Feline Leukemia Virus (FeLV)
Fred Scott, Former Director, Cornell Feline
James Richards, Director, Feline Health Center
The feline leukemia virus (FeLV) is the causative agent of the most important fatal infectious disease complex of American domestic cats today. It is an RNA (ribonucleic acid) virus belonging to the family Retroviridae. Oncogenic (tumor-causing) retroviruses similar to FeLV have been identified in a number of animal species: cattle, domestic fowl, certain nonhuman primates, and rodents. The oncogenic retroviruses are commonly referred to as RNA tumor viruses, or oncornaviruses (oncogenic RNA viruses).
Other retroviruses, known as lentiviruses, can produce noncancerous diseases in cats, sheep, goats, and horses. The feline lentivirus, known as feline immunodeficiency virus (FIV) (see Feline Immunodeficiency Virus section ), is the cause of an immunodeficiency syndrome similar to that produced in humans by the human immunodeficiency virus HIV, which causes AIDS.
Retroviruses carry with them an enzyme, reverse transcriptase. This enzyme is used to produce a DNA copy of the retroviral RNA, which is then inserted into the genetic material of the infected cell. This alien invader, known as a provirus, then is reproduced whenever the host cell reproduces and can serve as the blueprint for the production of new retrovirus particles. A cell infected with a retrovirus thus is infected for the length of its lifetime, as are all of its daughter cells. Because a version of their genetic material becomes a part of the total genetic information of the cells they infect, retroviruses are among the most intimate parasites known in nature.
THE CAUSE. Individual particles of FeLV consist of two distinct morphologic (structural) components: a dense inner core, or nucleoid, and an outer envelope containing an immunologically important protein known as gp 70. This protein is the principal antigen (substance against which an immune response can be mounted) present on the virus surface. Virus-neutralizing antibody (VNA) directed against gp70 is an essential component of a successful immunologic response to FeLV, and its presence in the blood is an indication of past FeLV exposure. Most cats with high levels of VNA are resistant to subsequent FeLV infection. Most persistently viremic cats (cats, many of which are otherwise healthy, in which FeLV circulates in blood cells for a prolonged period of time, as the result of an ineffective immune response) produce little or no VNA. It should be noted, however, that some cats with high VNA titers (levels) are not protected against FeLV infection, whereas some cats with little or no VNA are immune to infection.
A second major antigen of the FeLV particle is the protein p27, which is a structural component of the inner viral core. This protein can be found in great abundance in infected blood cells and in soluble form in plasma and serum of viremic cats. The primary importance of p27 lies in its role as the major FeLV antigen detected by the two FeLV tests-the IFA (immunofluorescence assay) test and the ELISA (enzyme-linked immunosorbent assay) test-commonly used in veterinary clinical practice today.
Suppression of normal protective immunologic responses is one of the most important consequences of persistent infection with FeLV. The significance of FeLV-induced immunosuppression is especially apparent when considering the array of secondary diseases associated with FeLV. A specific FeLV structural protein, p15(E), which is associated with the viral envelope, has been implicated in the production of some of this immunosuppression. The importance of p15(E) as an immunosuppressive agent is highly questionable, however, and incorporation of this protein in "inactivated" virus vaccines has not resulted in any apparent suppression of immune function in vaccinated cats.
In nature, FeLV infections appear to be restricted to members of the cat family, including domestic breeds and certain small exotic cats-sand cats, European wildcats, jungle cats, and possibly leopards. The prevalence of FeLV infection in domestic cats of the United States is estimated to be 2 to 3 percent, with most of the cases occurring in young adult cats (about 3 years of age).
PATHOGENESIS. After infection of lymphatic tissues surrounding the site of initial virus penetration, a low-grade transient viremia (brief presence of virus in the blood stream) involving small numbers of infected white blood cells occurs within two weeks of exposure. In this way, the virus is transported to other regions of the body, especially systemic lymphatic tissue, intestinal tissue, and bone marrow. These areas contain populations of rapidly dividing cells wherein FeLV replication can be enhanced. Infection of white blood cell and platelet (cells involved in blood clotting) precursors in the bone marrow, plus the subsequent release of infected cells into the circulation, results in a second, more profound viremia (persistent viremia). In those cats that resist widespread infection with FeLV, virus containment takes place in the early lymphatic stage of infection, after a transient viremia has occurred. In those animals destined to become persistently viremic, infection proceeds to extensive involvement of the bone marrow, pharynx, esophagus, stomach, bladder, respiratory tract, and salivary glands.
All persistently viremic FeLV cats excrete infectious FeLV and probably do so for the rest of their lives. Consequently, they serve as a source of infection for healthy, uninfected, susceptible cats with which they come into contact. Cats that develop immunity experience an initial transient viremia lasting from one to two days and for as long as eight weeks, during which time they too may shed infectious FeLV.
Excretion of FeLV occurs primarily in the salivary secretions, although the virus may also be present in respiratory secretions, feces, and urine. The social grooming habits of cats, licking and biting, sneezing, and the urban practice of sharing litter boxes and feeding bowls, probably represent the major modes of spread of FeLV among pet cats. In utero transfer of FeLV across the placenta and excretion of FeLV in colostrum and milk are also known to occur, so that kittens may become infected either through an infected queen or by close contact with other persistently viremic cats. Prolonged close contact (days to weeks) between cats is probably required for effective transmission of FeLV. Virus can also be spread in blood transfusions from viremic cats.
Very young kittens are the most susceptible to FeLV infection following exposure to the virus. Susceptibility to persistent infection decreases rapidly for older kittens and adult cats. Ultimately, about 60 to 70 percent of adult cats that are exposed to FeLV develop immunity and do not become persistently viremic. In some of these cats, however, the virus may remain sequestered for a variable period of time somewhere in the body as a latent infection. The primary hazard associated with latent infection is the possibility that some latently infected queens may transmit FeLV to their kittens through the milk. Latently infected cats do not transmit FeLV by any other route and are much less likely to develop any of the FeLV-associated diseases, although recent studies indicate that some of these cats may develop immunosuppression. The duration of these latent infections is variable, but most cats appear to become truly FeLV free within two or three years after their infection first occurred. Unfortunately, there is no readily available test to identify latently infected cats. Like a number of other similar viruses, FeLV is extremely labile (chemically unstable) once outside the cat and is rapidly inactivated by alcohol and most common household detergents and disinfectants. The infectivity of the virus in saliva left to dry at room temperature has been shown to decline to inconsequential levels within three or four hours.
CLINICAL SIGNS. Persistently viremic FeLV cats are subject to development of a number of diseases that are either directly or indirectly caused by FeLV. Those directly caused by FeLV include lymphosarcoma, a number of myeloproliferative disorders, several types of anemia, the panleukopenia-like and thymic atrophy syndromes (shrinking or wasting away of the thymus), at least one form of kidney disease, and certain reproductive disorders. Diseases indirectly caused by FeLV include a myriad of conditions that develop secondary to FeLV-induced immunosuppression. The prognosis for survival of persistently viremic cats is poor; approximately 50 percent die within six months of infection, while over 80 percent die within three years of infection.
Lymphosarcoma (LSA). Lymphosarcomas are among the most common malignancies of American domestic cats. These tumors consist primarily of solid masses of proliferating lymphocytes (a type of white blood cell) and comprise the majority of the malignancies caused by FeLV. Several forms of LSA have been identified; their classification is based most commonly on their anatomic distribution.
The alimentary form of LSA is characterized by tumor-cell infiltration of the digestive tract and other organs (e.g., lymph nodes, liver, kidneys, and spleen). Common presenting signs include inappetence, weight loss, vomiting, diarrhea, bloody stool, and jaundice. Occlusion (blockage) of the bowel by the proliferating tumor results in constipation or obstipation (difficult, painful bowel movements or complete blockage). The alimentary form of LSA is associated with persistent FeLV infection in only about 50 percent of affected cats.
The thymic (of thymus gland in the chest) or mediastinal (of area between the lungs) form is characterized by the presence of a large tumor mass infiltrating within the chest, with spread to regional lymphatic tissue and sometimes to other structures. Clinical signs are a reflection of pressure effects of the mass and the severe fluid accumulation within the chest that frequently accompanies the tumor. Physical examination may reveal difficult respiration, muffled heart sounds, coughing, difficult swallowing, and incompressibility of the chest wall. Thymic LSA is usually seen in young cats (less than three years of age).
The multicentric form of LSA is characterized by primary involvement of many lymphatic tissues of the body, with additional involvement of other structures, such as the liver, bone marrow, kidneys, spleen, and lungs. Presenting signs are variable, depending on the precise anatomic distribution of the tumor, but they often include painless swelling of peripheral lymph nodes and enlargement of the spleen, liver, and, often, of the intestinal lymph nodes.
Atypical forms of LSA also occur and consist usually of solitary tumor masses involving primary sites of origin in nonintestinal, nonlymphatic structures. These include the kidneys, central nervous system, eyes, and, rarely, the skin or bones. Presenting signs vary according to the location of the tumor.
Lymphocytic leukemia is characterized by the presence of circulating cancerous lymphocytes in the blood and bone marrow. Lymphocytic leukemia may precede the development of LSA, or it may be associated secondarily with LSA. Presenting signs usually consist of nonspecific inappetence, depression, and weight loss. More specific signs that may be seen include anemia, fever, jaundice, and enlargement of the liver, spleen, and lymph nodes.
Myeloproliferative disorders. These primary bonemarrow disorders are characterized by abnormal proliferation of one or more hematopoietic (blood cell-forming) cell lines. Presenting signs often include inappetence, depression, weight loss, relentlessly progressive anemia, fever, jaundice, peripheral lymph node enlargement, and enlargement of the liver and spleen secondary to massive infiltration by abnormally proliferating cells.
Nonregenerative anemia. NRA is probably one of the most common manifestations of FeLV infection. This type of anemia, also known as hypoplastic, aplastic, or depression anemia, is characterized by a severe reduction in the number of red cell precursors in the bone marrow, resulting in failure to produce an adequate number of circulating red cells. Sometimes there may be a pancytopenia, in which red cell, white cell, and platelet cell precursors are all affected. NRA may occur alone, or it may be associated with LSA or myeloproliferative disease, or it may precede the development of an FeLV-induced malignancy. Because many severely ill cats with NRA are euthanatized, the true incidence of subsequent malignancy cannot be accurately determined. Unfortunately, clinical signs are usually not detected until the anemia is well advanced. Common signs include inappetence, depression, weight loss, respiratory difficulty, pallor of the mucous membranes, and increased heart rate. Coinfection with Haemobartonella felis, the parasite causing feline infectious anemia, may contribute to the severity of the anemia.
Panleukopenia-like syndrome. As the name implies, this is a syndrome resembling panleukopenia (feline "distemper") that has been observed in some FeLV-infected cats known to be properly immunized against panleukopenia. Presenting signs often include inappetence, depression, dehydration, weight loss, fever, vomiting, diarrhea (which may be bloody), and a profound reduction in the number of circulating white blood cells. Anemia may also be present. Although affected cats may respond transiently to supportive therapy, the disease is progressive and always fatal.
Kittens born to persistently viremic queens often develop a syndrome of lethargy, inappetence, wasting, stunted growth, atrophy of the thymus gland and other lymphoid structures, and enhanced susceptibility to infection with other disease-causing agents ("fading kittens"). The degree of thymic atrophy can be severe, amounting to virtual disappearance of the organ in some cases. These kittens do not gain weight and often do not nurse vigorously. Many die from secondary bacterial or viral infections within the first few weeks of life. Those that survive are carriers of FeLV and thus are capable of transmitting the virus to other susceptible cats. The syndrome may also precede the development of an FeLV-induced malignancy.
Glomerulonephritis. This type of kidney disease has been described in cats in association with LSA, lymphocytic leukemia, and granulocytic leukemia (cancer of granulocytes, a type of white blood cell). In addition, glomerular disease in the absence of malignancy has been reported in FeLV-infected cats. In one study, the leading cause of death in an FeLV-infected household of 134 cats over a five-and-a-halfyear period was glomerulonephritis.
Queens infected with FeLV may experience one or more reproductive disorders, including fetal resorption (biochemical disintegration of the fetus), abortion, infertility, endometritis (inflammation of the uterine lining), and the birth of fading kittens. Abortions characteristically occur late in gestation and are more frequent in high-density, multiple-cat households. it has been reported that nearly 75 percent of FeLV-infected queens will experience abortions or fetal resorptions.
The array of secondary disease entities associated with FeLV-induced immunosuppression represents one of the most important manifestations of FeLV infection. it has been estimated that nearly 50 percent of all cats with severe bacterial infections and infectious anemia and 75 percent of cats with toxoplasmosis (a protozoan disease) have an underlying FeLV infection. In addition, FeLV-induced immunosuppression has also been associated with chronic mouth and gum infections, poorly healing or recurrent abscesses, deep skin infections, chronic respiratory infections, acute colitis (inflammation of the large bowel), severe ear infections, and feline infectious peritonitis. (It should be kept in mind that all of these problems may also be seen in cats not infected with FeLV.) FeLV induced immunosuppression probably contributes also to the development of FeLV-induced malignancies.
DIAGNOSIS OF FeLV INFECTION. Two types of FeLV blood tests are in common use: the enzyme-linked immunosorbent assay (ELISA, or kit test, which can be performed in the veterinarian's office) and the immunotluorescence assay (IFA, Hardy test, or slide test, which must be sent out to a diagnostic laboratory). Both tests detect the p27 protein of FeLV as it circulates in the bloodstream, either free in the blood (ELISA test) or within infected white blood cells (IFA test).
FeLV is present in the blood during two different stages of the infection. The ELISA test can detect the primary (or transient) viremia stage, before the bone marrow has become infected, when the cat's immune system has an opportunity to ward off the virus. Transiently viremic cats characteristically test ELISA-positive and then revert to negative status within about eight weeks. It is important that a positive FeLV test be repeated in eight to twelve weeks to determine whether the viremia is transient or persistent. The ELISA test can also detect the virus in the persistent viremia stage-after the virus, in a certain percentage of cats, invades the bone marrow and establishes a firm and lifelong foothold. ELISA tests are also available to detect FeLV in secretions-saliva and tears. There is some degree of variability in these latter tests, and some positive animals may be missed. At this time, saliva/tear tests are probably best reserved for screening purposes and for testing cats that are difficult to bleed.
The IFA test detects the circulating virus primarily during the second stage. If the infection progresses to this stage, a "point of no return" is reached. Thus the majority of cats testing positive by the IFA test remain positive for life. These cats are shedding FeLV in the saliva and are infectious to other cats. Occasional discrepancies between the two FeLV tests have been noted. When such a discrepancy arises, it is important to remember that the two tests detect FeLV in two different "compartments" of the blood (blood fluid versus white blood cells).
If a cat is positive by ELISA and negative by IFA at the same time, it may mean that the virus is at the primary viremia stage. However, some healthy cats may remain ELISA positive and IFA negative for a prolonged period of time. These cats are still carrying FeLV but are apparently not shedding it in saliva (and thus will not transmit it to companion cats), and most appear to be resistant to the disease-producing effects of FeLV.
TREATMENT. The therapeutic goals of the veterinarian in treating many of the FeLV-associated diseases are to provide palliative relief from clinical signs and to prolong life. However, therapy should be advocated only if there is the possibility of maintaining a good quality of life for the prospective patient. In addition, ethical questions regarding prolonged treatment of persistently viremic cats shedding an oncogenic (tumor-causing) virus into their environment must also be addressed by both the veterinarian and cat owner.
A variety of chemotherapeutic regimens have been developed for FeLV-induced tumors, and in certain cases these can produce a temporary remission. Cats in remission may continue in a reasonably healthy state for a period of weeks to several months (some longer). However, it must be understood that these are only remissions and, in most cases, not lifelong cures. The drugs that are used are very potent and their effects must be monitored carefully so as not to overdose the patient.
PREVENTION. Elimination of FeLV from an infected household can be achieved by implementation of an FeLV-test-and-removal program using the IFA test. This program has been highly effective in removing FeLV from infected multiple-cat households. In a survey of forty-five households from which 159 FeLV-positive cats were removed, 561 of 564 (99.5 percent) FeLV-negative cats remained negative on subsequent retesting. Multiple-cat households in which the FeLV test-and-removal program has not been implemented have experienced infection rates over forty times greater than those experienced by households in which the program has been successfully introduced.
FeLV-test-and-removal. All cats in the household should be tested by IFA, regardless of age or condition. All cats found positive should be removed and the household premises cleaned with a commercial detergent or disinfectant (a solution containing four ounces of household bleach per gallon of water is often recommended, but soap and water will work as well). All litter boxes and food and water bowls should be replaced. Cats that initially tested negative should be retested several times over a period of eight to twelve months, in the event that they were infected just before the first test, prior to the onset of detectable virernia, or are cycling in their level of detectable viremia. The time period between exposure and viremia is extremely variable, and an infected cat that tested negative initially may be positive when tested again later. During the testing period, no new cats should be allowed to enter the household. if any FeLV-positive cats are found on subsequent testing, then they should be removed and another period of quarantine and testing imposed. All cats in the household should test negative for FeLV on two tests taken at least three months apart for the household to be considered free of infectious FeLV.
All new cats entering an FeLV-negative household should be tested prior to entry. Any positive cats should be excluded from entering the household. ideally, cats testing negative should be quarantined in separate quarters for three months and retested negative one to two times before being allowed to intermix with the established FeLV-negative household population. New cats should ideally be obtained only from other FeLV-negative households or catteries. Routine yearly or twice-yearly testing for FeLV is suggested for cats in catteries because of the variable incubation period of infection. Persistently viremic cats should never be used for breeding purposes, in part because infected queens will transmit the virus to their viable offspring.
If an FeLV-positive cat is removed from a single-cat household, a waiting period (up to thirty days) should be observed before repopulation with one or more FeLV-negative cats. The litter box and feeding dishes should be replaced and the premises thoroughly cleansed.
Certain modifications of the test-and-removal program may be made for households in which both FeLV-negative and FeLV-positive cats are kept. The positive cats in these households should be isolated from contact with all other cats. This will not only prevent the spread of infectious FeLV to susceptible cats, but it will also decrease exposure of potentially immunosuppressed, viremic cats to other infectious agents, to which they may have a heightened susceptibility. No new cats should be introduced at any time, and the FeLV-positive cats should not be allowed to breed. Separate litter boxes and feeding dishes should be maintained for positive and negative cats. Cleanliness and personal hygiene should be observed at all times, and it has been suggested that separate clothing be kept for contact with FeLV-positive cats to minimize mechanical transmission of the virus. As we have seen, however, FeLV is relatively labile in the environment, and although the degree of virus transmission possible under these circumstances is uncertain, it is probably minimal.
Several vaccines are currently available commercially for prevention of FeLV infection; however, vaccination does not confer immunity against persistent FeLV infection in all cats. Vaccination should be considered an additional safeguard rather than a primary means of protection against FeLV infection. The decision to vaccinate is made on an individual basis and should be an important point of discussion with the veterinarian. There are complex pros and cons to vaccinating against FeLV; the advice and experience of the veterinarian are essential in helping owners reach a correct decision.
PUBLIC HEALTH SIGNIFICANCE. The public health significance of FeLV, most importantly the question of oncogenic potential for human beings, is still largely unsettled. Surveys designed to determine the prevalence of circulating FeLV and/or antibody to FeLV in human serum have produced conflicting results over the years. However, most recent surveys have failed to find evidence of FeLV infection of human beings, including many with LSA or other malignancies. Until a more complete understanding of the public health implications of FeLV can be obtained, it is prudent to restrict as much as possible human exposure to persistently viremic cats. Neonates (human infants) and immunosuppressed individuals (those on immunosuppressive drug therapy, or AIDS patients, for example) are of special concern in this regard. It must be emphasized, however, that as of this writing there is no conclusive evidence that any human illness (including cancer) has ever been caused by FeLV.
Excerpted from The Cornell Book of Cats
Available from The Cornell Feline Health Center