Endogenousenv elements: Partners in generation of pathogenic feline leukemia viruses

Abstract

Feline leukemia viruses (FeLVs), which are replication-competent oncoretroviruses of the domestic cat species, are contagiously transmitted in natural environments. They are capable of inducing either acute antiproliferative disease or, after prolonged latency, lymphoid malignancies in this animal population. Current knowledge of the recombinational events between infectious FeLV and noninfectious endogenously inherited FeLV-like elements is reviewed, and the potential role of the derived recombinant viruses in pathogenesis is discussed. Major observations made are as follows: (1) Up to three fourths of the exogenous FeLV envelope glycoprotein (SU), beginning from the N-terminal end, can be replaced by sequences from an endogenous FeLV to produce biologically active chimeric FeLVs. The in vitro replication efficiency or cell tropism of the recombinants appears to be influenced by the amount of SU sequences replaced by the endogenous partner, as well as by the locus of origin of the endogenous sequences. (2) Generation of FeLV recombinants in tissue culture cells corresponds closely to the findings from natural tumors. There is direct evidence, based on molecular genetic analysis, for the prevalence of recombinant proviruses in naturally arising FeLV-induced lymphomas. (3) Certain recombinants harboring an altered primary neutralizing epitope in the middle of SU corresponding to the endogenous FeLV sequence can evade immunity developed against common FeLV infection. In several other recombinants, the epitope sequence is found to be frequently mutated during the process of recombination. (4) FeLV variants with altered epitope, although they may not be efficient in replication in vivo, apparently are capable of causing focal infection in target organs. Evidence is also presented that when coinfected with an exogenous FeLV, the epitope sequence in the variants is reverted to the exogenous type, providing an explanation why this sequence is found to be conserved in all natural isolates of FeLV. (5) A prototype chimeric polyprotein containing most of the SU from the endogenous source is abnormally processed and becomes trapped in the endoplasmic reticulum. A functional consequence of such trapping is interference with specific FeLV infection. (6) Some recombinants, while only poorly replicating in the host, may have the ability to infect target erythroid progenitor cells for the induction of strong cytopathic effect. (7) Some other recombinants appear to potentiate lymphomagenesis by exogenous FeLV and others to acquire properties to infect CNS endothelial cells, an event that could potentially be related to FeLV-induced neuropathogenicity. (8) Of multiple recombinant viruses, a specific recombinant species was found to occur in each of the three cats examined in which lymphoma was experimentally induced, and it was exclusively seen in one of these cats. This recombinant FeLV may potentially be a candidate for strong leukemogenic function. In addition to commonly encountered virus envelope changes, another prominent vi...

Phylogenetic and Structural Diversity in the Feline Leukemia Virus Env Gene

“…FeLV-B env was present in 74 of the 167 (44.3%) samples of genomic DNA from FeLV antigen-positive cats in which the env gene had been detected via PCR. Our results regarding the incidence of FeLV-B infection were similar to results previously reported [2], [58], [59]. Our PCR method did not detect FeLV-B env fragments in any of the remaining samples from FeLV antigen-positive cats.…”

“…Retroviral recombination, such as transduction of cellular oncogenes and circulating recombinant forms (CRF), has been reported to involve ‘copy-choice’ or ‘template switching’ via formation of heteroduplexes of the viral RNA genome during reverse transcription [65], [66]. The endogenous FeLV env gene is expressed in normal cat lymphoid organs and FeLV-negative lymphomas [59], [67]. Therefore, exogenous FeLV infections involving these organs may expedite FeLV recombination.…”

Classification and characterization of human endogenous retroviruses; mosaic forms are common

“…Thus, HERVs show signs of the same recombination phenomena between replication competent retroviruses and ERVs as have been observed in mice [ 82 ] and cats [ 83 – 86 ]. These must have occurred in the distant past.…”

The surface glycoprotein of a natural feline leukemia virus subgroup A variant, FeLV-945, as a determinant of disease outcome

“…As measured by Fisher Exact Test, the incidence of FeLV-B at levels high enough to be detected by Southern blot was significantly greater in thymic lymphoma than in multicentric lymphoma (p = 0.015) (Ahmad and Levy, 2010). These results confirmed previous demonstrations of the frequent association of FeLV-B recombinants with thymic lymphoma (Jarrett, 1980, 1992; Roy-Burman, 1995; Sheets et al, 1993; Tsatsanis et al, 1994), but demonstrate occurrence of FeLV-B in multicentric lymphoma at low frequency and low levels.…”

“…FeLV-B can be identified in 30% – 50% of natural infections, always in conjunction with FeLV-A, but is overrepresented in the diseased tissues of animals with lymphoma as compared to asymptomatic, FeLV-infected cats. FeLV-B has been identified in the majority of thymic lymphomas in particular (Coelho et al, 2008; Jarrett, 1980, 1992; Neil et al, 1991; Roy-Burman, 1995; Sheets et al, 1993; Tsatsanis et al, 1994). Having identified FeLV-945 SU as a determinant of non-T-cell disease in infected cats, the question arose as to whether FeLV-945 SU acts together with recombinant FeLV-B in pathogenesis.…”