Studies of endogenous retroviruses reveal a continuing evolutionary saga

Key Points

  • Retroviral infection of germ cells can result in virus endogenization. Up to 10% of the vertebrate genome now comprises DNA derived from such germline invaders.

  • Analysis of such endogenous retroviruses (ERVs) shows that vertebrates have been subjected to multiple waves of infection by exogenous retroviruses, with essentially the same structures as modern viruses, over a period spanning many tens of millions of years.

  • Retroviral inheritance can have both positive and negative effects on hosts. Beneficial effects include the provision of functions necessary for placenta formation and resistance to novel retrovirus infection, whereas detrimental effects include tumour induction and (presumably) genome instability.

  • Control of retrovirus expression to protect against the negative effects of retrovirus replication seems to be of considerable importance; consequently, a range of systems for blocking virus replication have been developed, including epigenetic silencing and the evolution of specific virus restriction factors.

  • Evolutionary studies indicate that an arms race between viruses and hosts has taken place, with the development of a number of viral strategies to outwit host defences. Changes to virus and host are continuing to the present day.

  • Analysis of these interactions will greatly enhance our understanding of virus replication and may suggest novel therapeutic approaches to antiretroviral drug design.

Abstract

Retroviral replication involves the formation of a DNA provirus integrated into the host genome. Through this process, retroviruses can colonize the germ line to form endogenous retroviruses (ERVs). ERV inheritance can have multiple adverse consequences for the host, some resembling those resulting from exogenous retrovirus infection but others arising by mechanisms unique to ERVs. Inherited retroviruses can also confer benefits on the host. To meet the different threats posed by endogenous and exogenous retroviruses, various host defences have arisen during evolution, acting at various stages on the retrovirus life cycle. In this Review, I describe our current understanding of the distribution and architecture of ERVs, the consequences of their acquisition for the host and the emerging details of the intimate evolutionary relationship between virus and vertebrate host.

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Figure 1: Steps in the retroviral life cycle.
Figure 2: Retroviral structures.
Figure 3: Different effects of retroviral regulatory sequences on viral and host RNA expression.
Figure 4: Different obstructions in the life cycle of retroviruses.

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Acknowledgements

I thank numerous colleagues in the retrovirology community and at the National Institute for Medical Research, London, UK, for many helpful discussions, and I apologize to those whose publications could not be cited here on account of space restrictions. Work in my laboratory is supported by the UK Medical Research Council (file reference U117512710).

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Glossary

Tumorigenic

Capable of forming tumours. Some but not all retroviruses are capable of changing cell growth properties, resulting in cancer. The kinds of tumours seen include carcinomas, sarcomas and leukaemias.

Provirus

The DNA form of a retrovirus integrated into the genomes of retrovirus-infected cells or organisms. Coding sequences are flanked by long terminal repeats.

siRNA screens

(Small interfering RNA screens). Widely used 'knockout' studies of gene function that use siRNAs, which are double-stranded RNA molecules of 20–25 nucleotides in length that are capable of interfering with the expression of RNA.

Somatic cells

Differentiated cells of the body that lack potential to contribute to the germ line.

Solo LTRs

(Solo long terminal repeats). Lone LTRs in the genome. Homologous recombination between the two LTRs of a provirus results in excision of most of the provirus, leaving behind a solitary LTR in the genome at the site of the previous provirus.

Retrotransposons

Genetic elements that can increase in copy numbers by a mechanism involving reverse transcription of an RNA intermediate followed by integration into the genome.

Long interspersed nuclear elements

(LINEs). Long retrotransposons that encode reverse transcriptases but show genetic organizations and modes of amplification that are different from those of retroviruses; in particular, they lack long terminal repeats.

Short interspersed nuclear elements

(SINEs). Short retrotransposons with no coding sequences. They can be reverse transcribed by LINE-encoded reverse transcriptases.

Polyadenylation

mRNAs are characterized by a stretch of adenine residues at their 3′ termini. Addition of these poly(A) tails, polyadenylation, is an important step in mRNA maturation and is signalled by specific nucleotide sequences.

Splice acceptor

A sequence element that is important for RNA splicing. RNA splicing is a vital step in RNA maturation in which coding exons are joined by intron removal. It is signalled by specific splice donor and splice acceptor sequences.

Epigenetic mechanisms

Means by which gene expression can be modulated without altering the primary nucleotide sequences of the genes. Examples include cytosine methylation and histone deacetylation.

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Stoye, J. Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat Rev Microbiol 10, 395–406 (2012). https://doi.org/10.1038/nrmicro2783

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