Origins of the Endogenous and Infectious Laboratory Mouse Gammaretroviruses

Mouse leukemia viruses (MLVs) are found in the common inbred strains of laboratory mice and in the house mouse subspecies of Mus musculus. Receptor usage and envelope (env) sequence variation define three MLV host range subgroups in laboratory mice: ecotropic, polytropic, and xenotropic MLVs (E-, P-, and X-MLVs, respectively). These exogenous MLVs derive from endogenous retroviruses (ERVs) that were acquired by the wild mouse progenitors of laboratory mice about 1 million years ago. We analyzed the genomes of seven MLVs isolated from Eurasian and American wild mice and three previously sequenced MLVs to describe their relationships and identify their possible ERV progenitors. The phylogenetic tree based on the receptor-determining regions of env produced expected host range clusters, but these clusters are not maintained in trees generated from other virus regions. Colinear alignments of the viral genomes identified segmental homologies to ERVs of different host range subgroups. Six MLVs show close relationships to a small xenotropic ERV subgroup largely confined to the inbred mouse Y chromosome. env variations define three E-MLV subtypes, one of which carries duplications of various sizes, sequences, and locations in the proline-rich region of env. Outside the env region, all E-MLVs are related to different nonecotropic MLVs. These results document the diversity in gammaretroviruses isolated from globally distributed Mus subspecies, provide insight into their origins and relationships, and indicate that recombination has had an important role in the evolution of these mutagenic and pathogenic agents. IMPORTANCELaboratory mice carry mouse leukemia viruses (MLVs) of three host range groups which were acquired from their wild mouse progenitors. We sequenced the complete genomes of seven infectious MLVs isolated from geographically separated Eurasian and American wild mice and compared them with endogenous germ line retroviruses (ERVs) acquired early in house mouse evolution. We did this because the laboratory mouse viruses derive directly from specific ERVs or arise by recombination between different ERVs. The six distinctively different wild mouse viruses appear to be recombinants, often involving different host range subgroups, and most are related to a distinctive, largely Y-chromosome-linked MLV ERV subtype. MLVs with ecotropic host ranges show the greatest variability with extensive inter-and intrasubtype envelope differences and with homologies to other host range subgroups outside the envelope. The sequence diversity among these wild mouse isolates helps define their relationships and origins and emphasizes the importance of recombination in their evolution. Mouse leukemia viruses (MLVs) with ecotropic, xenotropic, and polytropic host ranges (E-MLVs, X-MLVs, and P-MLVs, respectively) are readily isolated from the classical strains of the laboratory mouse (reviewed in reference 1). E-MLVs can infect murine cells but not cells of heterologous species; these viruses use the amino acid transporter, CAT-...

Section: Resultsmentioning

confidence: 99%

Sequence Diversity, Intersubgroup Relationships, and Origins of the Mouse Leukemia Gammaretroviruses of Laboratory and Wild Mice

Bamunusinghe

Naghashfar

Buckler-White

et al. 2016

“…They are gradually attenuated or inactivated by preinsertional mutations that occur during viral replications and by postinsertional mutations that occur during host genome replication. Nucleotide changes in the long terminal repeats (LTR) diminish the transcription activity of the virus, and amino acid changes in the viral genes disrupt or modify the functions of their coding proteins (7)(8)(9)(10)(11)(12).…”

Section: Domestic Cats Are Colonized With Various Exogenous Retrovirumentioning

confidence: 99%

Ancestral Mutations Acquired in Refrex-1, a Restriction Factor against Feline Retroviruses, during its Cooption and Domestication

Ito

Baba

Kawasaki

et al. 2016

Endogenous retroviruses (ERVs) are remnants of ancestral retroviral infections of germ cells. Retroviral endogenization is an adaptation process for the host genome, and ERVs are gradually attenuated or inactivated by mutation. However, some ERVs that have been "domesticated" by their hosts eventually gain physiological functions, such as placentation or viral resistance. We previously reported the discovery of Refrex-1, a soluble antiretroviral factor in domestic cats that specifically inhibits infection by feline leukemia virus subgroup D (FeLV-D), a chimeric virus of FeLV, and a feline ERV, ERV-DC. Refrex-1 is a truncated envelope protein (Env) encoded by both ERV-DC7 and ERV-DC16 proviral loci. Here, we reconstituted ancestral and functional Env from ERV-DC7 and ERV-DC16 envelope genes (env) by inducing reverse mutations. Unexpectedly, ERV-DC7 and ERV-DC16 full-length Env (ERV-DC7 fl and ERV-DC16 fl), reconstructed by removing stop codons, did not produce infectious viral particles. ERV-DC7 fl and ERV-DC16 fl were highly expressed in cells but were not cleaved into surface subunits (SU) and transmembrane subunits, nor were they incorporated into virions. G407R/N427I-A429T and Y431D substitutions within the SU Cterminal domain of ERV-DC7 fl and ERV-DC16 fl, respectively, caused these dysfunctions. The residues glycine 407 and tyrosine 431 are relatively conserved among infectious gammaretroviruses, and their substitution causes the same dysfunctions as the tested retroviruses. Our results reveal that specific mutations within the SU C-terminal domain suppressed Env cleavage and incorporation into virions and indicate that these mutations contributed to the domestication of Refrex-1 through multistep events that occurred in the postintegration period. IMPORTANCEDomestic cats are colonized with various exogenous retroviruses (exRVs), such as feline leukemia virus (FeLV), and their genomes contain numerous ERVs, some of which are replication-competent proviruses. The feline hosts, exRVs, and ERVs have complicated genetic interactions and provide an interesting field model for triangular relationships: recombination between FeLV and ERV-DC, which is a feline ERV, generated FeLV-D, a chimeric virus, and FeLV-D is restricted by Refrex-1, an antiretroviral factor corresponding to truncated Env of ERV-DC7 and ERV-DC16. Here, we reconstructed ancestral, functional Env from ERV-DC7 and ERV-DC16 env by inducing reverse mutations to elucidate how Refrex-1 was generated from its ancestor. Our results reveal that they were repeatedly inactivated by mutations preventing Env maturation. Our results provide insights into how ERVs were "domesticated" by their hosts and identify the mutations that mediated these evolutions. Notably, experiments that restore inactivated ERVs might uncover previously unrecognized features or properties of retroviruses. E ndogenous retroviruses (ERVs) are present in all vertebrate genomes and are thought to be the remnants of ancestral germ line infections by exogenous retroviruses (exRVs)...

“…The ERVs encoding the Refrex-1 proteins also appear to be fixed in the domestic cat population (13), but their presence in other felid species has not been reported. Fv4 was first characterized in Gstrain lab mice but was later found to be present in wild populations of Asian mice (11). Fv4 (Akvr1) was also characterized in a wild California mouse population descended from feral Asian mice; the California mice demonstrated resistance to naturally circulating ecotropic MLV but not amphotropic MLV (10).…”

Section: Recent and Repeated Emergence Of Antiviral Endogenous Env Genesmentioning

confidence: 99%

“…Resistance to mink cell focus-forming virus (Rmcf) is derived from an endogenous polytropic MLV and defends against polytropic mink cell focus-forming MLV (11). Rmcf2, derived from an endogenous xenotropic MLV, also confers resistance against polytropic MLV (11). Not to be outperformed by mice, domestic cats also carry a set of truncated env genes (ERV-DC7 and ERV-DC16) which encode the Refrex-1 restriction factors.…”

Section: Recent and Repeated Emergence Of Antiviral Endogenous Env Genesmentioning

confidence: 99%

“…At least 3 distinct antiviral env genes have been documented in mice. Friend virus susceptibility protein 4 (encoded by the Fv4 gene), also known as AKR virus restriction 1 (Akvr1 [10]), is derived from an endogenous ecotropic murine leukemia virus (MLV) and restricts ecotropic MLV (11). Resistance to mink cell focus-forming virus (Rmcf) is derived from an endogenous polytropic MLV and defends against polytropic mink cell focus-forming MLV (11).…”

Section: Recent and Repeated Emergence Of Antiviral Endogenous Env Genesmentioning

confidence: 99%

See 1 more Smart Citation

Fighting Fire with Fire: Endogenous Retrovirus Envelopes as Restriction Factors

Malfavon-Borja

Feschotte

2015

A considerable portion of vertebrate genomes are made up of endogenous retroviruses (ERVs). While aberrant or uncontrolled ERV expression has been perceived as a potential cause of disease, there is mounting evidence that some ERVs have become integral components of normal host development and physiology. Here, we revisit the longstanding concept that some of the gene products encoded by ERVs and other endogenous viral elements may offer to the host protection against viral infection. Notably, proteins produced from envelope (env) genes have been shown to act as restriction factors against related exogenous retroviruses in chickens, sheep, mice, and cats. Based on the proposed mode of restriction and the domain architecture of known antiretroviral env, we argue that many more env gene-derived restriction factors await discovery in vertebrate genomes, including the human genome.