Feline Leukemia Virus Infection

Chapter 22

Feline Leukemia Virus Infection

Etiology and Epidemiology

FeLV is an enveloped RNA virus that belongs to the genus Gammaretrovirus of the family Retroviridae. FeLV infection remains an important cause of mortality in domestic cats through its ability to cause immune suppression, bone marrow disorders, and hematopoietic neoplasia. FeLV also causes disease in wild felids such as the highly endangered Iberian lynx.2

FeLV infection progresses more rapidly than FIV infection and is more pathogenic, so most cats that develop progressive infections ultimately die of FeLV-related disease. However, in contrast to FIV infection, many cats in the early state of FeLV infection regress to a permanent state of viral latency (“regressive infection”). It is possible that some cats, after exposure to a low dose of FeLV, may eliminate the infection altogether (“abortive infection”), although this appears to be a rare outcome. Regardless, a positive test result for FeLV infection in an apparently healthy cat does not always imply that FeLV-related disease and mortality will occur.

The structure of FeLV is similar to that of FIV, except that the capsid is icosahedral rather than cone shaped (Figure 22-1). There are three main subtypes of FeLV: FeLV-A, FeLV-B, and FeLV-C. Each subtype uses a different receptor to enter cells (Table 22-1). All cats infected with FeLV-B and FeLV-C are co-infected with FeLV-A, and only FeLV-A is transmitted between animals. FeLV-B and FeLV-C are more pathogenic than FeLV-A. FeLV-B arises through recombination of FeLV-A proviral DNA with endogenous FeLV sequences present in host cellular DNA.3 FeLV-C arises from accumulation of mutations or insertions in the env (SU) gene of FeLV-A.4,5 The FeLV subtype influences the clinical expression of disease (see Table 22-1). For example, FeLV-C is associated with nonregenerative anemia. Even within an FeLV subtype, mutations in the SU and the LTR regions of the viral genome affect disease outcome.6,7 An additional subtype, FeLV-T, has been associated with immunodeficiency.

Transmission of FeLV-A primarily results from close contact with salivary secretions, such as through licking, mutual grooming, and shared food and water dishes. Other routes of transmission, such as by biting, blood transfusion, in milk, and possibly by fleas, can also occur.8-10 The virus survives poorly outside the cat and is readily inactivated by disinfectants, soap, and desiccation. The overall prevalence of FeLV infection has declined over the past two decades with more extensive testing and vaccination. Before the institution of widespread testing and vaccination, more than 30% of cats in some catteries were infected.11 In the early 1990s, the overall prevalence of infection was 13% in nearly 28,000 sick cats from North America that were at risk for exposure.12 The prevalence was just 7% in a similar population of approximately 1400 cats in 2006.13 The prevalence of FeLV infection in European cats has also declined markedly.14 Currently, the overall prevalence of infection in mixed populations of cats is 1% to 6%.13,1519 Cats with access to the outdoors; those that have contact with other cats; cats that are male, aggressive, or intact; and cats that are co-infected with FIV are at increased risk of FeLV infection.12,13,15,17 Male cats are less strongly predisposed to FeLV infection than to FIV infection, and in some studies,20 no male predisposition has been recognized. Adult cats are more likely to be infected with FeLV than cats aged less than 6 months,13,17 but the median age of cats infected with FeLV is 3 years,15 which is lower than that for FIV. This reflects a) the greater degree of pathogenicity of FeLV than FIV and its ability to significantly reduce lifespan; and b) the phenomenon of age-related resistance to FeLV, whereby exposure of cats that are less than 4 months of age to the virus is much more likely to lead to progressive infection than exposure of adults.21 When 12- to 16-week old kittens are exposed to a multicat household with endemic FeLV infection, between 60% and 70% of kittens will become infected within a 5-month time period. In contrast, less than 5% of cats aged 6 months or older will become infected over the same time period; over a 2-year period, 40% to 50% of these adult cats will become infected. Infection of adult cats can also still occur with exposure to high doses of the virus or when there is underlying host immune compromise.

Clinical Features

Signs and Their Pathogenesis

The outcome of FeLV infection is extremely variable and depends strongly on the virus strain involved, the challenge dose, the route of inoculation, and factors that influence host immune function such as age, genetics, co-infections, stress, and treatment with immunosuppressive drugs. After oronasal exposure to the virus, the virus replicates in oral lymphoid tissue and then circulates in a few monocytes and lymphocytes within peripheral blood. Some cats develop systemic signs, such as fever, lethargy, and/or lymphadenopathy, during this period. A small number of infected lymphocytes then travel to the bone marrow, where the virus infects rapidly dividing precursor cells and subsequently lymphoid and epithelial cells throughout the body. This infection of the bone marrow is considered a critical step in the pathogenesis of FeLV infection. Once infection of epithelial cells in the salivary glands occurs, the virus is shed in massive quantities in saliva; low quantities of virus can also be shed in urine and feces.

Possible outcomes of infection with FeLV are shown in Figure 22-2. The immune system of some infected cats suppresses viral replication within a few weeks after infection, before significant infection of the marrow occurs. These cats develop a regressive infection, whereby proviral DNA is present in the host cell genome but production and shedding of virus no longer occurs (see Chapter 21). This may occur after the initial period of viremia, or viremia may never be detectable.22 Regressive infection can persist for life and may be reactivated with immunosuppression, such as might occur during pregnancy or following treatment with immunosuppressive drugs.23 Later in life, an unknown percentage of cats with regressive infections may develop FeLV-negative malignancies as a result of integration of viral DNA within host cellular oncogenes. Most cats with regressive infection, however, never develop clinical signs related to FeLV infection. Viral genome sequences may eventually be incompletely replicated, and as a consequence, reactivation of virus replication will become impossible in some cats over time. In abortive infections, no viremia occurs after infection, and virus cannot be detected using any method. Cats with abortive infections have been exposed to low doses of FeLV, and although they fail to develop viremia, they will develop antibodies to the virus.24 Some cats that never test antigen-positive may have focal infections, that is, evidence of proviral DNA in some tissues but not in blood or bone marrow.9 Cats develop progressive infection once involvement of the marrow is established and cellular destruction by the virus exceeds the ability of the host’s immune system to suppress viral replication. Persistent viremia and progressive FeLV-related disease result (Box 22-1).

Opportunistic Infections

Opportunistic infections may develop in FeLV infections as a result of myelo suppression or an acquired cell-mediated immunodeficiency. The immunosuppressive properties of FeLV are not fully understood but have been linked in part to the viral envelope peptide, p15E, which inhibits T and B cell function, inhibits cytotoxic lymphocyte responses, alters monocyte morphology and distribution, and has been associated with impaired cytokine production and responsiveness.25-28 Kittens with progressive FeLV infection have impaired T cell and, to a lesser extent, B cell function.2932 Infected cats may develop lymphopenia, thymic atrophy, and depletion of lymphocytes within lymph node paracortical zones. CD4+ T cell malfunction may contribute to a decreased humoral and cell-mediated immune response in affected cats,33,34 and the response to vaccination may also be impaired. Impaired neutrophil function compounds the effect of neutropenia in some infected cats.3537 Opportunistic infections that result include bacterial infections of the upper and lower urinary tract, hemoplasmosis, upper respiratory tract infections, feline infectious peritonitis, chronic stomatitis, toxoplasmosis, dermatophytosis, and cryptococcosis (Figure 22-3). The prevalence of some of these infections in cats with FeLV infection does not differ significantly from that in cats not infected with FeLV, but clinical signs are more severe and refractory to therapy. Infection with FeLV is an established risk factor for hemoplasma infection. In one study, it was also a risk factor for Bartonella henselae infection, but no evidence of clinical disease was identified in the cats infected with B. henselae.38


FeLV causes neoplasia in cats primarily as a result of insertional mutagenesis, by which the virus activates proto-oncogenes (especially c-myc, but also others such as flit-1) or disrupts tumor suppressor genes.39 The most common types of neoplasia in cats infected with FeLV are lymphoma and leukemia. Cats infected with FeLV are more than 60-fold more likely to develop lymphoma than cats not infected with FeLV; this compares with approximately 5-fold for FIV.40 Lymphoma or leukemia can be detected in nearly one quarter of cats with progressive FeLV infection at necropsy.41 In the 1980s, as many as 70% of cases of feline lymphoma were associated with FeLV infection, but with improved control measures and vaccination, the vast majority of cats (more than 80% to 90%) seen at veterinary clinics with lymphoma now test negative for FeLV antigen.4244 The most common types of lymphoma in cats infected with FeLV are thymic (mediastinal), multicentric, spinal, renal, or ocular lymphoma. FeLV-associated lymphomas are mostly of T-cell origin, but B cell lymphoma can also occur. In contrast, FIV-associated lymphomas tend to be of B-cell origin.42 Approximately 80% of cats with thymic lymphoma test positive for FeLV antigen, whereas fewer than 10% of cats with gastrointestinal lymphoma are FeLV antigen-positive. Large granular lymphoma is rarely associated with FeLV infection.45 Cats with thymic lymphoma typically develop clinical signs of lethargy, tachypnea, and sometimes regurgitation. Most FeLV-positive cats with lymphoma are less than 4 years of age.14

Cats with regressive infection appear to be at greater risk for development of lymphoma than cats that were never exposed to FeLV. FeLV-negative cats that live with cats that test positive for FeLV antigen have a more than 40-fold increased risk of lymphoma compared to that expected without exposure to FeLV.46 Several studies have investigated the prevalence of FeLV proviral DNA in tumor cells from cats that test negative for FeLV antigen. Some studies (including more recent studies that used real-time PCR assays) found no evidence of FeLV proviral DNA in feline lymphomas.14,47,48 In older studies that used conventional PCR, more than 20% of antigen-negative lymphomas tested positive.49,50 Additional studies from a variety of geographic locations that use multiple real-time PCR assays are required to clarify the role that FeLV plays in lymphomas and leukemias that develop in cats that test negative for FeLV antigen.

FeLV is responsible for the majority of myelogenous leukemias, erythroleukemias, megakaryocytic, and lymphoid leukemias in cats, although not all cats with these tumors test positive for FeLV antigen. Most FeLV-associated leukemias are acute. FeLV infection can underlie chronic eosinophilic leukemia,51 chronic myelomonocytic leukemia,52 and chronic lymphocytic leukemia. However, most cats with chronic lymphocytic leukemia are seronegative for FeLV antigen.

FeLV infection can result in the development of multiple fibrosarcomas in young cats. These occur when FeLV-A recombines with cellular oncogenes (such as c-fes, c-fms, or c-fgr) to form feline sarcoma viruses (FeSV). These viruses then develop mutations in these oncogenes that, when reinserted into cellular DNA, cause malignant transformation.53,54 To replicate, FeSV requires the presence of FeLV-A, which supplies proteins such as those encoded by the env gene. Thus, all cats infected with FeSV test positive for FeLV antigen. FeSV-associated fibrosarcomas are characterized by multifocal, locally invasive, often ulcerated cutaneous masses that metastasize readily to the lung and other sites with a poor prognosis. FeLV-FeSV DNA sequences have been detected in some uveal melanomas from cats,55 but other studies have failed to identify an association between FeSV and ocular melanomas or sarcomas in cats.56,57 FeLV infection does not appear to be important in the pathogenesis of solitary fibrosarcomas or injection-site sarcomas in cats.58,59

Other tumor types that are variably associated with FeLV infection are feline olfactory neuroblastomas, cutaneous horns, and osteochondromatosis (multiple cartilaginous exostoses).60 Feline olfactory neuroblastomas are rare and aggressive tumors of the nasal cavity that can lead to signs of rhinosinusitis and neurologic signs. Osteochondromatosis is characterized by benign cartilage-capped exostotic growths that arise from the surface of a bone, which can cause pain, lameness, disfigurement, and paresis due to spinal cord compression. Cutaneous horns occur as a result of benign keratinocyte hyperplasia.

Anemia and Bone Marrow Disorders

Multiple mechanisms can lead to anemia in cats infected with FeLV (Box 22-2). Approximately 90% of FeLV-associated anemias are nonregenerative.61 A variety of bone marrow disorders lead to decreased red blood cell production. FeLV-C infection results in pure red cell aplasia, a severe nonregenerative anemia associated with erythrocyte macrocytosis and depletion of erythroid precursors in the bone marrow. This occurs because FeLV-C binds to and interferes with a heme exporter protein, which results in subsequent heme toxicosis to the developing erythrocyte.62 The presence of macrocytosis in the absence of reticulocytosis should thus raise suspicion for FeLV infection. FeLV infection can also lead to aplastic anemia in some cats, which is a deficiency in all cell lineages (platelets, myeloid, and erythroid) in the bone marrow, and replacement of the bone marrow space by adipose tissue. Anemia and bone marrow dysfunction may also result from myelophthisis secondary to leukemia, myeloid and/or erythroid dysplasia, or myelofibrosis (progressive replacement of the marrow with collagenous connective tissue) (Figure 22-4). Myelodysplasia is characterized by disordered maturation of marrow precursors, which in some cases precedes emergence of leukemia. FeLV infection underlies many myelodysplastic syndromes (MDS) and leukemia in cats.63 However, over the past two decades, 50% of 28 cats with myelodysplasia and 44% of 41 cats with leukemia seen at the University of California, Davis, tested negative for FeLV antigen in peripheral blood, and only 36% of 34 cats with dysmyelopoiesis seen at the University of Minnesota were positive for FeLV antigen.64 Several different classification systems have been used to describe feline MDS.64 The French-American-British (FAB) classification scheme used for humans has been modified for dogs and cats. This divides MDS into 2 groups: 1) MDS with refractory cytopenia (less than 6% myeloblasts in the bone marrow, MDS-RC) and 2) MDS with excessive numbers of myeloblasts (6% to 30% myeloblasts, MDS-EB). The presence of more than 30% blasts indicates leukemia. The most common form of MDS in cats is MDS-EB.64 Regressive FeLV infections have been detected by proviral DNA PCR in some cats with bone marrow disorders,65 but the relationship between the presence of proviral DNA and the pathogenesis of disordered marrow function is unclear.

Anemia in cats with FeLV infection may also result from anemia of inflammatory disease, which can be triggered by opportunistic infections or neoplastic disease. Erythrocyte destruction occurs in some FeLV-infected cats as a result of secondary immune-mediated hemolytic anemia (IMHA) or co-infection with hemoplasmas (see Chapter 41). Hemorrhage as a result of thrombocytopenia or defective platelet function may also contribute to anemia. Mechanisms of thrombocytopenia include immune-mediated thrombocytopenia (ITP) and bone marrow dysfunction. Similarly, neutropenia can result from myeloid hypoplasia, myelofibrosis, myelodysplasia, myelophthisis, or maturation arrest at the myelocyte or metamyelocyte stages. In some cases, peripheral neutropenia accompanied by myeloid hyperplasia reflects underlying immune-mediated neutropenia.

Immune-Mediated Disorders

In addition to immune-mediated cytopenias, other immune-mediated disorders that can occur in association with progressive FeLV infection are glomerulonephritis,66 uveitis,67 and polyarthritis.68 Circulating immune complexes have been detected in infected cats.6971 Because primary immune-mediated disorders are otherwise rare in cats, retrovirus testing is essential in cats that are diagnosed with these conditions before immunosuppressive drug treatment is initiated.

Neurologic Disorders

Neurologic disorders in cats with progressive FeLV infections may occur secondary to central nervous system (CNS) neoplasia, opportunistic infections, or FeLV infection itself. The envelope protein of FeLV may be neurotoxic.72,73 Anisocoria, mydriasis, Horner’s syndrome, and urinary incontinence can occur. FeLV infection may be one of the most frequent causes of urinary incontinence in cats, an otherwise uncommon condition. A myelopathy has been described in FeLV-infected cats that showed various neurologic signs such as disorientation, lethargy, increased vocalization, progressive ataxia, paresis, paralysis, hyperesthesia, urinary incontinence, recurrent constipation, and anisocoria with diminished pupillary light reflexes.74 At necropsy, abundant FeLV antigen was detectable within neurons, endothelial cells, oligodendroglia, and astrocytes within the spinal cord.74

Gastrointestinal Disease

Uncommonly, FeLV causes enteritis that clinically and histologically resembles that caused by feline panleukopenia virus (FPV), except that lymphoid depletion is absent.75 Clinical signs include vomiting, acute or chronic diarrhea that may be hemorrhagic, inappetence, weight loss, and dehydration. FeLV-infected cats with “panleukopenia-like syndrome” have intestinal crypt destruction and pancytopenia that results from myeloid destruction (Figure 22-5).76 Although now very rare, co-infections with FeLV and FPV can also occur, and the 2 viruses may enhance each other’s pathogenicity.77 Co-infections with FeLV and other enteric viruses, such as feline coronavirus, also occur.78 In most cases, diarrhea in cats infected by FeLV results from an etiology other than FeLV alone.

Reproductive Disorders

Transplacental spread of FeLV can lead to fetal resorption, abortion, neonatal death, and fading kitten syndrome.76 Fetal loss may also result from secondary endometritis. Kittens infected in late gestation or after birth develop thymic atrophy, failure to nurse, dehydration, lethargy, and death within the first 2 weeks of life.

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Jul 10, 2016 | Posted by in INTERNAL MEDICINE | Comments Off on Feline Leukemia Virus Infection

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