Definitions

viral delivery vector

Lentivirus

[len-tuh-vahy-ruhs]
Lentivirus (lenti-, Latin for "slow") is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period. Lentiviruses can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses.

Classification

Five serogroups of lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, cats, and cattle). The primate lentiviruses are distinguished by the use of CD4 protein as receptor and the absence of dUTPase. 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 viruses related to FIV and the ovine/caprine lentiviruses. Description is on taxonomic level of genus.

Morphology

Virions enveloped; slightly pleomorphic; spherical; 80-100 nm in diameter. Surface projections of envelope small (surface appears rough), or barely visible; spikes (of about 8nm); dispersed evenly over all the surface. Nucleocapsids (cores) isometric. Nucleoid concentric and rod-shaped, or shaped like a truncated cone.

Genome organization and replication

Features of the genome: infectious viruses have 3 main genes coding for the viral proteins in the order: 5´-gag-pol-env-3´. There are additional genes (also called accessory genes) depending on the virus (e.g., for HIV-1: vif, vpr, vpu, tat, rev, nef) whose products are involved in regulation of synthesis and processing viral RNA and other replicative functions. The Long terminal repeat is about 600nt 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 (RT) 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. RT also has RNaseH activity for destruction of the RNA-template. Integrase (IN) binds both the viral cDNA generated by RT and the host DNA. Processing of the LTR by IN is performed prior to insertion of the viral genome into the host DNA.

Although transmission is generally via infectious particles, lentiviruses are capable of infecting neighboring cells in direct contact with the host cells, without having to form extracellular particles.

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.

Biological

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 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 solely genomic
    • 2 copies packed per particle (held together by hydrogen bonds to form a dimer).
  • Proteins 11
    • Virions contain 60 % protein
    • Five structural virion proteins found (major)
      • Protein size largest 120000 Da. Gp120 glycosylated surface envelope protein SU, encoded by the viral gene env
      • Protein size of 2nd largest 41000 Da. Gp41 glycosylated transmembrane envelope protein TM, also encoded by the viral gene env.
      • Protein size of 3rd largest 24000 Da. P24 non-glycosylated capsid protein CA.
      • Protein size of 4th largest 17000 Da. P17 non-glycosylated matrix protein MA.
      • Protein size of 5th largest 7000-11000 Da. Non-glycosylated capsid protein NC.
      • Proteins MA, CA and NC are all encoded by the gag gene. Virion structural proteins are glycosylated. Are the following: the envelope proteins SU and TM.
    • Usually four non-structural proteins found, or three non-structural proteins found (in the primate lentiviruses).
      • Protein size 66000 Da. Reverse transcriptase RT encoded by the pol gene.
      • Protein size of 2nd largest 32000 Da. Integrase IN also encoded by the pol gene.
      • Protein size of 3rd 14000 Da. Protease PR encoded by the pro gene. dUPTase DU, the role of which is still unknown.
  • Lipids: Virions contain 35 % lipid.
  • Carbohydrates: Other compounds detected in the particles 3% carbohydrates.

Practical applications

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. 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 a disease.

Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For example, a model of mouse hemophillia is corrected by expressing wild-type platelet-factor VIII, the gene that is mutated in human hemophillia. Lentiviral infection have 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), 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.

Notes

References

Further reading

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