Feline Leukemia Virus (FeLV): A Constant Threat to Our Cat Companion
Maigan Espinili Maruquin
It was believed that the Feline Leukemia Virus (FeLV) is the one responsible in most disease- related deaths in cats. It was Jarrett, et al., 1964 who first identified FeLV as a causative agent of the viral infection of cats more than 40 years ago by electron microscopy (EM). However, the prevalence of FeLV as the disease- causing agent in cats has declined, and so is the death rate caused by the infection. Despite FeLV being a threat in the life expectancy of the cats, owners still choose to provide the proper treatment for their cats and proper care, leaving FeLV-infected cats live for many years with good quality of life (Hartmann 2012).
Structure and Replication
Fig. 01. The structure of FeLV containing two identical strands of RNA, reverse transcriptase, integrase, and protease inside the capsid protein (p27), surrounded by a matrix and all enclosed by the envelope containing gp70 glycoprotein and the transmembrane protein p15E (https://veteriankey.com/feline-leukemia-virus-infection/).
FeLV is approximately 8.4kb in length. It belongs to the genus Gammaretrovirus. Retroviruses have three- layered structure and RNA (two copies of single-stranded RNA), which makes the genetic material, is in the innermost- layer; together with the essential enzymes for its viral activities (including integrase, reverse transcriptase and protease) and nucleocapsid protein. The capsid protein in the middle layer surrounds the genome. And, the outer layer is the envelope from which glycoprotein ‘spikes’ project (Westman, Malik et al. 2019).
The envelope spikes are responsible for the attachment of the virus to the target cell surface receptors which also represents an essential target for the host immune response. During replication, RNA is being reverse transcribed into DNA through the enzyme reverse transcriptase. This interrupts the normal cellular flow of genetic information, the Central Dogma, making this enzyme the target of many anti- viral drugs. The synthesized DNA from the RNA integrates into the genome of the target cell as a provirus, which is a required component for the viral replication, assisted by a second viral enzyme, the ‘integrase’. This provirus remains in the genome of the cell and upon cellular division, the provirus is expressed, leading to the production of progeny virions and virus shedding (Lavialle, Cornelis et al. 2013, Willett and Hosie 2013, Chiu, Hoover et al. 2018, Westman, Malik et al. 2019).
On a previous research, there were three important observations following FeLV Infection: (a) some cats can eliminate the virus before it progresses local replication after enough time and appropriate immune response; (b) some cats become persistently viraemic; (c) some cats are viraemic before immunity responds to eliminate the transient viraemia after 2–16 weeks, but not before a latent infection is established as DNA provirus (Westman, Malik et al. 2019).
Antigen-negative, provirus positive cats are considered FeLV carriers. This was after cats infected with FeLV were found to remain provirus-positive. Following reactivation, they can act as a source of infection. As FeLV provirus is integrated into the cat’s genome, it is unlikely to be fully cleared over time and possibly in a transcriptionally silent (latent) state. Antigen-negative, provirus-positive cats do not shed the virus, but reactivation is possible (Torres, O’Halloran et al. 2008, Hartmann 2012).
FeLV undergoes different stages of infection. On abortive infection, virus starts initial replication but an effective immune response may terminate the viral replication and avoid becoming viraemic by eliminating the FeLV-infected cells (Hofmann-Lehmann, Cattori et al. 2008, Torres, O’Halloran et al. 2008, Hartmann 2012)(Torres, Mathiason et al. 2005).
In regressive infection, effective immune response contains the replication of the virus prior to or shortly after bone marrow infection (Hartmann 2012) despite retaining a low level of FeLV-infected cells in circulation and tissues. In some cases, infected cells are also eliminated and undergo abortive infection (Torres, Mathiason et al. 2005). Mainly, virus shed in saliva however, in this infection, viremia is terminated within weeks or months. However, virus undergoes latency since it is not completely eliminated, harboring viral DNA in circulation, and integrating the proviral DNA in the bone marrow stem cells and lymphoid tissues. The proviral DNA is not translated into proteins making it non- infectious. The cats are considered ‘protected’ from the development of viraemia and thus disease, but they remain infected. Under latent infection, viral replication is delayed. Therefore, these regressively infected cats are not infectious to others but the infection could be reactivated when antibody production decreases (Torres, Mathiason et al. 2005, Hofmann-Lehmann, Cattori et al. 2008, Torres, O’Halloran et al. 2008, Hartmann 2012).
For the progressive infection, the infection is not contained early, resulting to extensive viral replication. They remain positive after 16 weeks of infection. This makes the cats persistently viraemic and infectious to other cats. They develop FeLV- related diseases, and most of them die within a few years.
On the other hand, it is focal or atypical infection if there’s a persistent atypical local viral replication (e.g., in mammary glands, bladder, eyes). This leads to an irregular production of antigen causing alternate results of positive and negative (Hartmann 2012).
Clinical Signs/ Pathogenesis
There are two possible results following the first 4 weeks FeLV exposure of the host: (a) failure to contain the viral replication; and (b) successful immune response of the host against the virus (Rojko, Hoover et al. 1982, Hoover and Mullins 1991, Torres, Mathiason et al. 2005).
After a long asymptomatic phase, cats can develop clinical signs including tumors, hematopoietic disorders, neurologic disorders, immunodeficiency, immune-mediated diseases, stomatitis, immunosuppression, hematologic disorders, immune-mediated diseases, and other syndromes (including neuropathy, reproductive disorders, fading kitten syndrome). This is determined by a combination of viral and host factors (Hartmann 2012).
Mostly, tumors in cats are associated with FeLV, commonly lymphoma and leukemia, less often other hematopoietic tumors and rarely other malignancies (including neuroblastoma, osteochondroma, and others). FeLV vaccination resulted to a major decrease of FeLV infection in the overall cat population which is also the major reason of the decreased association of FeLV with lymphoma (Hartmann 2012) (Jackson, et al., 1993).
Lymphoma and lymphocytic infiltrations in brain or the spinal cord are neurological signs for the FeLV- infected cats. However, in the absence of the detected tumors, FeLV- induced neurotoxicity is suspected (Hartmann 2012).
Leukemia develops from haemopoietic cells of the bone marrow. It is considered in acute phase by the presence of blast cells at an early stage of maturation, whereas it is chronic by the presence of blast cells at a more advanced stage of maturation (Adam, Villiers et al. 2009, Wong, Hoff et al. 2013, Cristo, Biezus et al. 2019). After infecting lymphoid cells, the virus undergoes the process of insertional mutagenesis, leading to the formation of tumors (Fujino, Ohno et al. 2008)
Related to FeLV infections are hematologic changes including anemia (non-regenerative or regenerative), persistent, transient, or cyclic neutropenia, platelet abnormalities (thrombocytopenia and platelet function abnormalities), aplastic anemia (pancytopenia), and panleukopenia-like syndrome. Moreover, Hartmann, K., 2012 also stated that the bone marrow suppression caused by the FeLV as its major pathogenic mechanism, requires active viral replication. On the other hand, in some FeLV antigen-negative cats, regressive FeLV infection without viremia may also be responsible for bone marrow suppression (Hartmann 2012).
Furthermore, immunosuppression is one of the major concerned consequence of the FeLV infection. This may lead to secondary infectious diseases, which decreases the tumor surveillance mechanisms, increasing the risk of tumor development. Although FeLV may cause immunosuppression, not all concurrent bacterial, viral, protozoal, and fungal infections are direct consequence (Hartmann 2012).
Knowing the difference between the regressive and progressive infection leads to proper diagnosis and clinical management for FeLV- infected cats (Westman, Norris et al. 2019). Following the identification of the FeLV are researches that greatly impacted on the gradual decline of the cases related to FeLV infection. These veterinary interventions include rigorous testing with vaccination, and isolation or euthanasia of infected animals. Biosecurity protocols were implemented and has effectively given protection to cats (Hofmann-Lehmann, Cattori et al. 2008, Lutz, Addie et al. 2009, Mostl, Egberink et al. 2013, Willett and Hosie 2013, Westman, Norris et al. 2019).
Various methods could be used in diagnosing FeLV (Lutz, Addie et al. 2009). The enzyme-linked immunosorbent assay (ELISA) and immunochromatography tests are far the most common diagnostic methods used. Another method used in the detection of cell-associated viral core protein p27 in blood smears is through Immunofluorescent antibody test (IFA). Both IFA and virus isolation are recorded with high concordance rates, IFA testing may not be able to detect the shedding of virus during the early infection stages, making it not a good option for screening tests (Victor, Bicalho et al. 2020).
The use of the qPCR documented that cats that are believed to be immune to FeLV infection turns into parvovirus- positive after virus challenge (Hofmann-Lehmann, Huder et al. 2001, Tandon, Cattori et al. 2005, Torres, Mathiason et al. 2005, Hofmann-Lehmann, Tandon et al. 2006, Hofmann-Lehmann, Cattori et al. 2008). This proviral DNA were integrated to the host cell genome (Cattori, Tandon et al. 2006). Assays of quantitative real-time TaqMan PCR and RT-PCR resulted to be highly specific and more sensitive in measuring for FeLV exposure than antigen detection, virus isolation or immunofluoresence assays (Hofmann-Lehmann, Cattori et al. 2008).
Currently, the detection of FeLV antigens are collected from blood, whether whole blood, plasma or serum testing the viral capsid protein p27. This viral protein is most abundant in the plasma of viraemic cats (Willett and Hosie 2013).
On the other hand, a quick diagnosis of FeLV infection is also possible. Bioguard Corporation manufactures diagnostic kit targeting FeLV Ag. This uses samples including cat’s serum, plasma, or whole blood. It is highly sensitive 98.9% and sensitive 100% vs Western Blot Assay. Moreover, immediate isolation of infected cats is necessary upon confirmation of FeLV infection to prevent the spread (Willett and Hosie 2013).
Vaccine and Disease Managements
Vaccines against FeLV have been developed and used in veterinary for years already (Jarrett and Ganiere 1996, Sparkes 1997, Sparkes 2003) while recently, qPCR is being used for the quantification of FeLV proviral and viral loads(Cattori, Tandon et al. 2006). While latent infection is important, FeLV-specific real-time PCR methods so far developed are not capable of differentiating episomal from integrated forms of the provirus (Lassen, Han et al. 2004, Tandon, Cattori et al. 2005, Cattori, Tandon et al. 2006).
There are three developed FeLV vaccines commercially available to include: inactivated vaccine; sub- unit vaccine from gp70 Env expressed in E. coli (Marciani, Kensil et al. 1991); canarypox virus recombinant vaccine (Tartaglia, Jarrett et al. 1993, Poulet, Brunet et al. 2003). In the situation of proviral integration in vaccinated cats, there will be no shed nor transmittance of virus, becoming the vaccinated cat a dead- end host of the FeLV (Willett and Hosie 2013).
Although, it was also reported that reactivation of the FeLV infection is possible, FeLV vaccines still has a great impact despite the failure in preventing minimal viral replication and proviral integration (Hofmann-Lehmann, Cattori et al. 2007).
On the other hand, antiretroviral therapies are also being encouraged which includes the targeting of enzyme itegrase. This enzyme helps in the insertion of the viral cDNA of the host cell for replication (Cattori, Tandon et al. 2006). However, the properties shared between the integrase and other enzymes with interaction to the nucleic acid subtrates is a challenge (Magden, Kaariainen et al. 2005). Nevertheless, the vaccination significantly prolongs life expectancy of cats, thus, the need to improved vaccine against FeLV infection (Hofmann-Lehmann, Cattori et al. 2007).
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