Pushing the endogenous envelope

Henzy, Jamie E.; Johnson, Welkin E.

doi:10.1098/rstb.2012.0506

Cited by 55 publications

(77 citation statements)

References 75 publications

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“…These classes can be further subdivided into groups (not families, a term reserved for higher order taxa of viruses) each apparently derived from individual germ line infections (43). However, a number of discrepancies arise when ERVs are analyzed on the basis of their env genes, a finding that illustrates the confounding effects of recombination on phylogenetic analysis (44).…”

Section: Structure and Classificationmentioning

confidence: 99%

Mammalian Endogenous Retroviruses

Mager

Stoye²

2015

Microbiol Spectr

161

103

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Over 40% of mammalian genomes comprise the products of reverse transcription. Among such retrotransposed sequences are those characterized by the presence of long terminal repeats (LTRs), including the endogenous retroviruses (ERVs), which are inherited genetic elements closely resembling the proviruses formed following exogenous retrovirus infection. Sequences derived from ERVs make up at least 8 to 10% of the human and mouse genomes and range from ancient sequences that predate mammalian divergence to elements that are currently still active. In this chapter we describe the discovery, classification and origins of ERVs in mammals and consider cellular mechanisms that have evolved to control their expression. We also discuss the negative effects of ERVs as agents of genetic disease and cancer and review examples of ERV protein domestication to serve host functions, as in placental development. Finally, we address growing evidence that the gene regulatory potential of ERV LTRs has been exploited multiple times during evolution to regulate genes and gene networks. Thus, although recently endogenized retroviral elements are often pathogenic, those that survive the forces of negative selection become neutral components of the host genome or can be harnessed to serve beneficial roles.

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Section: Structure and Classificationmentioning

confidence: 99%

Mammalian Endogenous Retroviruses

Mager

Stoye²

2015

Microbiol Spectr

161

103

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“…Recent work demonstrated that HERV-K ENV imparts broad tropism among mammalian cells (27). Endogenous beta-type envelopes are present in mammals, whereas gamma types are found throughout metazoans (18,28). However, betaretroviral gag-pol regions and gamma-type env genes are present in nonmammalian species (29)(30)(31), suggesting that there may be an ENV-dictated species-specific tropism restriction for beta-type envelopes.…”

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confidence: 99%

Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein

Robinson

Whelan

2016

J Virol

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Endogenous retroviruses (ERVs), the majority of which exist as degraded remnants of ancient viruses, comprise approximately 8% of the human genome. The youngest human ERVs (HERVs) belong to the HERV-K(HML-2) subgroup and were endogenized within the past 1 million years. The viral envelope protein (ENV) facilitates the earliest events of endogenization (cellular attachment and entry), and here, we characterize the requirements for HERV-K ENV to mediate infectious cell entry. Cell-cell fusion assays indicate that a minimum of two events are required for fusion, proteolytic processing by furin-like proteases and exposure to acidic pH. We generated an infectious autonomously replicating recombinant vesicular stomatitis virus (VSV) in which the glycoprotein was replaced by HERV-K ENV. HERV-K ENV imparts an endocytic entry pathway that requires dynamin-mediated membrane scission and endosomal acidification but is distinct from clathrin-dependent or macropinocytic uptake pathways. The lack of impediments to the replication of the VSV core in eukaryotic cells allowed us to broadly survey the HERV-K ENV-dictated tropism. Unlike extant betaretroviral envelopes, which impart a narrow species tropism, we found that HERV-K ENV mediates broad tropism encompassing cells from multiple mammalian and nonmammalian species. We conclude that HERV-K ENV dictates an evolutionarily conserved entry pathway and that the restriction of HERV-K to primate genomes reflects downstream stages of the viral replication cycle. IMPORTANCEApproximately 8% of the human genome is of retroviral origin. While many of those viral genomes have become inactivated, some copies of the most recently endogenized human retrovirus, HERV-K, can encode individual functional proteins. Here, we characterize the envelope protein (ENV) of the virus to define how it mediates infection of cells. We demonstrate that HERV-K ENV undergoes a proteolytic processing step and triggers membrane fusion in response to acidic pH-a strategy common to many viral fusogens. Our data suggest that the infectious entry pathway mediated by this ENV requires endosomal acidification and the GTPase dynamin but does not require clathrin-dependent uptake. In marked contrast to other betaretroviruses, HERV-K ENV imparts broad species tropism in cultured cells. This work provides new insights into the entry pathway of an extinct human virus and provides a powerful tool to further probe the endocytic route by which HERV-K infects cells. E ndogenous retroviruses (ERVs) comprise approximately 8% of the human genome (1). Such ERVs provide a physical record of ancient infections by once exogenous retroviruses; however, the degraded states of most sequences largely obscure their biological properties. Consequently, relatively little is known about the earliest events of endogenization, including how the viruses initially entered the germ line to become vertically transmitted elements. The process of endogenization begins with cellular attachment and viral entry, which is mediated by the envel...

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“…Class II retroviruses, in particular, can be found with any of the three described Env protein types (6). The Betaretrovirus genus, for example, is split between members having a beta-type (noncovalent) Env protein and those having a gamma-type (covalent) Env protein.…”

mentioning

confidence: 99%

“…While SU is the most variable region of the genome, TM is highly conserved and can be aligned across a wide variety of retroviruses (4). The majority of retroviral envelope glycoproteins can be divided into those with Env subunits that are covalently associated (gamma-type) and those with noncovalently associated subunits (beta-type), and the two groups can be readily distinguished by sequence motifs in TM (5,6) (Fig. 1).…”

mentioning

confidence: 99%

A Novel Recombinant Retrovirus in the Genomes of Modern Birds Combines Features of Avian and Mammalian Retroviruses

Henzy

Gifford

Johnson

et al. 2014

J Virol

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Endogenous retroviruses (ERVs) represent ancestral sequences of modern retroviruses or their extinct relatives. The majority of ERVs cluster alongside exogenous retroviruses into two main groups based on phylogenetic analyses of the reverse transcriptase (RT) enzyme. Class I includes gammaretroviruses, and class II includes lentiviruses and alpha-, beta-, and deltaretroviruses. However, analyses of the transmembrane subunit (TM) of the envelope glycoprotein (env) gene result in a different topology for some retroviruses, suggesting recombination events in which heterologous env sequences have been acquired. We previously demonstrated that the TM sequences of five of the six genera of orthoretroviruses can be divided into three types, each of which infects a distinct set of vertebrate classes. Moreover, these classes do not always overlap the host range of the associated RT classes. Thus, recombination resulting in acquisition of a heterologous env gene could in theory facilitate cross-species transmissions across vertebrate classes, for example, from mammals to reptiles. Here we characterized a family of class II avian ERVs, "TgERV-F," that acquired a mammalian gammaretroviral env sequence. Although TgERV-F clusters near a sister clade to alpharetroviruses, its genome also has some features of betaretroviruses. We offer evidence that this unusual recombinant has circulated among several avian orders and may still have infectious members. In addition to documenting the infection of a nongalliform avian species by a mammalian retrovirus, TgERV-F also underscores the importance of env sequences in reconstructing phylogenies and supports a possible role for env swapping in allowing cross-species transmissions across wide taxonomic distances. IMPORTANCERetroviruses can sometimes acquire an envelope gene (env) from a distantly related retrovirus. Since env is a key determinant of host range, such an event affects the host range of the recombinant virus and can lead to the creation of novel retroviral lineages. Retroviruses insert viral DNA into the host DNA during infection, and therefore vertebrate genomes contain a "fossil record" of endogenous retroviral sequences thought to represent past infections of germ cells. We examined endogenous retroviral sequences in avian genomes for evidence of recombination events involving env. Although cross-species transmissions of retroviruses between vertebrate classes (from mammals to birds, for example) are thought to be rare, we here characterized a group of avian retroviruses that acquired an env sequence from a mammalian retrovirus. We offer evidence that this unusual recombinant circulated among songbirds 2 to 4 million years ago and has remained active into the recent past.

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Pushing the endogenous envelope

Cited by 55 publications

References 75 publications

Mammalian Endogenous Retroviruses

Mammalian Endogenous Retroviruses

Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein

A Novel Recombinant Retrovirus in the Genomes of Modern Birds Combines Features of Avian and Mammalian Retroviruses

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