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16.5

Retroviruses as gene vectors

SU TM plasma membrane

Figure 16.10 Retrovirus assembly late stages. The envelope is acquired by budding from the plasma membrane. During and after budding Gag and GagPol are cleaved to form the virion proteins.

16.3.7 Overview of retrovirus replication


The retrovirus replication cycle is summarized in Figure16.11.

Some genetically modied retroviruses are used as gene vectors. They can introduce genes into a variety of cell types, where the genes are expressed at high levels after integration into the cell genomes. Technologies have been developed for expression of genes in cell cultures and for clinical treatments of genetic disorders and cancers. One of the most commonly used viruses in these applications is murine leukaemia virus. Lentiviral vectors have also been developed; these have the advantage that they can deliver genes into non-dividing cells and tissues. Patients with the genetic disorder X-linked severe combined immunodeciency (X-SCID) have been successfully treated with retroviral vectors. The procedure involves taking stem cells from the patient and infecting them with a recombinant retrovirus, the genome of which contains a good copy of the gene that is defective. If the vector provirus is integrated into the cell genome, and if the good copy of the gene is expressed, then the patient is able to develop a normal immune system. The successes, however, have been tempered by the development of cancer in a few treated patients.

16.4

Examples of retroviruses

Retroviruses can be classed as either simple or complex, depending on the complexity of their genomes. The simple retroviruses are those that have only the three standard retrovirus genes (gag, pol, env ), or in some cases one additional gene, called an oncogene because its expression might result in its host cell developing into a tumour cell. An example of an oncogene is src in the genome of Rous sarcoma virus, which infects chickens (Figure 16.12). The complex retroviruses have additional genes, the products of which have a variety of functions in the replication cycle. The human immunodeciency viruses are complex retroviruses; because of their importance the next chapter is devoted entirely to them. The genera of the family Retroviridae and some representative viruses are listed in Table 16.3. As the names of the viruses imply, many of them of them are causative agents of disease in mammals (feline leukaemia virus), birds (Rous sarcoma virus) and sh (walleye dermal sarcoma virus).

16.6

Endogenous retroviruses

It has been known for some time that the genomes of vertebrate animals contain retroviral sequences. The genomes of most of these endogenous retroviruses (ERVs) are defective. Sequencing the human genome has revealed the presence of almost 100 000 human ERV (HERV) sequences, and ERVs have been found in the genomes of other species as they have been sequenced. Some ERVs are closely related to normal retroviruses (exogenous retroviruses); for example, there are ERVs in mice that have very similar sequences to the genome of mouse mammary tumour virus. It is highly likely that ERVs originated as a result of exogenous retroviruses infecting germ line cells (sperm and/or egg). If one of these cells with an integrated provirus survived to be involved in the reproductive process, then each cell in the body of the offspring would contain a copy of the provirus. Over time ERVs have copied themselves to other locations in the genome, giving rise to families of related ERV elements.

RETROVIRUSES

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8 1 2 7 reverse transcription complex

RNA

tRNA

DNA

pre-integration complex

Golgi

Env An 5 NUCLEUS rough endoplasmic reticulum

Gag An provirus cell chromosome 4 6 mRNA An An An 5 Gag-Pol

cell RNA pol II

An An progeny genomes

1. Attachment 2. Entry 3. Reverse transcription 4. Transcription 5. Translation 6. Genome replication 7. Assembly 8. Exit

Figure 16.11 The retrovirus replication cycle. Note that there is an additional step in retrovirus replication: reverse transcription, which takes place between entry and transcription.

cap R U5

gag

pol

env

src

U3 R An

Figure 16.12 Rous sarcoma virus genome. There is an oncogene (src) in addition to the three standard retrovirus genes.

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Table 16.3

Examples of retroviruses

Simple retroviruses Genus Virus examples Alpharetrovirus Betaretrovirus Gammaretrovirus Rous sarcoma virus Mouse mammary tumour virus Murine leukaemia virus Feline leukaemia virus

Genus Deltaretrovirus Epsilonretrovirus Lentivirus Spumavirus

Complex retroviruses Virus examples Human T-lymphotropic viruses 1 & 2 Walleye dermal sarcoma virus Human immunodeciency virus 1 Chimpanzee foamy virus

As stated above, most ERVs are defective, so they do not normally replicate. There are circumstances, however, when some ERVs can replicate. Missing functions may be supplied by another ERV or an exogenous retrovirus. Some ERVs do not replicate in cells of the species in which they occur, but are able to replicate in the cells of other species; e.g., some mouse ERVs and some pig ERVs can replicate in human cells. There are also some ERVs that are not defective; they have an intact genome (gag, pol and env genes) and can initiate a productive infection. Because of these ndings concern has been expressed that there may be a risk of transmitting retroviruses from pigs into humans if pigs are used as sources of cells, tissues and organs because of shortages of their human counterparts for transplant purposes.

Sources of further information


Books
Flint S. J. et al. (2004) Chapter 7 in Principles of Virology: Molecular Biology, Pathogenesis and Control of Animal Viruses, 2nd edn, ASM Press Knipe D. M. and Howley P. M. (2001) Chapter 27 in Fundamental Virology, 4th edn, Lippincott, Williams and Wilkins Lewin B. (2004) Chapter 17 in Genes VIII, Pearson PrenticeHall

Journals
Baillie G. J. et al. (2004) Multiple groups of endogenous betaretroviruses in mice, rats, and other mammals Journal of Virology, 78, 57845798 Baum C. et al. (2006) Retrovirus vectors: toward the plentivirus? Molecular Therapy, 13, 10501063 Bushman F. et al. (2005) Genome-wide analysis of retroviral DNA integration Nature Reviews Microbiology, 3, 848858 DSouza V. and Summers M. F. (2005) How retroviruses select their genomes Nature Reviews Microbiology, 3, 643655 Muriaux D. et al. (2001) RNA is a structural element in retrovirus particles Proceedings of the National Academy of Sciences USA, 98, 52465251

Learning outcomes
By the end of this chapter you should be able to describe the retrovirus virion; describe the main features of the retrovirus genome; explain the main features of the retrovirus replication cycle; give examples of retroviruses and explain their importance; discuss endogenous retroviruses.