Differential Pathogenicity of Two Feline Leukemia Virus Subgroup A Molecular Clones, pFRA and pF6A

Abstract

F6A, a molecular clone of subgroup A feline leukemia virus (FeLV) is considered to be highly infectious but weakly pathogenic. In recent studies with a closely related subgroup A molecular clone, FRA, we demonstrated high pathogenicity and a strong propensity to undergo recombination with endogenous FeLV (enFeLV), leading to a high frequency of transition from subgroup A to A/B. The present study was undertaken to identify mechanisms of FeLV pathogenesis that might become evident by comparing the two closely related molecular clones. F6A was shown to have an infectivity similar to that of FRA when delivered as a provirus. Virus load and antibody responses were also similar, although F6A-infected cats consistently carried higher virus loads than FRA-infected cats. However, F6A-infected cats were slower to undergo de novo recombination with enFeLV and showed slower progression to disease than FRA-infected cats. Tumors collected from nine pF6A-or pFRAinoculated cats expressed lymphocyte markers for T cells (seven tumors) and B cells (one tumor), and non-T/B cells (one tumor). One cat with an A-to-A/C conversion developed erythrocyte hypoplasia. Genomic mapping of recombinants from pF6A-and pFRA-inoculated cats revealed similar crossover sites, suggesting that the genomic makeup of the recombinants did not contribute to increased progression to neoplastic disease. From these studies, the mechanism most likely to account for the pathologic differences between F6A and FRA is the lower propensity for F6A to undergo de novo recombination with enFeLV in vivo. A lower recombination rate is predicted to slow the transition from subgroup A to A/B and slow the progression to disease.

Unique Long Terminal Repeat and Surface Glycoprotein Gene Sequences of Feline Leukemia Virus as Determinants of Disease Outcome

“…6). These findings are consistent with other studies showing that FeLV-A/61E typically induces thymic lymphoma of T-cell origin after prolonged latency and that tumor cells exhibit the surface phenotype of immature thymocytes (22,28). The findings further demonstrate that substitution of the FeLV-945 LTR into FeLV-A/61E did not alter the tumorigenic spectrum.…”

“…These observations are consistent with previous studies demonstrating FeLV-A/61E to be a weakly pathogenic virus. Experimental infection with FeLV-A/ 61E has been associated with the induction of thymic lymphoma in some animals after prolonged latency for up to 2 years (22,25,28), but other infected animals have remained healthy in studies that continued for as long as 812 days (25). By comparison, animals infected with 61E/945L succumbed to disease between 26 and 57 weeks postinoculation (average, 47 weeks), and those infected with 61E/945SL succumbed to disease between 38 and 72 weeks postinoculation (average, 50 weeks) ( Table 1).…”

“…in a final volume of 0.6 ml of HEPES-buffered saline. The DNA-DOTAP mixture was inoculated intradermally into five sites over the dorsal thorax and thighs as described by others (22).…”

“…Infection with FeLV-A is associated with prolonged, asymptomatic persistent infection that may lead to malignant lymphoma, typically of T-cell origin. For example, experimental infection with FeLV-A/61E in several studies induced thymic lymphoma in some animals after prolonged latency for up to 2 years (22,25,28), but other animals remained healthy for even longer periods of observation (25). FeLV-A is present in all natural infections and gives rise to the other subgroups by envelope (env) gene mutation, insertion, or recombination events de novo (19,20,34).…”

Advances in understanding molecular determinants in FeLV pathology

“…One case was of mixed phenotype including CD4+CD8− (65%), CD4−CD8− (23%), and CD4+CD8+ (12%). These findings are consistent with other studies showing that FeLV-A typically induces thymic lymphoma of T-cell origin, and that tumor cells exhibit the surface phenotype of immature thymocytes (Rohn et al, 1994;Phipps et al, 2000). In contrast, substitution of both the FeLV-945 LTR and SU gene into FeLV-A/61E changed the disease outcome entirely.…”