Feline Leukaemia Virus: Generation of Pathogenic and Oncogenic Variants

Neil, James C.; Fulton, Ruth; Rigby, Mark A.; Stewart, Monica

doi:10.1007/978-3-642-76524-7_4

Cited by 78 publications

(106 citation statements)

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“…The sequence differences in FeLV-945 SU included point mutations restricted largely to domains that play essential roles in receptor recognition and entry, i.e., VRA, VRB and PRR (Battini et al, 1992;Boomer et al, 1997;Tailor and Kabat, 1997;Sugai et al, 2001). These sequences differences were considered remarkable because FeLV SU is strongly conserved (~97%) among natural FeLV-A isolates (Donahue et al, 1988;Neil et al, 1991;Overbaugh and Bangham, 2001). Experiments were performed to test the possibility that the mutational changes in FeLV-945 SU may alter receptor utilization, increase growth kinetics, or change disease spectrum relative to a prototype FeLV-A isolate.…”

Section: The Felv-945 Ltr Activates a Distinctive Set Of Oncogenes Inmentioning

confidence: 99%

“…Our research objective over many years has been to examine the selective pressures operative in natural FeLV infection that lead to the predominance of viral variants, many of which have significant consequences for infection and disease progression. Natural isolates of FeLV most commonly exhibit sequence variation within the viral long terminal repeat (LTR) or the surface glycoprotein (SU) gene (Neil et al, 1991;Overbaugh and Bangham, 2001). The LTR of FeLV, like that of other retroviruses, is a modular structure in which the U3 region contains the transcriptional promoter and enhancer elements required to direct gene expression.…”

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confidence: 99%

“…It has been shown that subtle mutational changes accumulate in FeLV SU during infection in vivo, and may alter biological properties of the virus such as receptor utilization or affinity, replication kinetics or pathogenic potential (Neil et al, 1991;Brojatsch et al, 1992;Kristal et al, 1993;Rohn et al, 1998;Gwynn et al, 2000;Lauring et al, 2001;Overbaugh and Bangham, 2001). As is typical of gammaretroviruses, the FeLV SU protein comprises an aminoterminal receptor-binding domain (RBD) followed by a proline-rich region (PRR) that mediates conformational changes required for entry.…”

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confidence: 99%

“…FeLV-A is a weakly pathogenic, ecotropic virus thought to represent the predominant agent spread horizontally cat-to-cat in nature. The known isolates of FeLV-A share ~97% amino acid sequence identity in SU, particularly remarkable since they were isolated over more than a decade from distant geographic locations across the world (Donahue et al, 1988;Neil et al, 1991;Overbaugh and Bangham, 2001). FeLV-B, -C and -T subgroups are thought to arise from FeLV-A de novo through point mutation, insertion and/or recombination with endogenous FeLV-related sequences during virus replication in the infected animal.…”

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confidence: 99%

“…FeLV-B, -C and -T subgroups are thought to arise from FeLV-A de novo through point mutation, insertion and/or recombination with endogenous FeLV-related sequences during virus replication in the infected animal. While FeLV-A infection is typically associated with the induction of thymic lymphoma of T-cell origin (Neil et al, 1991;Rezanka et al, 1992), the FeLV-B, -C and -T subgroups are specifically associated with lymphoma, anemia or immunodeficiency disease, respectively (Donahue et al, 1991;Neil et al, 1991;Rohn et al, 1998).…”

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confidence: 99%

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Advances in understanding molecular determinants in FeLV pathology

Lévy

2008

Veterinary Immunology and Immunopathology

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Feline leukemia virus (FeLV) occurs in nature not as a single genomic species but as a family of closely related viruses. The disease outcome of natural FeLV infection is variable and likely reflects genetic variation both in the virus and the naturally outbreeding host population. A series of studies have been undertaken with the objectives of examining natural FeLV genetic variation, the selective pressures operative in FeLV infection that lead to predominance of natural variants, and the consequences for infection and disease progression. Genetic variation among FeLV isolates was examined in a cohort of naturally infected cats with thymic lymphoma of T-cell origin, non-T-cell multicentric lymphoma, myeloproliferative disorder or anemia. The predominant isolate in the cohort, designated FeLV-945, was identified exclusively in disorders of non-T-cell origin. The FeLV-945 LTR was shown to contain a unique 21-bp repeat element, triplicated in tandem downstream of enhancer. The 21-bp triplication was shown to act as a transcriptional enhancer and to confer a replicative advantage through the assembly of a distinctive transcription factor complex. Oncogene utilization during tumor induction by FeLV-945 was studied using a recombinant Moloney murine leukemia virus containing the FeLV-945 LTR. This approach identified novel loci of common proviral integration in tumors, including the regulatory subunit of PI-3Kgamma. Mutational changes identified in FeLV-945 SU were shown not to alter receptor usage as measured by host range and superinfection interference, but to significantly increase the efficiency of receptor binding. To determine whether the unique sequence elements of FeLV-945 influence the course of infection and disease in vivo, recombinant viruses were constructed in which the FeLV-945 LTR alone, or the FeLV-945 SU gene and LTR were substituted into the prototype isolate FeLV-A/61E. Longitudinal studies of infected animals showed that substitution of the FeLV-945 LTR into FeLV-A/61E resulted in a significantly more rapid disease onset, but did not alter the tumorigenic spectrum. In contrast, substitution of both the FeLV-945 LTR and SU gene changed the disease outcome entirely. Together, these observations indicate that the distinctive LTR and SU gene of FeLV-945 mediate a rapid pathogenesis with distinctive clinical features and oncogenic mechanisms.

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Section: The Felv-945 Ltr Activates a Distinctive Set Of Oncogenes Inmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Advances in understanding molecular determinants in FeLV pathology

Lévy

2008

Veterinary Immunology and Immunopathology

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Feline Leukaemia Virus

Jarrett

Neil

2012

Encyclopedia of Life Sciences

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Feline leukaemia virus (FeLV) is a gammaretrovirus that causes a variety of fatal diseases including leukaemia and lymphoma in its host, the domestic cat, and occasionally in large cat species. Many cats become persistently infected and develop disease after an incubation period of several years, during which virus can be transmitted to other cats. Disease is often associated with the generation of FeLV variants with increased pathogenic potential that can arise by mutation of envelope sequences, duplication of transcriptional enhancer elements or recombination with host proto‐oncogene sequences. FeLV can also produce variants by recombination with endogenous proviruses related to FeLV that are found in the domestic cat and its close relatives. The prevalence of FeLV infection has been reduced in many cat populations by isolation of infected carriers and more recently by vaccines that augment the natural ability of most cats to control infection. Key Concepts: The outcome of infection by FeLV depends on the infectious dose, age and immunocompetence of the host. Many cats achieve lifelong control, if not elimination of infection. Cats that become persistently viraemic are at risk of a variety of FeLV‐related diseases after a latent period of up to several years. The common infectious form, FeLV‐A can acquire altered entry receptor specificity by envelope gene mutation (to FeLV‐C) or recombination with endogenous FeLV‐related proviruses (to FeLV‐B). FeLV envelope variants may induce fatal diseases of rapid onset including nonregenerative anaemia (FeLV‐C) or wasting and immunodeficiency (FeLV‐T). The oncogenic potential of FeLV can evolve by duplication of transcriptional enhancer control elements in the long‐terminal repeat or by transduction of host proto‐oncogene sequences. Although the immune parameters of vaccine protection remain unclear, FeLV demonstrates the feasibility of effective immunisation against the gamma retroviruses. Commercial FeLV vaccines in recent or current use include inactivated FeLV, infected cell extracts, recombinant envelope protein and live recombinant poxvirus vaccines.

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Feline Leukaemia Virus Infection

Jarrett¹,

Hosie²

2004

Feline Medicine and Therapeutics

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Feline Leukaemia Virus: Generation of Pathogenic and Oncogenic Variants

Cited by 78 publications

References 105 publications

Advances in understanding molecular determinants in FeLV pathology

Advances in understanding molecular determinants in FeLV pathology

Feline Leukaemia Virus

Feline Leukaemia Virus Infection

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