1. Evolutionary Biology
  2. Microbiology and Infectious Disease
Download icon

Virology: Pushing the envelope

  1. Julia H Wildschutte
  2. John M Coffin  Is a corresponding author
  1. Bowling Green State University, United States
  2. Tufts University, United States
  • Cited 0
  • Views 1,290
  • Annotations
Cite this article as: eLife 2017;6:e26397 doi: 10.7554/eLife.26397


Primates have co-opted a viral gene to produce an envelope protein that prevents infection by the HERV-T virus and likely contributed to the extinction of this virus.

Main text

To counter the constant threat posed by viruses, vertebrate species have evolved a variety of antiviral mechanisms. In return, however, rapid mutation and turnover rates permit viruses to swiftly evolve to evade such mechanisms. This on-going ‘arms race’ between viruses and their hosts has had an important role in shaping the evolution of the species we observe today (tenOever, 2016).

Before a virus infects a cell, envelope proteins displayed on its surface must bind to a receptor located on the surface of the host cell. This receptor-envelope interaction is highly specific and, in turn, determines whether the virus is able to infect a particular cell type or species. In other words, in the absence of the receptor the virus loses its ability to infect the cell.

In a process termed ‘receptor interference’, an envelope protein from a previous viral infection can block cell receptors, preventing infection by a new virus – even an unrelated one – that also binds to that receptor (Figure 1). Remarkably, envelope proteins from such pre-infecting retroviruses can mediate receptor interference even if they have been extinct for millions of years (Boeke and Stoye, 1997). To date, clear examples of such interference have been limited to animal models, including chickens (Payne et al., 1971) and mice (Buller et al., 1987). Now, in eLife, Daniel Blanco-Melo, Robert Gifford and Paul Bieniasz of the Rockefeller University and MRC-University of Glasgow Centre for Virus Research report the first example of such interference in humans (Blanco-Melo et al., 2017).

Co-option of a viral protein for receptor interference.

Left: Cells expressing MCT1 (blue), which is the receptor for a retrovirus called HERV-T, are susceptible to infection from a virus that encodes a surface envelope protein produced by an ancestral form of HERV-T (red). Right: Our genome contains proviruses – copies of the DNA of ancient retroviruses, including HERV-T. Blanco-Melo et al. found that human cells can still produce envelope proteins from their copy of the env gene of the HERV-T provirus. These envelope proteins protect the cells from the resurrected virus by blocking the MCT1 receptors directly, or through the degradation of the resulting receptor-protein complex.

When a retrovirus infects a cell it integrates a DNA copy of its own genome (called a provirus) into the host cell’s genome. Because retroviruses occasionally infect germ line cells, the infection may lead to a provirus that is passed to offspring, and that can sometimes become fixed in the population. We refer to such proviruses as ‘endogenous retroviruses’. Over millions of years, large numbers of endogenous retroviruses have accumulated within vertebrate genomes, including humans, thus providing a ‘fossil record’ of previously circulating retroviruses that covers vast evolutionary scales.

While the majority of endogenous retrovirus lineages are ancient and now contain many mutations, recently formed examples tend to more closely resemble their infectious counterparts. This similarity means that, unless it is harmful, an endogenous retrovirus may retain the ability to produce functional RNA and protein products for long periods of time. Indeed, a few such endogenous retroviruses have been ‘co-opted’ to produce RNA or proteins that benefit the host (Ting et al., 1992; Mi et al., 2000; Stoye and Coffin, 2000).

The HERV-T lineage of endogenous retroviruses is an ancient member of a large group of retroviruses called gammaretroviruses (which includes leukemia viruses that affect cats and rodents). As detailed by Blanco-Melo et al., the HERV-T ancestor appears to have first invaded primate germlines about 43 to 32 million years ago, with the last invasion happening around 8 million years ago. Why did this lineage become extinct? Blanco-Melo et al. used an approach known as ‘paleovirology’ (Emerman and Malik, 2010) to begin to investigate this question.

By assessing the distribution of fossilized endogenous retroviruses among modern primate species, Blanco-Melo et al. identified a single HERV-T locus that appeared in the germline approximately 19 to 7 million years ago, whose envelope (env) gene, remarkably, has retained the ability to be translated. As other genes in the same provirus have been inactivated by mutations, this observation strongly suggests that this env gene has been selectively retained. However, its product cannot perform any ‘normal’ retroviral functions. Why, then, should this gene have been so clearly preserved throughout evolution?

Blanco-Melo et al. reconstructed an ancestral HERV-T sequence from the HERV-T proviruses found in the genomes of modern humans and other primates. A variety of cell lines could be infected by reconstructed viruses that encoded the ancestral env product, but those cells that had the version of env that is found in the host were resistant to infection. Blanco-Melo et al. then demonstrated that the product of the host-maintained env gene is able to block infection by viruses that encode the ancestral env gene by depleting the receptor they identified as MCT-1 (monocarboxylate transporter-1) from the surface of the host cell. The results imply that the HERV-T env gene in the host was co-opted and selected for antiviral protection through receptor interference.

The work from Blanco-Melo et al. highlights how endogenous retroviruses can act as raw material for potential use by the host in the host-virus arms race. This result raises the issue of the extent to which the co-option of endogenous retrovirus coding material for antiviral protection is widespread among vertebrates. Could such maintained env genes have contributed to the apparent extinction of other infectious retroviruses in the lineage leading to contemporary humans? We are eager to see whether the HERV-T picture represents a predictable pattern among endogenous retroviruses in other vertebrate lineages.


    1. Boeke JD
    2. Stoye JP
    Retrotransposons, Endogenous Retroviruses, and the Evolution of Retroelements, Retroviruses, Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press.
    1. Buller RS
    2. Ahmed A
    3. Portis JL
    Identification of two forms of an endogenous murine retroviral env gene linked to the rmcf locus
    Journal of Virology 61:29–34.

Article and author information

Author details

  1. Julia H Wildschutte

    Department of Biological Sciences, Bowling Green State University, Bowling Green, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6096-750X
  2. John M Coffin

    Department of Molecular Biology and Microbiology, Tufts University, Boston, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3856-762X

Publication history

  1. Version of Record published: April 13, 2017 (version 1)


© 2017, Wildschutte et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 1,290
    Page views
  • 175
  • 0

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Evolutionary Biology
    2. Genetics and Genomics
    Julia M Kreiner et al.
    Research Article

    Causal mutations and their frequency in agricultural fields are well-characterized for herbicide resistance. However, we still lack understanding of their evolutionary history: the extent of parallelism in the origins of target-site resistance (TSR), how long these mutations persist, how quickly they spread, and allelic interactions that mediate their selective advantage. We addressed these questions with genomic data from 18 agricultural populations of common waterhemp (Amaranthus tuberculatus), which we show to have undergone a massive expansion over the past century, with a contemporary effective population size (Ne) estimate of 8x107. We found variation at seven characterized TSR loci, two of which had multiple amino acid substitutions, and three of which were common. These three common resistance variants show parallelism in their mutational origins, with gene flow having shaped their distribution across the landscape. Allele age estimates supported a strong role of adaptation from de novo mutations, with a median allele age of 30 suggesting that most resistance alleles arose soon after the onset of herbicide use. However, resistant lineages varied in both their age and evidence for selection over two different timescales, implying considerable heterogeneity in the forces that govern their persistence. The evolutionary history of TSR has also been shaped by both intra- and inter-locus allelic interactions. We report a signal of extended haplotype competition between two common TSR alleles, and extreme linkage with genome-wide alleles with known functions in resistance adaptation. Together, this work reveals a remarkable example of spatial parallel evolution in a metapopulation, with important implications for the management of herbicide resistance.

    1. Developmental Biology
    2. Evolutionary Biology
    Sarah E Westrick et al.
    Feature Article

    The Puerto Rican coquí frog Eleutherodactylus coqui (E. coqui) is both a cultural icon and a species with an unusual natural history that has attracted attention from researchers in a number of different fields within biology. Unlike most frogs, the coquí frog skips the tadpole stage, which makes it of interest to developmental biologists. The frog is best known in Puerto Rico for its notoriously loud mating call, which has allowed researchers to study aspects of social behavior such as vocal communication and courtship, while the ability of coquí to colonize new habitats has been used to explore the biology of invasive species. This article reviews research on the natural history of E. coqui and opportunities for future research.