Refrex-1, a Soluble Restriction Factor against Feline Endogenous and Exogenous Retroviruses

Ito, Jumpei; Watanabe, Shinya; Hiratsuka, Takahiro; Kuse, Kyohei; Odahara, Yuka; Ochi, Haruyo; Kawamura, Morio; Nishigaki, Kazuo

doi:10.1128/jvi.01267-13

Cited by 54 publications

(118 citation statements)

References 49 publications

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“…This work, together with another recent study (41), revealed that ERV-DCs have two receptor interference groups; one includes genotypes I and II, and the other includes genotype III. These results were expected given that Refrex-1 inhibits ERV-DC genotype I and FeLV-D but not genotype III (41). Genotype II is the most ancient ERV-DC group, and therefore, genotype III may have been generated from genotype II by switching its receptor usage from its ancestral one.…”

Section: Discussionsupporting

confidence: 60%

“…Notably, ERV-DC10 (the q12-q21 region on chromosome C1) and ERV-DC18 (q14 on chromosome D4), both of which belong to genotype III, are replication competent in cultured cells and can infect a broad range of cells, including human cells. Furthermore, we identified FeLV-D, a novel subgroup of FeLV that has an infection tropism different from that of other FeLVs, and reported that this is a recombinant virus between FeLV and ERV-DC genotype I in the env region (40,41). FeLV can be categorized into several FeLV subgroups based on their viral receptor usage and interference capacities.…”

Section: Domestic Cats Are Colonized With Various Exogenous Retrovirumentioning

confidence: 99%

“…We recently reported the discovery of Refrex-1, which is a feline soluble restriction factor against ERV-DCs and FeLV-D (41). All of the ERV-DCs and FeLV-D fall into two receptor interference groups, and Refrex-1 specifically inhibits the group that includes ERV-DC genotype I and FeLV-D. Refrex-1 is a truncated ERV-DC Env, and it includes a signal peptide and a SU N-terminal domain, which is also called a receptor binding domain, but it lacks a TM because of a premature stop codon present in the middle of the env ORF.…”

Section: Domestic Cats Are Colonized With Various Exogenous Retrovirumentioning

confidence: 99%

“…Sequence diversity of ERV-DC7 env within domestic cats. We previously identified two molecular clones of ERV-DC7, IS10 (40) and Kyoto SPF1 (41), and in this study, we used Kyoto SPF1 for the reconstitution of its ancestral Env. However, we noticed that, surprisingly, ERV-DC7 IS10 did not possess a G407R substitution, which is one of the determinants of ERV-DC7 fl dysfunction.…”

Section: Determination Of the Mutations Responsible For The Dysfunctimentioning

confidence: 99%

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

Ito

Baba

Kawasaki

et al. 2016

J Virol

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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)...

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Section: Discussionsupporting

confidence: 60%

Section: Domestic Cats Are Colonized With Various Exogenous Retrovirumentioning

confidence: 99%

Section: Domestic Cats Are Colonized With Various Exogenous Retrovirumentioning

confidence: 99%

Section: Determination Of the Mutations Responsible For The Dysfunctimentioning

confidence: 99%

See 2 more Smart Citations

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

Ito

Baba

Kawasaki

et al. 2016

J Virol

Self Cite

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“…eline leukemia viruses (FeLVs) are pathogenic retroviruses of domestic cats (1, 2), which are classified into subgroups A (the parent virus), B, C, D, and T based on their interference and in vitro host range properties (3,4,5,6,7,8). Subgroups B and D arose from the recombination of FeLV-A env and the env genes of endogenous FeLV or endogenous retroviruses in the genomes of domestic cats (ERV-DCs) (7, 9, 10).…”

mentioning

confidence: 99%

Novel Feline Leukemia Virus Interference Group Based on the env Gene

Miyake

Watanabe

Hiratsuka

et al. 2016

J Virol

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cFeline leukemia virus (FeLV) subgroups have emerged in infected cats via the mutation or recombination of the env gene of subgroup A FeLV (FeLV-A), the primary virus. We report the isolation and characterization of a novel env gene, TG35-2, and report that the TG35-2 pseudotype can be categorized as a novel FeLV subgroup. The TG35-2 envelope protein displays strong sequence identity to FeLV-A Env, suggesting that selection pressure in cats causes novel FeLV subgroups to emerge. Feline leukemia viruses (FeLVs) are pathogenic retroviruses of domestic cats (1, 2), which are classified into subgroups A (the parent virus), B, C, D, and T based on their interference and in vitro host range properties (3,4,5,6,7,8). Subgroups B and D arose from the recombination of FeLV-A env and the env genes of endogenous FeLV or endogenous retroviruses in the genomes of domestic cats (ERV-DCs) (7, 9, 10). Subgroups C and T possibly arose from mutations in FeLV-A env (11,12). The recombination or mutation of env often alters the interference and host ranges of FeLVs by affecting their receptor usage (5,6,13,14,15,16).FeLV env genes were isolated by PCR from the blood DNA of a 1-year-old castrated male cat, TG35, with a bite injury, stomatitis, loss of appetite, and FeLV infection, although he had been vaccinated with inactivated FeLV (genotype III) (16). Five clones (TG35-1 to -5) were isolated, and we focused on TG35-2, TG35-4, and TG35-5. The env sequences of these clones showed strong similarity ( Fig. 1), and the viruses clustered phylogenetically with those of genotype I/clade I FeLV, found mainly in Japan (16). The encompassing variable region A (VRA) of TG35-2 Env differs at eight amino acids from those of the TG35-4 and TG35-5 Env proteins. The proline-rich regions of TG35-2 and TG35-4, but not TG35-5, contain an inserted sequence of 25 amino acids (Fig. 1) not found in the cat genome database and of unknown origin.To identify the FeLV subgroup to which this viral strain belongs, we used an interference assay (16) and generated ␤-galactosidase (LacZ)-encoding pseudotype viruses expressing TG35-2, TG35-4, or TG35-5 envelope (Env) proteins in GPLac cells (7). Pseudotype viruses TG35-2, -4, and -5 infected uninfected HEK293T cells (Table 1). However, HEK293T cells preinfected with FeLV-A/clone 33 (293T/clone 33 cells) (17) or FeLV-A/Glasgow-1 (293T/Glasgow-1 cells) (9) were infected by pseudotype virus TG35-2, but not by TG35-4 or TG35-5. Neither cell type was infected by FeLV-A/clone 33 or FeLV-A/Glasgow-1. Therefore, only the TG35-4 and TG35-5 viruses interfered with FeLV-A. Neither the TG35-2, TG35-4, nor TG35-5 pseudotype interfered with other subgroups of FeLV, or with retroviruses such as ERV-DC10, a replication-competent feline ERV (7) ( Table 1). Therefore, FeLV TG35-4 and TG35-5 belong to the FeLV-A subgroup. However, TG35-2 could not be categorized.We next constructed a replication-competent virus (33TGE2) containing the TG35-2 env gene and the LTR, gag, and pol genes of When we examined AH927 feline cells, the TG35-2...

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Characterization of the endogenous retrovirus‐derived placenta‐specific soluble protein EnvV‐Fca from domestic cats

Pramono,

Sugimoto,

Kimura

et al. 2024

FEBS Letters

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Endogenous retroviruses (ERVs) are remnants of ancestral viruses in the host genome. The present study identified the expression of a defective retroviral env gene belonging to the ERV group V member Env (EnvV) in Felis catus (EnvV‐Fca). EnV‐Fca was specifically detected in the placental trophoblast syncytiotrophobic layer and expressed as a secreted protein in cultured cells. Genetic analyses indicated that EnvV2 genes are widely present in vertebrates and are under purifying selection among carnivores, suggesting a potential benefit for the host. This study suggests that birds, bats, and rodents carrying EnvV2 may play significant roles as intermediate vectors in spreading or cross‐transmitting viruses among species. Our findings provide valuable insights into the evolution of ERV in vertebrate hosts.

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Refrex-1, a Soluble Restriction Factor against Feline Endogenous and Exogenous Retroviruses

Cited by 54 publications

References 49 publications

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

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

Novel Feline Leukemia Virus Interference Group Based on the env Gene

Characterization of the endogenous retrovirus‐derived placenta‐specific soluble protein EnvV‐Fca from domestic cats

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