Feline Leukemia Virus Infection - A Review

Daniel Iyer, DVM, Bruce E. LeRoy, DVM, PhD, Kenneth S. Latimer, DVM, PhD, and Holly Moore, DVM

Class of 2005 (Iyer) and Department of Pathology (LeRoy, Latimer, Moore) College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Feline leukemia virus (FeLV) infection is still an important cause of morbidity in cats despite the development and use of FeLV vaccine. There are many syndromes that are caused by FeLV viral infection. Persistent FeLV infection can cause severe immunosuppression, severe non-regenerative anemia, and a variety of neoplasms. FeLV is distributed worldwide. The domestic cat is the predominant host, but the virus can also infect other felidae.

Etiology and Epidemiology

FeLV is a retrovirus in the family Oncovirinae. Many other diseases are caused by oncoviruses besides cancer including degenerative, proliferative, and immunologic disorders.

There are 3 main subtypes of FeLV that have been designated FeLV-A, FeLV-B, and FeLV-C. These viral subtypes may act alone or in combination to cause diverse disease processes. Specific core proteins and antigens on the virus envelope are used to differentiate these viral subtypes. FeLV-positive cats can be infected with one, two, or all three types:

• FeLV-A occurs in all FeLV-infected cats and causes severe immunosuppression.

• FeLV-B occurs in about 50% of all FeLV-infected cats and causes neoplastic diseases more often than in cats infected only with FeLV-A.

• FeLV-C occurs in about 1% of FeLV-infected cats and causes severe anemia.

Most cats are infected with FeLV-A, but other subtypes also may be found. Coinfection with FeLV-B is found in 50% of infected cats with FeLV-A. FeLV-C coinfection may be observed with FeLV-A and, in some instances, with both A and B subtypes.

FeLV Testing and Viral Transmission

Currently available serologic tests only identify FeLV infection and not the specific subtype of virus(es) that are present. The rate of FeLV infection is directly related to the population density of cats; therefore, multicat households and catteries are most susceptible to viral infection due to the increased density of individuals. About 1-2% of apparently healthy stray cats are actually persistently viremic. These cats probably serve as the primary reservoir of FeLV. These carriers excrete the FeLV in saliva, urine, feces, and tears, with saliva and urine being the primary routes of spread. Cats housed indoors are less likely to contract this infection. Indoor/outdoor cats increase their chances of FeLV infection because biting serves as an efficient mode of viral transmission.

Age resistance is an important factor as young kittens are more susceptible to FeLV infection than are older cats. The virus envelope is very fragile and prolonged contact between cats may be necessary to initiate viral infection. The chances of FeLV infection also are increased by exposure to large numbers of viral particles. FeLV can be transmitted horizontally (by secretions and excretions) or vertically (in utero or transmammary).

Neutralizing Antibodies and Membrane Antigens

The major envelope glycoprotein (gp70) varies with the subtype of FeLV. This protein is used to bind to target cells. In the case of FeLV-A, The virus binds to T lymphocytes. Therefore, antibodies directed toward the gp 70 protein result in neutralization of the virus and provide host immunity to reinfection with the virus.

Feline oncornavirus cell membrane antigen (FOCMA) is present on the cell membranes of malignant cells and is not found on non-transformed cells, even if they are infected with FeLV. It is theorized that antibodies directed at the FOCMA will enable cats to resist the development of leukemia and lymphoma regardless of viremia.

Pathogenesis and Clinicopathologic Findings

FeLV enters the cat’s body though oronasal inoculation and travels to the oropharyngeal lymph tissue for viral replication. At this point, there can be an effective immune or ineffective response. If an effective immune response occurs, FeLV is cleared and there is no further illness. If an ineffective immune response occurs, the virus will be carried to the spleen, lymph nodes, epithelial cells of the intestine and bladder, salivary glands, and bone marrow by infected mononuclear cells in the peripheral blood. At this point, a partially effective or ineffective immune response can occur in the bone marrow. A partially effective immune response will keep the virus latent in the marrow. Viremia will not occur and FeLV will not replicate. However, this situation may lead to the development of hematopoietic malignancy in a cat that is FeLV-negative on serology. In the absence of an immune response, the provirus may cause a persistent viremia (40%). This scenario may result in an apparently healthy cat that is a carrier of viral infection or in an active FeLV infection that is FeLV-positive on serology. Viremia is usually evident 2-4 weeks after FeLV infection. Persistently viremic cats develop fatal diseases after a variable time period. Approximately 50% of persistently viremic cats die within 1 year of FeLV infection, while 83% of apparently healthy cats with FeLV infection die within 3.5 years of viral detection.

Various disorders caused by FeLV are grouped into cytoproliferative and cytosuppressive diseases. Patient outcome is governed by the specific FeLV subtype, the age of the cat at the time of infection, immune status of the cat, and the particular genotype of the cat in question. Persistently viremic cats may manifest single or multiple disease processes including the following:

• Malignant lymphoma (Fig. 1) is often associated with FeLV infection. Most cases of feline lymphoma are caused by this retrovirus, which initiates activation of proto-oncogenes such as myc. There are numerous subtypes of lymphoma, such as thymic lymphoma (usually in young cats <3 years old). Alimentary lymphoma occurs in older cats and may involve the liver, spleen, intestines, and or lymph nodes. Multicentric lymphoma primarily occurs in mature cats and involves many organs. Finally, unclassified lymphoma is represented by an isolated mass in nonlymphoid tissues such as the eye or nervous system. If the immunophenotype is of T-cell origin it may denote a poorer clinical prognosis.
  
  

  Figure 1. Thymic lymphoma in a feline leukemia virus-infected cat. The mass of neoplastic lymphocytes occupies most of the thoracic cavity and displaces the heart and lungs (image courtesy of Noah’s Arkive, the University of Georgia).

• Lymphocytic leukemia may occur independently of or in conjunction with malignant lymphoma.

• Erythroid and myeloid leukemias, including myeloproliferative disorders, are the most common hematologic malignancies in cats.

• Fibrosarcoma is caused by a defective mutant of FeLV designated feline sarcoma virus or FSV. In some cats, FeLV lacks the viral machinery to replicate and may use the FSV retrovirus as a helper virus to initiate viral replication.

• Myelodysplastic syndrome (Fig. 2) is characterized by anemia, leukopenia, and/or thrombocytopenia. This is a frequent outcome, especially from infection with FeLV subtype C, as many anemic cats display a normochromic, normocytic or macrocytic non-regenerative anemia. Macrocytosis may represent skipped mitosis of the RBCs in the presence of a normocellular to hypocellular bone marrow. The concentration of erythropoietin is usually high, but erythropoiesis is suppressed because FeLV kills stem cells and precursors of myeloid and erythroid cells. Although FeLV may not be detected in the bone marrow, it is speculated that 30% of affected cats can attribute their anemia to this retrovirus. Anemias are characterized as regenerative or nonregenerative. The presence of nucleated RBCs alone (unaccompanied by polychromasia) is not a sign of erythroid egeneration in a viremic cat. Regenerative anemia secondary to extravascular hemolysis may occur in viremic cats with other disorders such as Mycoplasma haemofelis (Hemobartonella felis) infection or immune-mediated hemolytic anemia. M. haemofelis infection may occur secondary to FeLV infections, probably as a result of immunosuppression. A transient anemia of chronic disease also may be present. Cats that have pure red cell aplasia lack erythroid precursors within the bone marrow and suggests infection with FeLV subtype C. This viral subtype also has been associated with medullary osteosclerosis wherein viral infection of osteocytes and osteoblasts is associated with defective bone resorption and remodeling, resulting in excessive trabeculae within the marrow cavity.
  
  

  Figure 2. Bone marrow aspirate from a cat with myeloproliferative disease. Mild dyserythropoiesis is present (Wright stain; image courtesy of Noah’s Arkive, the University of Georgia).

  The leukocyte count may be increased, normal, or decreased in FeLV-infected cats. If myelosuppression is present, neutropenia usually is present. The total numbers of CD4+ and CD8+ T lymphocytes also may be decreased. The pathogenesis is uncertain, but is thought to be immune-mediated. Studies on the bone marrow have shown that the total colony forming units - granulocyte-macrophage (CFU-GM) are normal, but arrested at the metamyelocyte stage of development.

  FeLV also infects megakaryocytes and platelets. Thrombocytopenia, if present, is due to viral damage to megakaryocytes or platelets.

• Immunosuppression occurs commonly in FeLV-positive cats. Both T and B lymphocytes are decreased, which predisposes cats to secondary pathogens (often affecting the respiratory system). Neutropenia, if present, also predisposes affected cats to secondary infections. The presence of FeLV /FIV co-infection probably intensifies the immunosuppression and also increases the possibility of lymphoma.

• Enteropathy may develop from viral infection intestinal crypt epithelial cells. This manifestation of FeLV infection may mimic feline panleukopenia.

• Infertility, fetal resorption or abortion (Fig. 3) may occur with FeLV infection. FeLV also is a cause of the "fading kitten" syndrome or neonatal death.
  
  

  Figure 3. Neonatal deaths associated with feline leukemia virus infection (image courtesy of Noah’s Arkive, the University of Georgia).

Laboratory Diagnosis of FeLV Infection

IFA and/or ELISA tests detect FeLV p27 protein. The p27 protein is one of several core proteins that are products of the gag gene. The IFA test may detect p27 in neutrophils and platelets from blood or bone marrow. The ELISA test detects p27 in whole blood, plasma, serum, saliva, or tears. Serum is the fluid of choice for ELISA testing because saliva and tears may not contain sufficient p27 for viral detection. Antibody titers to FeLV envelope antigens and FOCMA antibodies may be used for diagnostic purposes, but are of little clinical relevance.

There are 6 stages of FeLV infection as follows:

• Stages 1-3 - FeLV is disseminated through the lymphoid tissue.

• Stage 4 – FeLV infects the bone marrow.

• Stage 5 - Viral-infected neutrophils and platelets are released from the bone marrow.

• Stage 6 – FeLV appears in epithelial tissues (e.g., salivary glandular epithelium).

ELISA testing can detect p27 at stages 2-6, while IFA detects FeLV at stages 5-6. Therefore, ELISA testing is the first diagnostic assay to detect a positive result. Cats seropositive following ELISA testing should be evaluated by IFA or retested by ELISA 4-6 weeks later. Some seropositive cats can revert to a negative status due to the latency of the virus in the bone marrow. However, the presence of FeLV can still be detected by virus isolation to prove latency. IFA-positive cats correlate with viremia as a positive IFA will always be ELISA positive. Cats that are ELISA positive but IFA negative are called discordant, meaning that there is either a false positive ELISA, false negative IFA, or the virus is yet not in stages 5-6 of infection. The most specific way to identify latent infections is by viral isolation or PCR amplification of FeLV sequences from cells of the bone marrow.

Gross pathological findings depend on the type of disease that occurs. Bone marrow hypercellularity often accompanies leukemias. Lymphoplasmacytic infiltrates of the gingiva, lymph nodes, spleen, kidney, and liver may be seen. Intestinal lesions similar to those seen in feline panleukopenia may occur with enteric FeLV infection. These gross changes include an edematous, turgid small intestine with petechial to ecchymotic hemorrhages on the serosal and/or mucosal surfaces of the jejunum and ileum.

Treatment

Treatment will vary depending on the subset of diseases caused by FeLV infection. Each will be discussed briefly as a separate entity.

Lymphoma- Chemotherapy is used most commonly for cats with lymphoma, whether or not the cat has FeLV infection. Most cats that are not treated for lymphoma will die within 2 months of diagnosis. The staging of lymphoma may be difficult, because most cats with this neoplasm have the alimentary form. There are specific protocols for chemotherapy including the COP protocol which includes administration of cyclophosphamide, vincristine, and prednisone. Doxorubicin can be added as it is specific for lymphoma. Monitoring CBC is essential to detect adverse reactions such as myelosuppression. The median survival time of cats following treatment for lymphoma is approximately 10 to 12 months.

Bone Marrow Suppression/Myelodysplastic Disease- Blood transfusions are often necessary to normalize the PCV. Even though endogenous erythropoietin concentration is high in affected cats with non-regenerative anemia, it has been shown that administration of recombinant erythropoietin can help increase the PCV. Iron supplementation usually is not indicated unless a source of chronic hemorrhage is identified.

FeLV- Unfortunately, human antiviral drugs have little to no effect in clearing this virus. AZT (3’-azido-3’-deoxythymidine) can prevent viremia if given early after inoculation of FeLV. Experimental studies have shown that antiviral drugs may decrease antigenemia, but also may cause myelosuppression. Interferon alpha 2-b, administered along with AZT, may decrease the antigenemia. Unfortunately, these drugs may trigger an antibody response that decreases the efficacy of these antiviral drugs to ~7 weeks duration. Staphylococcal protein A (SPA) also has been used in the therapy of FeLV infection. SPA binds the Fc portion of IgG. Experimental studies have demonstrated decreased viremia and remission of lymphoma in some cats. SPA has also been used to treat hemolytic anemia that has been associated with FeLV infection in some cats.

Prevention of FeLV Infection

Current commercial vaccines include a killed virus with adjuvant, killed virus without adjuvant, or a recombinant gp70 protein vaccine with an adjuvant. Administration of these vaccines does not interfere with FeLV testing via IFA or ELISA. A potential adverse consequence of FeLV vaccination inludes the development of injection site-sarcomas. It has been speculated that the adjuvant predisposes to the development of these highly invasive tumors. Currently, the recommended site for FeLV vaccination is on the left rear thigh or tail. If a sarcoma subsequently develops, the location will be more amenable to surgical excision. Before vaccinating cats against FeLV, owners should consider the risks of FeLV exposure versus the potential of vaccine-related complications.

Living with a FeLV-Positive Cat

Many FeLV-positive cats have a good quality of life. Seropositive cats must be kept indoors so they will not be able to transmit the virus to other cats. If other negative cats are housed together with a FeLV-positive cat, there is a 10-15% chance of acquiring viral infection. Because FeLV infection may be immunosuppressive or cause tumor development, infected cats should be monitored carefully for weakness, lymph node enlargement, labored breathing, or other potential signs of disease.

References

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Acknowledgement

The copyrighted watercolor image "Cat - Lovely on Linen" by Edie Schneider is from her website Designs by Edie and is used with permission.

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