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Delayed cytopathicity of a feline leukemia virus variant is due to four mutations in the transmembrane protein gene.

ABSTRACT: Two molecularly cloned, replication-defective variants of feline leukemia virus, called 61B and 61C, have both been shown to cause fatal immunodeficiency in cats when coinfected with a replication-competent, minimally pathogenic helper virus, but 61B exhibits a longer latency period between infection and disease (J. Overbaugh, E. A. Hoover, J. I. Mullins, D. P. W. Burns, L. Rudensey, S. L. Quackenbush, V. Stallard, and P. R. Donahue, Virology 188:558-569, 1992). Infection of the 3201 feline T-cell line with 61B plus helper virus also results in longer time from infection to cytopathic effect compared with 61C plus helper virus, providing an in vitro system with which to study the mechanism for this difference. We report that the primary determinant of cytopathicity of 61B maps to gp70, the extracellular envelope glycoprotein. The long latency of 61B, on the other hand, maps to the extracellular portion of the envelope transmembrane protein, in which there are only four predicted amino acid differences between 61B and 61C. These differences render 61B replication defective, and two of the predicted amino acid changes lie in a region that is highly conserved among many retroviruses. The eventual onset of 61B cytopathicity in cell culture was associated with the outgrowth of an apparent recombinant virus that encodes the pathogenic gp70 of 61B and replaces the transmembrane protein of 61B with that of the helper virus. Thus, during in vitro infection, a cytopathic virus evolved from a replication-defective virus and a nonpathogenic virus, suggesting that recombination between multiple variants in natural infection may influence progression of feline leukemia virus-associated immunodeficiency disease.

SUBMITTER: Thomas E

PROVIDER: S-EPMC237989 | biostudies-other | 1993 Oct

REPOSITORIES: biostudies-other

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Delayed cytopathicity of a feline leukemia virus variant is due to four mutations in the transmembrane protein gene.

Thomas E E Overbaugh J J

Journal of virology 19931001 10

Two molecularly cloned, replication-defective variants of feline leukemia virus, called 61B and 61C, have both been shown to cause fatal immunodeficiency in cats when coinfected with a replication-competent, minimally pathogenic helper virus, but 61B exhibits a longer latency period between infection and disease (J. Overbaugh, E. A. Hoover, J. I. Mullins, D. P. W. Burns, L. Rudensey, S. L. Quackenbush, V. Stallard, and P. R. Donahue, Virology 188:558-569, 1992). Infection of the 3201 feline T-ce ...[more]

PMID: 8396654

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Project description:Feline leukemia virus (FeLV) is horizontally transmitted among cats and causes a variety of hematopoietic disorders. Five subgroups of FeLV, A to D and T, each with distinct receptor usages, have been described. Recently, we identified a new FeLV Env (TG35-2) gene from a pseudotyped virus that does not belong to any known subgroup. FeLV-A is the primary virus from which other subgroups have emerged via mutation or recombination of the subgroup A env gene. Retrovirus entry into cells is mediated by the interaction of envelope protein (Env) with specific cell surface receptors. Here, phenotypic screening of a human/hamster radiation hybrid panel identified SLC19A1, a feline reduced folate carrier (RFC) and potential receptor for TG35-2-phenotypic virus. RFC is a multipass transmembrane protein. Feline and human RFC cDNAs conferred susceptibility to TG35-2-pseudotyped virus when introduced into nonpermissive cells but did not render these cells permissive to other FeLV subgroups or feline endogenous retrovirus. Moreover, human cells with genomic deletion of RFC were nonpermissive for TG35-2-pseudotyped virus infection, but the introduction of feline and human cDNAs rendered them permissive. Mutation analysis of FeLV Env demonstrated that amino acid substitutions within variable region A altered the specificity of the Env-receptor interaction. We isolated and reconstructed the full-length infectious TG35-2-phenotypic provirus from a naturally FeLV-infected cat, from which the FeLV Env (TG35-2) gene was previously isolated, and compared the replication of the virus in hematopoietic cell lines with that of FeLV-A 61E by measuring the viral RNA copy numbers. These results provide a tool for further investigation of FeLV infectious disease.IMPORTANCE Feline leukemia virus (FeLV) is a member of the genus Gammaretrovirus, which causes malignant diseases in cats. The most prevalent FeLV among cats is FeLV subgroup A (FeLV-A), and specific binding of FeLV-A Env to its viral receptor, thiamine transporter feTHTR1, is the first step of infection. In infected cats, novel variants of FeLV with altered receptor specificity for viral entry have emerged by mutation or recombination of the env gene. A novel FeLV variant arose from a subtle mutation of FeLV-A Env, which altered the specific interaction of the virus with its receptor. RFC, a folate transporter, is a potential receptor for the novel FeLV variant. The perturbation of specific retrovirus-receptor interactions under selective pressure by the host results in the emergence of novel viruses.

Project description:Studies of feline leukemia virus (FeLV) have illustrated the importance of the genotype of the infecting virus in determining disease outcome. In FeLV infections, as in other retroviral infections, it is less clear how virus variants that evolve from the transmitted virus affect pathogenesis. We previously reported an analysis of the genotypic changes that occur in the viral envelope gene (env) in cats infected with a prototype transmissible FeLV clone, 61E (J. Rohn, M. Linenberger, E. Hoover, and J. Overbaugh, J. Virol. 68:2458-2467, 1994). In one cat, each variant (81T) had evolved, in addition to scattered amino acid changes, a four-amino-acid insertion with respect to 61E. This insertion was located at the same site in the extracellular envelope glycoprotein where the immunodeficiency-inducing molecular clone 61C possesses a six-amino-acid insertion critical for its pathogenic phenotype, although the sequences of the insertions were distinct. To determine whether acquisition of the four-amino-acid insertion was associated with a change in the replication or cytopathic properties of the virus, we constructed chimeras encoding 81T env genes in a 61E background. One representative chimeric virus, EET(TE)-109, was highly cytopathic despite the fact that it replicated with delayed kinetics in the feline T-cell line 3201 compared to the parental 61E virus. The phenotype of this virus was also novel compared to other FeLVs, including both the parental virus 61E and the immunodeficiency-inducing variant 61C, because infection of T cells was associated with syncytium formation. Moreover, in single-cycle infection assays, the 81T-109 envelope demonstrated receptor usage properties distinct from those of both 61E and 61C envelope. Thus, these studies demonstrate the evolution of a novel T-cell cytopathic and syncytium-inducing FeLV in the host. The 81T virus will be valuable for dissecting the mechanism of T-cell killing by cytopathic variants in the FeLV model.

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Delayed cytopathicity of a feline leukemia virus variant is due to four mutations in the transmembrane protein gene.

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Delayed cytopathicity of a feline leukemia virus variant is due to four mutations in the transmembrane protein gene.

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