Advances in understanding molecular determinants in FeLV pathology

Abstract

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.

Induction and characterization of a replication competent cervid endogenous gammaretrovirus (CrERV) from mule deer cells

“…There are hundreds of endogenous CrERVs in each deer genome; moreover, the deer cells used in the coculture were different from those we analyzed previously. We cannot exclude that recombination events between several endogenous CrERVs were involved in the generation of CrERV-IND, similar scenario was described for several other ERVs (Anai et al, 2012;Levy, 2008;Shimode et al, 2015;Young et al, 2012). Interestingly, although we analyzed only a few CrERV genomes, there seems to be a trend towards higher degree of purifying selection in gag and pro/pol than in env.…”

“…ERV genomes can recombine among different endogenous loci or with related exogenous retroviruses. This can lead to the generation of fully infectious virus from two defective ERV genomes, or to the altered properties, for example altered tropism, of the exogenous partner involved in the recombination (Anai et al, 2012;Levy, 2008;Paprotka et al, 2011;Shimode et al, 2015;Young et al, 2012). In addition, through recombination with cellular genes, ERVs can form acutely transforming retroviruses (Kozak, 2015).…”

“…The research on these viruses has lead to important insights into the process of genome invasion by an ERV and of the changes that accompany endogenization (Anai et al, 2012;Arnaud et al, 2007a;Lavillette and Kabat, 2004;Li et al, 2012;Oliveira et al, 2007;Tarlinton et al, 2006). In koalas, sheep and cats and mice, exogenous counterparts of the respective ERVs are circulating in natural populations and are associated with disease (Armezzani et al, 2014;Kozak, 2015;Levy, 2008;Xu et al, 2015). Replication-competent variants of PERV have also been reported (Preuss et al, 2006).…”

Mutation Patterns in Human Menin

“…At least two explanations are proposed to explain why some amino acids are mutated more frequently than the others, namely, the "hotspot" sites sensitive to endogenous and exogenous mutagens [22,23], and the disruption of protein functions dependent upon the mutation position in a protein [24,25]. However, the mutation patterns based on them are difficult to model, which loses the meaning of generalization.…”

The frequency of occurrence and nature of recombinant feline leukemia viruses in the induction of multicentric lymphoma by infection of the domestic cat with FeLV-945

“…Such variation has led to four naturally occurring FeLV subgroups, designated A, B, C, and T, that are distinguished genetically by sequence differences in the surface glycoprotein gene (SU) and functionally by interaction with distinct host cell receptors for entry. The weakly pathogenic FeLV subtype A (FeLV-A) is thought to represent the predominant agent spread horizontally cat-to-cat in nature, from which FeLV-B, -C and -T arise de novo in the infected animal by envelope ( env ) gene recombination, mutation or insertion events (Levy, 2008; Overbaugh and Bangham, 2001). While FeLV-A is associated with prolonged asymptomatic infection in the cat that may lead to malignant disease, typically a T-cell lymphoma of the thymus (Neil et al, 1991; Rezanka, Rojko, and Neil, 1992), the FeLV-B, -C and -T subgroups facilitate and/or redirect disease outcome to lymphoma, anemia or immunodeficiency disease, respectively (Levy, 2008; Overbaugh and Bangham, 2001).…”