KJ, Ray CG, eds. (2004). Sherris Medical Microbiology: An Introduction to Infectious Diseases (4th ed.). New York: McGraw Hill. ISBN 978-0-8385-8529-0.
  • Desport, M, ed. (2010). Lentiviruses and Macrophages: Molecular and Cellular Interactions. Caister Academic Press. ISBN 978-1-904455-60-8.
  • Knipe DM, Howley PM, eds. (2013). Fields Virology (6 ed.). Lippincott Williams & Wilkins. ISBN 978-1-4511-0563-6.

Further reading

External links