A Friend virus mutant encodes a small glycoprotein that causes erythroleukemia

Hoatlin, Maureen E.; Ferro, Frank; Kozak, Susan L.; Kabat, David

doi:10.1128/jvi.68.6.4053-4056.1994

Cited by 5 publications

(5 citation statements)

References 38 publications

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“…The common occurrence of the identical 585-base (195-amino-acid) deletion in natural SFFVs, including the independently isolated Friend and Rausher SFFVs, has been confusing because expanded deletions in this region do not reduce pathogenesis. Indeed, these deletions substantially enhance pathogenicity in mice homozygous for the Fv-2 r resistance allele (15,28). The surprising result that we report here is that although the BER cells infected with virus from mouse 1129 or 1218 became factor independent, and this correlated with the detection of Env glycoproteins on Western blots, these Env glycoproteins did not include all four of the SFFV characteristic features that were common to previously analyzed gp55s.…”

Section: Discussionmentioning

confidence: 50%

An Array of Novel Murine Spleen Focus-Forming Viruses That Activate the Erythropoietin Receptor

Gómez-Lucı́a¹,

Zhi

Nabavi³

et al. 1998

J Virol

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The Friend spleen focus-forming virus (SFFV) env gene encodes a 409-amino-acid glycoprotein with an apparentM r of 55,000 (gp55) that binds to erythropoietin receptors (EpoR) to stimulate erythroblastosis. We reported previously the in vivo selection during serial passages in mice of several evolutionary intermediates that culminated in the formation of a novel SFFV (M. E. Hoatlin, E. Gomez-Lucia, F. Lilly, J. H. Beckstead, and D. Kabat, J. Virol. 72:3602–3609, 1998). A mouse injected with a retroviral vector in the presence of a nonpathogenic helper virus developed long-latency erythroblastosis, and subsequent viral passages resulted in more pathogenic isolates. The viruses taken from these mice converted an erythropoietin-dependent cell line (BaF3/EpoR) into factor-independent derivatives. Western blot analysis of cell extracts with an antiserum that broadly reacts with murine retroviral envelope glycoproteins suggested that the spleen from the initial mouse with mild erythoblastosis contained an array of viral components that were capable of activating EpoR. DNA sequence analysis of the viral genomes cloned from different factor-independent cell clones revealedenv genes with open reading frames encoding 644, 449, and 187 amino acids. All three env genes contained 3′ regions identical to that of SFFV, including a 6-bp duplication and a single-base insertion that have been shown previously to be critical for pathogenesis. However, the three env gene sequences did not contain any polytropic sequences and were divergent in their 5′ regions, suggesting that they had originated by recombination and partial deletions of endogenously inherited MuLV envsequences. These results suggest that the requirements for EpoR activation by SFFV-related viruses are dependent on sequences at the 3′ end of the env gene and not on the polytropic regions or on the 585-base deletions that are common among the classical strains of SFFV. Moreover, sequence analysis of the different recombinants and deletion mutants revealed that short direct and indirect repeat sequences frequently flanked the deletions that had occurred, suggesting a reverse transcriptase template jumping mechanism for this rapid retroviral diversification.

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Section: Discussionmentioning

confidence: 50%

An Array of Novel Murine Spleen Focus-Forming Viruses That Activate the Erythropoietin Receptor

Gómez-Lucı́a¹,

Zhi

Nabavi³

et al. 1998

J Virol

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“…Whereas mutant BB6 was isolated by repetitive forced passages in homozygous (Fv-2 r ) mice (57), mutant Pvu⌬ formed spontaneously in culture and was isolated on the basis of its small size and ability to activate EpoR (18). Recently, we described its env gene sequence and its ability to cause advanced erythroleukemia in NIH/Swiss (Fv-2 s ) mice (22). Because its deletion overlaps that of mutant BB6, we tested the possibility that Pvu⌬ might also overcome Fv-2 rr resistance.…”

Section: Resultsmentioning

confidence: 99%

“…As shown in Table 2, the resulting cell lines bound 125 I-Epo. (22,23,44). The virus was a passaged virus stock as previously described (22,23).…”

Section: Resultsmentioning

confidence: 99%

“…Our results strongly imply that deletions in the ecotropic domain are responsible for this host range expansion, that mutants with deletions in this domain will predictably have this extended host range, and that the entire ecotropic domain is not essential for pathogenesis. Nevertheless, the mutant SFFVs that overcome Fv-2 rr resistance are less pathogenic than wild-type SFFV in Fv-2 ss mice (19,22,28). Consequently, ecotropic sequences of gp55 have positive or negative effects on pathogenesis depending on the Fv-2 alleles of the host mice.…”

Section: Discussionmentioning

confidence: 99%

“…The overlapping Pvu⌬ and BB6 mutants both encode glycoproteins that form disulfide-bonded oligomers (Fig. 6) that are processed to cell surfaces (22,28). In contrast, many SFFV mutants that are nonpathogenic encode glycoproteins that remain as monomers in the rough endoplasmic reticulum (18,31,32).…”

Section: Discussionmentioning

confidence: 99%

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Deletions in one domain of the Friend virus-encoded membrane glycoprotein overcome host range restrictions for erythroleukemia

Hoatlin

Ferro

Geib

et al. 1995

J Virol

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Although the Friend virus-encoded membrane glycoprotein (gp55) activates erythropoietin receptors (EpoR)to cause erythroblastosis only in certain inbred strains of mice but not in other species, mutant viruses can overcome aspects of mouse resistance. Thus, mice homozygous for the resistance allele of the Fv-2 gene are unaffected by gp55 but are susceptible to mutant glycoproteins that have partial deletions in their ecotropic domains. These and other results have suggested that proteins coded for by polymorphic Fv-2 alleles might directly or indirectly interact with EpoR and that changes in gp55 can overcome this defense. A new viral mutant with an exceptionally large deletion in its ecotropic domain is now also shown to overcome Fv-2 rr resistance. In all cases, the glycoproteins that activate EpoR are processed to cell surfaces as disulfide-bonded dimers. To initiate analysis of nonmurine resistances, we expressed human EpoR and mouse EpoR in the interleukin 3-dependent mouse cell line BaF3 and compared the abilities of Friend virus-encoded glycoproteins to convert these cells to growth factor independence. Human EpoR was activated in these cells by erythropoietin but was resistant to gp55. However, human EpoR was efficiently activated in these cells by the same viral mutants that overcome Fv-2 rr resistance in mice. By construction and analysis of human-mouse EpoR chimeras, we obtained evidence that the cytosolic domain of human EpoR contributes to its resistance to gp55 and that this resistance is mediated by accessory cellular factors. Aspects of host resistance in both murine and nonmurine species are targeted specifically against the ecotropic domain of gp55.

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Independent roles of perforin, granzymes, and Fas in the control of Friend retrovirus infection

et al. 2004

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Cytotoxic T-cells (CTL) play a central role in the recovery of mammalian hosts from retroviral infections. However, the molecular pathways that mediate the antiretroviral activity of CTL are still elusive. Here we explore the protective role of the two main cytolytic pathways of CTL, that is, granule exocytosis and Fas/Fas ligand (FasL), in acute and persistent Friend retrovirus (FV) infection of mice. For this purpose, we have used mutant mouse strains with targeted gene defects in one or more components of the two cytolytic pathways including perforin, granzyme A, granzyme B, Fas, and FasL. The important function of CTL in resistance of C57BL/6 (B6) mice to FV is emphasized by the finding that depletion of CD8+ T-cells prior to virus infection resulted in severe splenomegaly and high viral loads in blood and spleen tissue. Analysis of primary FV infection in knockout mice revealed that acute infection was readily controlled in the absence of functional Fas. Most notably in the presence of Fas/FasL each of the three effector molecules of the exocytosis pathway (i.e., perforin, granzyme A, and granzyme B) was capable on its own to mediate suppression of virus replication and protection from leukemia. However, triple knockout mice lacking perforin and the two granzymes were fully susceptible to FV-induced leukemia. In contrast to acute infection the Fas/FasL pathway was mandatory for effective control of FV replication during persistent infection. These findings suggest novel pathways of CTL-mediated viral defense and contribute towards a better understanding of the molecular mechanisms of CTL activity in retroviral infections.

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A Friend virus mutant encodes a small glycoprotein that causes erythroleukemia

Cited by 5 publications

References 38 publications

An Array of Novel Murine Spleen Focus-Forming Viruses That Activate the Erythropoietin Receptor

An Array of Novel Murine Spleen Focus-Forming Viruses That Activate the Erythropoietin Receptor

Deletions in one domain of the Friend virus-encoded membrane glycoprotein overcome host range restrictions for erythroleukemia

Independent roles of perforin, granzymes, and Fas in the control of Friend retrovirus infection

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