FELINE RETROVIRUS INFECTIONS

Margaret C. Barr, D.V.M., Ph.D.

August 4-8,1994

Sheraton Inn Ithaca, New York FELINE RETROVIRUS INFECTIONS Margaret C. Barr, DVM, PhD Adapted from "Feline Viral Diseases," Textbook of Veterinary Internal Medicine, 4th Edition, 1994

Feline leukemia virus (FeLV) and viruses is a significant cause of morbidity feline immunodeficiency virus (FIV) are and mortality in domestic cats. retroviruses which infect domestic cats Feline im m unodeficiency virus and produce disease, usually following belongs to the lentivirus subfamily. an asymptomatic period of months to Lentiviruses infect a broad range of years. The retrovirus family (the mammals and include human (HIV), Retroviridae) uses reverse transcriptase, simian (SIV), and bovine (BIV) an RNA-dependent DNA polymerase im m unodeficiency viruses, equine {pot), to produce a double-stranded DNA infectious anemia virus (EIAV), maedi- copy of the virion RNA. The name visna virus (M W ) of sheep, and caprine retrovirus is derived from this arthritis-encephalitis virus (CAEV). The "backwards" flow of information from immunodeficiency disease resulting from RNA to DNA. The DNA copy, called a FIV infection in domestic cats is similar provirus, integrates into the host cell to human acquired immune deficiency chromasomes and thus can replicate along syndrome (AIDS) and thus provides a with the infected host cell. useful animal model for HIV infection Retroviruses are divided into three and AIDS. subfamilies, the Spumavirinae, the Clinically, FeLV and FIV infections Oncornavirime, and the Lentivirinae, in cats have very similar presentations, based on shared physical and biochemical although there are some distinct properties. Cats are susceptible to differences. The following discussion infection by viruses from each of these will compare and contrast these 2 subfamilies. Feline syncytium-forming important feline retroviruses. virus (FeSFV), a spumavirus or "foamy virus," has been isolated from both FELINE LEUKEMIA VIRUS healthy and diseased cats. In some cat populations, the infection rate in older Feline leukemia virus is associated cats may be 70% or greater. In general, with both neoplastic and nonneoplastic FeSFV is considered to have little or no (immunosuppressive) diseases in the cat. pathogenicity in domestic cats. Chronic Isolates of FeLV can be divided into 3 progressive polyarthritis has been linked subgroups (A, B, and C) according to in with FeSFV infection but the disease has v itro h o st-ra n g e characteristics. not been reproduced by experimental Subgroup A is found in more than 90% FeSFV infection. of FeLV-positive cats; it is easily Many oncogenic animal retroviruses, transmitted from cat to cat and causes a including FeLV, belong to the oncovirus rapid viremia after infection. Subgroup A subfamily. Three types of feline alone is not highly pathogenic in cats, oncoviruses have been described: (1) the although persistent infection may result in endogenous oncoviruses, such as lymphosarcomas after a long incubation RD114, which are present in all feline time. The FeLV-B and FeLV-C cells but do not replicate or cause disease; subgroups are the result polymorphism in (2) the exogenous, replication-competent the envelope protein gp70 because of in oncovirus, FeLV; and (3) the exogenous, vivo mutation or recombination of replication-defective oncoviruses, subgroup A env sequences with including feline sarcoma virus (FeSV), endogenous retroviral sequences. which rapidly induces fibrosarcomas. Subgroup B occurs as a coinfection with Infection with FeLV and its associated subgroup A FeLV in about 50% of infected cats; it is not readily transmitted and is slow to produce viremia. Most developing detectable titers of these cats with myeloproliferative, antibodies. The intramembrane protein, myelosuppressive, and pl5E, may be associated with the immunosuppressive diseases are pathogenesis of immunosuppression and coinfected with subgroups A and B. One nonregenerative anemia of FeLV isolate, FeLV-FAIDS, induces a rapidly infection. The importance of pl5E in the fatal immunodeficiency disease as the pathogenesis of FeLV infection is still result of a subtle mutation in the env unclear because the use of vaccines gene; this isolate is replication-defective prepared with whole inactivated virus due to another mutation in the gag gene. (thus containing pl5E) does not result in Only about 1% of FeLV-infected cats immunosuppression. carry subgroup C virus, again as a The feline oncornavirus-associated coinfection with subgroup A; usually, cell membrane antigen (FOCMA) is also infection with subgroup C FeLV results of questionable significance. It is in persistent viremia only in neonatal expressed on the cell membrane of FeLV- kittens. Aplastic anemia is a common and FeSV-induced tumor cells and is result of persistent FeLV-C infections. believed to be the product of genetic Feline sarcoma viruses are mutants of recombination between FeLV gp70 and FeLV which arise by in vivo endogenous retroviral sequences. recombination between the genes of Antibodies to FOCMA have some FeLV and host cells. The virus: host protective activity against the fusion proteins that result from the development ofFeLV-related neoplasia, genetic recombination in FeSVs are but they do not prevent FeLV-induced responsible for the relatively rapid and nonneoplastic diseases. The presence of efficient production of fibrosarcomas by FOCMA antibody in nonviremic, FeLV- these viruses. These viruses are exposed cats may indicate a persistent replication-defective and require the latent or low-activity FeLV infection. presence of replication-competent FeLV These cats are more likely to have signs in order to produce the proteins necessary of immunodeficiency than nonviremic, for assembly of virions, infection of new FOCMA-negative cats. cells, and initiation of replication. Epizootiology and Transmission Immunogenic Proteins of FeLV of FeLV The major core or capsid protein, Feline leukemia virus infects domestic p27, is the antigen detected in commercial cats worldwide. In addition, FeLV assays for FeLV. Antibodies to p27 are infection occurs sporadically in some not protective against viremia; in fact, nondomestic cats. An estimated 2 to 3% immune complexes of p27 antigen and of cats in the U.S. are infected with antibody probably are involved in the FeLV. Sick cats are 3 times more likely pathognensis o f immune-mediated than asymptomatic cats to be FeLV- disease in FeLV-infected cats. The positive. The FeLV antigen-positive glycoprotein gp70 is found on the surface male:female ratio is 1.7:1, and the of the viral envelope. This protein is prevalence of FeLV infection is highest involved in binding the membrane for cats between 1 and 6 years of age, receptor on the surface of susceptible with a mean age of about 3 years. cells. The development of virus- Infection of nondomestic cats with neutralizing antibodies to gp70 is believed FeLV occurs sporadically, primarily in to play an essential role in a protective the Felis species. Most cases of positive immune response. These antibodies may tests for FeLV antigen in nondomestic not be necessary or sufficient for cats have not been confirmed by protection in some cats; apparently, some additional testing, and several have been persistently viremic cats have gp70 shown to be false positives due to anti­ neutralizing antibodies, while a few cats mouse or anti-rabbit activity; however, recover from FeLV infection without ever FeLV has been isolated from 1 of 2 antigen-positive free-roaming European macrophages which serve to disseminate wildcats. the virus throughout the cat's body Persistently viremic cats shed large amounts FeLV in their saliva, urine, tears, and milk. Cat to cat transmission Replication of FeLV in the spleen, gut- occurs through exposure to these fluids associated lymphoid tissues, lymph by fighting, grooming, or contact with nodes, intestinal crypt epithelial cells and contaminated food, water, or litter pans. bone marrow precursor cells Bite wounds are an effecient method of spread, but prolonged, close contact between cats also enhances the likelihood Release of infected neutrophils and of FeLV transmission. Infection with platelets from the bone marrow into the FeLV results in fetal and neonatal death circulatory system of kittens from 80% of affected queens; in addition, transplacental and I transmammary transmission of FeLV Infection of multiple epithelial and occurs in at least 20% of surviving kittens glandular tissues, including tissues of the from infected queens. salivary gland and urinary bladder, with subsequent shedding of virus into the Pathogenesis of FeLV Infection saliva and urine. Susceptibility to persistent FeLV viremia is strongly influenced by the age An adequate immune response of cats at exposure. The development of curtails the progression of infection at age-related resistance is attributed to the stage 2 or 3 (by the first 4 to 8 weeks increasing immunocompetence of the cat. following exposure) and forces the virus In adult cats, infection with FeLV may into latency. Cats which become result in persistent viremia or in apparent persistently viremic progress through all recovery (no persistent viremia). Some 5 stages; persistent viremia (stages 4 and cats never have detectable viremia; other 5) frequently develops beginning 4 to 6 recovered cats may be transiently viremic, weeks after infection. Persistently develop an immune response, and revert viremic cats usually succumb to FeLV- to a seronegative status. Whether these related diseases within 2 to 3 years after cats are truly virus-free is a topic of infection. debate; rather, the virus may be latent in Recently, the development of many of these cats. Latent infection may immunosuppression in FeLV-positive not be important because aviremic cats cats has been shown to be associated with rarely progress to viremia or develop neuroendocrine dysfunction. Plasma neoplastic disease; however, the recent levels of luteinizing hormone-releasing correlation of the presence of antibody to factor, follicle stimulating hormone and FOCMA with immunodeficiency disease luteinizing hormone are reduced as early in cats suggests some clinical impact of as 4 to 6 weeks after infection, and latency. testosterone levels decline a few weeks The initial pathogenesis of FeLV later. infection can be divided into 5 partially Tumor induction in FeLV-infected overlapping stages: cats often occurs when the DNA provirus integrates into the cat's chromasomal Viral replication in the tonsils and DNA in critical regions ("oncogenes") for pharyngeal lymph nodes (oronasal a specific cell type. For example, FeLV exposure) or in regional lymph nodes integration near the cellular gene, c-myc, (inoculation or bite wound exposure) or near genes which influence the expression of c-m yc, is frequently responsible for the induction of thymic Infection of small numbers of circulating lymphosarcoma. An additional factor in lymphocytes (primarily B cells) and tumorigenesis appears to be changes in the env gene of FeLV, either due to lymphomas, which arise in the intestinal mutations or recombinations with lymphoid tissues and frequently involve endogenous retroviral env sequences. the mesenteric lymph nodes, are associated with FeLV antigenemia in only Clinical Presentation of FeLV- about 50% of affected cats; however, Associated Diseases recent studies using polymerase chain In most cats, the onset of FeLV- reaction have detected the presence of associated disease occurs over a period of FeLV proviral sequences in some months to years following infection. The lymphosarcomas from FeLV antigen- FeLV-associated diseases can be negative cats. Miscellaneous lymphomas categorized as neoplastic or nonneoplastic are found in nonlymphoid tissues in nature, with most of the nonneoplastic (extranodal origin) and most frequently or degenerative diseases resulting from involve the eye and nervous system of immunosuppression. Clinical signs of FeLV-positive cats. Lymphoid and FeLV-induced immunodeficiency cannot nonlymphoid leukemias are less common be distinguished from those of FIV- than solid tumors. Lymphoid leukemia induced immunodeficiency (see Table 1 usually develops with the multicentric and the section on FIV-associated form of lymphoma, but it occasionally diseases). Immune complex diseases involves only the blood and bone such as thrombocytopenia, immune- marrow. Nonlymphoid leukemias can mediated hemolytic anemia, and involve any of the hemopoietic cell glomerulonephritis are more common in lineages; erythroid and myelomonocytic FeLV-infected cats than in FIV-positive le u k e m ia s are predominant. cats. Thymic atrophy (fading kitten Fibrosarcomas (and possibly syndrome) is observed in young kittens hemangiosarcomas or melanomas) may infected with FeLV; it is rarely associated develop in cats which are coinfected with with FIV infection probably because very FeLV and FeSV, and occur most few young kittens are infected with FIV. frequently in young cats. Erythroblastopenia (nonregenerative anemia) is a very common clinical finding Prevention and Control of FeLV in FeLV-infected cats. The bone marrow Infection is most often hypercellular due to an The ideal method of FeLV control is arrest in differentation of erythroid cells., to prevent contact between infected and although true aplastic anemia with uninfected cats. Test and removal hypocellular bone marrow may be programs have been effective in induced by FeLV-C infection. The controlling FeLV-related disease in many production of aplastic anemia by FeLV-C catteries and multiple-cat households with has been associated with its increased a history of enzootic FeLV. A typical ability to replicate in macrophages and a program has 4 important requirements: correlated increase in production of TNF- (1) All cats are tested for FeLV, and alpha. Finally, some cases of positive cats are removed from the facility nonregenerative anemia are the result of immediately ; (2) The facility and myeloproliferative disease rather than a equipment (especially food and water manifestation of degenerative FeLV dishes and litter pans) are cleaned and; disease. disinfected; (3) All cats are retested at 3 to Lymphoma (lymphosarcoma) is the 6 month intervals until the entire most common FeLV-associated population has tested negative for 8 to 12 neoplastic disease. Lymphomas can be months; and (4) Incoming cats are classified as thymic, multicentric, quarantined for at least 4 weeks and alimentary, or miscellaneous according to tested for FeLV before entry into the their location or distribution in the cattery. affected cat. Thymic and multicentric Vaccination can be used to control the lymphomas are highly associated with spread of FeLV; it is most effective when FeLV infection in cats. Alimentary it is considered as an adjunct to appropriate husbandry practices. Several secondary infections. The disease is vaccines against FeLV infection are known as felin e immunodeficiency available (see Table 2). The efficacy of a syndrome (FIS) or, more commonly, FeLV vaccine usually is determined by its feline AIDS. Like human AIDS, FIS ability to prevent persistent viremia in appears to be caused by impairment of vaccinated cats. Localized replication of immune system function through FeLV and transient viremia may not be infection and/or damage of lymphocytes. prevented by immunization. Most of the commercial FeLV vaccines induce virus- Epizootiology and Transmission neutralizing antibodies specific for gp70; of FIV however, these antibodies probably are Serologic tests for FIV indicate that not the only important component of a the virus is distributed widely throughout protective immune response. Several North America. In the U.S., the independent or semi-independent vaccine prevalence of FIV infection is estimated trials of various products have reported to be 1.5 to 3% in the healthy cat inconsistent or conflicting results. The population and 9 to 15% in cats efficacy of most FeLV vaccines is exhibiting signs of clinical illness. somewhat less than 100%, and Antibodies to FIV have also been detected apparently none of the vaccines is clearly in cats from Japan, the United Kingdom, superior to the other products. the Netherlands, France, Australia, New Vaccination against FeLV infection is Zealand, and Taiwan. In addition, recommended for all cats that are at risk retrospective serologic surveys conducted of exposure to FeLV. Cats housed alone in the U. S., Great Britain, and Japan indoors and cats in multiple-cat facilities indicate that FIV infection has been well known to be free of FeLV infection may established in the domestic cat population not require vaccination. Most cats should for more than 20 years. be tested for FeLV p27 antigen prior to Infections with FIV-like lentiviruses initial vaccination; if prevaccination have been detected by serologic methods testing is not conducted, clients should be in several species of captive and free- aware that their cats may be already ranging nondomestic cats. Lentiviruses infected with FeLV. have been isolated from several antibody- A recent study has revealed an positive Florida panthers and from a association between FeLV vaccination Pallas' cat. The pathogenic potential of and development of fibrosarcomas at the feline lentivirus infection in nondomestic site of inoculation. This association also cats is unknown. has been made for inoculation of rabies Male cats are approximately 3 times and, to a lesser extent, other feline as likely to be infected with FIV as female vaccines, usually when administered cats. Free-roaming cats are much more subcutaneously. The incidence of likely to be infected than cats housed fibrosarcoma development following strictly indoors; very few purebred cats vaccination is unknown but is estimated housed in catteries are infected with FIV. to be quite low (less than 0.1%), but it The prevalence of FI V infection increases appears to have increased substantially with age, with a mean age of about 5 over the past 5 or 6 years. years at the time of diagnosis. Feline immunodeficiency virus is FELINE IMMUNODEFICIENCY efficiently transmitted through bite VIRUS wounds, with virus being shed in the saliva of infected cats, possibly in the Feline im m unodeficiency virus form of infected white blood cells. infection is associated with an Transmission through casual contact is at immunosuppressive disease in domestic best inefficient under natural conditions. cats, characterized by fever, Although early attempts to demonstrate lymphadenopathy, leukopenia, anemia, transmission of FIV through casual or anorexia and cachexia, and chronic sexual contact among cats were unsuccessful, viral RNA and proviral Infection of regional lymph nodes DNA have been detected in samples from (primarily T cells) HV-seronegative cats housed in contact with FIV-infected cats. The significance i of this finding is unknown, and Replication in T cells (in germinal centers additional study will be required to of lymphoid tissues and in the thymic determine the potential for transmission cortex), and nonproductive infection of FIV through casual contact. of B cells Placental or colostral transmission of FIV from a queen to her offspring occurs infrequently. In utero and postnatal Infection of macrophagesi (becomes transmission have been documented predominant after 6 to 8 weeks of experimentally, primarily when the infection queen's initial exposure to FIV occurs during gestation or lactation. Thus, I fetuses or kittens exposed to FIV prior to Infection of spleen, gastrointestinal and antibody development in the queen appear systemic lymphoid tissues to be at highest risk of infection.

Immunogenic Proteins of FIV [Infection of astrocytes and microglial When cats are experimentally infected cells in the brain; infection of bone with FIV, neutralizing antibodies appear marrow megakaryocytes and monocytic 3 to 4 weeks after infection; however, cells] - only in some cats, and usually late virus can be isolated from infected cats in in infection spite of high neutralizing antibody titers. Antibodies to the envelope glycoprotein (gpl20) and the major core (gag) proteins Immunopathogenesis of FIV Infection - develop first, with antibodies to the The underlying immunopathology of FIV transmembrane protein (gp40) and the pol infection appears to be similar to that seen gene products generally appearing 4 to 8 in HIV-infected humans. FIV has been weeks after infection. The time of demonstrated to preferentially infect seroconversion partially depends on the interleukin 2 (IL2)-stimulated peripheral dose of FIV given, with more rapid blood mononuclear cells, presumably T seroconversion in cats receiving the lymphocytes, under laboratory greater dose of virus. Antibody levels conditions; however, unlike HIV peak after several weeks and remain high infection of human lymphocytes which is for months to years following infection. restricted to CD4+ lineages, FIV lyrically Although most cats develop high infects both feline CD4+ (helper) and antibody levels within a few weeks after FIV infection, several antibody-negative, feline CD8+ (cytotoxic) T lymphocytes. virus-positive cats have been identified. Recently, the putative cellular receptor for Some cats may require months to FIV has been identified as the feline seroconvert, and FIV antibody levels may homologue of the human leukocyte decrease in some cats during the terming differentiation antigen, CD9, rather than stages of disease. the feline CD4 molecule. In spite of the ability to infect both Pathogenesis of FIV Infection CD4+ and CD8+ subsets of T cells in The stages involved in the vitro, FIV appears to selectively and establishment of persistent viremia with progressively decrease feline CD4+ cells FIV have not been as well defined as in vivo. The basis of this selective killing those of FeLV infection. Preliminary of CD4+ cells is not known, but a recent studies suggest the following study su g g ests that apoptosis progression: (programmed cell death) may play a role. The inversion of the CD4+:CD8+ ratio infection and lasts for up to 4 months. becomes significant in cats infected for Lymphadenopathy, neutropenia, fever, longer than 18 months, and an absolute and diarrhea may be observed; however, decrease of CD4+ T lymphocytes occurs many cats exhibit no clinical signs during in cats with experimental FIV infections acute infection. The AC stage (clinically of 25 to 40 months duration. After long inapparent infection) may last several term (>25 months) FIV infection, cats months to years. A short period (less may have a decreased ability to respond than 4 months) of PGL follows the AC to T-dependent antigens, resulting in stage. The ARC and AIDS stages of impairment of cell-mediated immunity; disease (or FIS) are not clearly defined however, immunologic responses to T- for FIV infection, but cats with ARC independent antigens are not affected. usually suffer from chronic respiratory, Feline immunodeficiency virus also gastrointestinal, and skin disorders, infects feline peritoneal macrophages. accompanied by PGL. The development Infected macrophages are thought to be of opportunistic infections, severe the main "reservoir" of HIV in infected emaciation, and lymphoid depletion humans; they may play a similar role in signals a progression to AIDS. The FIV-infected cats. Very little is known estimated life expectancy for cats with about additional target cells for FIV AIDS is 1 year or less. infection. Brain astrocytes and microglial In one study of naturally FIV-infected cells can be infected in vitro and may be cats, the rate of disease progression was targets for infection in the cat. variable, with death occurring in about Megakaryocytes and mononuclear bone 18% of infected cats within the first 2 marrow cells may be infected in some years 6f observation (4.5 to 6 years after cats, while other FIV-positive cats have the estimated time of infection). An no evidence of bone marrow infection. additional 18% of infected cats developed Coinfection with FeLV apparently increasingly severe disease; however, extends the host cell range of FIV to more than 50% of the infected cats include cells of kidney, brain, and liver. remained clinically asymptomatic during In addition, FIV strain differences may the same time period. dictate which host cells become infected. Early lymphadenopathy and PGL is associated with follicular hyperplasia and Clinical Presentation of FIV- massive paracortical infiltration with Associated Diseases plasmacytes. In some lymph nodes, a Because of the immunosuppressive mixture of follicular hyperplasia and nature of FIV infection, clinical signs in follicular depletion or involution may be domestic cats are diverse. Diseases observed. In the terminal stage of associated with FIV infection cannot be disease, lymphoid depletion is the distinguished clinically from FeLV- predominant finding. associated immunodeficiencies (see Table Abnormal hemograms are common in 1). Feline immunodeficiency virus FIV-positive cats. Clinically ill cats (i.e. infection can be divided into stages cats with FIS) are most likely to have similar to the acute (first), asymptomatic hematologic abnormalities, especially carrier (AC, second), AIDS-related cytopenias. Anemia, lymphopenia, complex (ARC, fourth) and AIDS (fifth) neutropenia, and hypergamma­ stages of HIV infection. A state similar globulinemia are the most frequent to the third clinical stage of HIV findings; however, neutrophilia and infection, persistent generalized lymphocytosis may be observed in some lymphadenopathy (PGL) with no other cats. Thrombocytopenia is often seen in signs of illness, also occurs briefly in FeLV-infected cats, but it is found in less cats; however, most cats with PGL show than 10% of FIV-infected cats. Bone concurrent clinical signs. The acute marrow abnormalities in FIV-infected phase begins about 4 to 6 weeks after cats may include increased cellularity due to elevated numbers of lymphocytes, plasma cells or eosinophils, is reversible if the griseofulvin is myeloproliferative disease, dysmorphic withdrawn early enough, secondary syndromes and neoplasia. Cats infected infections associated with the condition with FIV may be more susceptible to can be life-threatening; therefore, this Haemobartonella felis-induced anemia drug should be avoided or used with and related disease. Since it can be extreme caution in FIV-positive cats. difficult to detect the organisms, anti- Severe wasting occurs in some cats; rickettsial therapy may be indicated for the cachexia and the chronic fever seen in any cat exhibiting signs of regenerative FIS may be due to an overproduction of hemolytic anemia. tumor necrosis factor. Abortion, Among the most common clinical infertility and other reproductive failures findings in FIV-infected cats are have been reported in infected queens; gingivitis, stomatitis, and periodontitis. however, reproductive disorders have not Oral lesions, reported in 25 to 50% of been linked statistically with FIV positive cats, may be ulcerative infections. (frequently associated with calicivirus), Some FIV-infected cats have proliferative, or a combination of both experienced seizures, behavioral types. These lesions often consist of abnormalities and other neurologic lymphocytic and plasmacytic infiltrates. disorders, usually in the terminal stages The plasmacytic infiltrates may extend to of disease. Anisocoria, delayed reflexes, the draining lymph nodes and the spleen altered sleep patterns, and delayed visual of affected cats. and auditory evoked potentials have been Chronic upper respiratory tract observed in experimentally infected cats. disease occurs in about 30% of FIV- FIV-specific antibodies have been positive cats, and persistent diarrhea due detected in the cerebrospinal fluid of to chronic enteritis occurs in 10 to 20% of some infected cats, and FIV has been infected cats. Feline herpesvirus and isolated from the brains of a few cats. calicivirus infections may be partially Some strains of FIV may be more responsible for upper respiratory disease neurotropic than others, resulting in direct including rhinitis, conjunctivitis and or indirect damage to the central nervous keratitis. Intestinal lesions similar to system. Brain lesions primarily consist those seen with feline parvovirus of mononuclear cell infiltration and infection have been observed in several gliosis of the subcortical structures and cats with diarrhea. The etiology of the basal ganglia. enteritis may be bacterial or fungal Three types of ophthalmic disease overgrowth, parasite-induced common in FIV-positive cats are anterior inflammation, or possibly inflammation uveitis, pars planitis and glaucoma. induced by direct infection of the H istologic changes may include gastrointestinal epithelium with FIV. plasmacytic, lymphocytic infiltrates in the Chronic, nonresponsive or recurrent iris and ciliary body similar to the type of infections of the external ear and skin are infiltrates found in other tissues of FIV- commonly seen. Skin lesions and infected cats. The pathogenesis of ocular abscesses are often due to disease in FIV infection is unknown. Staphylococcus or other bacterial The virus may be responsible for direct infections. Generalized notoedric and damage to the uveal or vascular demodectic mange, parasitic diseases epithelium, resulting in inflammation. which are uncommon in otherwise Other potential mechanisms of ocular healthy cats, have been reported in FIV- pathogenesis are immune-mediated positive cats. Dermatophytosis may be inflammation and opportunistic especially difficult to treat in FIV-positive infections, such as cytomegalovirus and cats. Severe neutropenias have Toxoplasma gondii infections. FIV- been induced in several FIV- positive cats are frequently coinfected infected cats treated with with Toxoplasma, and reactivation of griseofulvin. Although the neutropenia latent toxoplasmosis is suspected to occur in these cats when they become to a shared mode of transmission rather immunosuppressed. One or more of these than any cofactor effect. In 1 study, factors may be involved in the initiation infection of cats with FeSFV did not of ocular disease in an individual cat. enhance or alter early disease progression Although lentiviruses are not when the cats were coinfected with FIV. considered to be directly oncogenic, several types of neoplasia have been Prevention and Control of FIV reported in FIV-positive cats. Because Infection older cats are most likely to be infected Prevention of exposure to FIV- with FIV and also to develop infected cats is the only available method nonretrovirus-related tumors, it is of control. Because casual contact difficult to determine just what role FIV between cats and contact with fomites are may be playing in the neoplastic process. inefficient methods of transmission, FIV-infected cats are 5 times more likely preventing exposure to FIV is relatively to develop leukemia/lymphoma than straightforward. Cats should not be uninfected cats. This relative risk for allowed to roam free or to interact with development of leukemia/lymphoma feral or free-roaming cats. All new cats increases to 62 times normal for FeLV- should be screened for FIV infection infected cats and to 77 times normal for prior to entering an FIV-negative cats with dual FeLV/FIV infections. multiple-cat household or cattery. If Lymphomas associated with FIV possible, a 6 to 8 week quarantine period infection frequently are extranodal in should be enforced to allow time for origin. In addition to recently infected cats to develop leukemia/lymphoma, neoplastic diseases detectable levels of antibody. which have been reported in FIV-positive If an FIV-positive cat is identified in cats include fibrosarcoma, mastocytoma, an established household, removal of the squamous cell carcinoma, and cat may not be necessary since the myeloproliferative disease. likelihood of transmission of FIV by Coinfection of cats with FIV and casual contact is slight; however, FeLV occurs under natural conditions but separation of seropositive cats from infection with one virus does not appear seronegative cats probably is advisable. to predispose the cat to infection with the Cats with severe oral inflammation or in second virus. Researchers at the the terminal stages of disease shed University of California/Davis have relatively large amounts of virus and thus demonstrated that pre-existing FeLV may pose a greater threat to uninfected infection acts as a potentiator for FIV- cats than asymptomatic FIV-infected cats. related disease in experimentally infected Ultimately, the decision on management cats. The increased severity of disease of FIV-positive cats in a multiple-cat apparently is due to an increased amount facility must be made by an informed of FIV replication in lymphoid tissues client based on individual circumstances. (where the virus usually is found in cats Commercial vaccines for protection infected with FIV alone) and to the against FIV infection or disease are not presence of FIV in non-lymphoid tissues available. The development of a vaccine (where FIV usually does not replicate for FIV has been hindered by at least 2 when alone). Cats with naturally factors: 1) the virus is able to infect cells acquired dual infections also suffer from of the immune system and may spread severe disease. Because of the increased from cell to cell, avoiding detection and severity of FIV-related disease, cats elimination by the cat's immune coinfected with FIV and FeLV have an response, and 2) FIV isolates have a high extremely poor prognosis. degree of genetic diversity, especially in Coinfection of cats with FIV and env, resulting in heterogeneous surface FeSFV are very common, probably due envelope proteins with little antigenic cross-reactivity. DIAGNOSIS OF FELINE Diagnostic Tests for FeLV RETROVIRUS INFECTIONS Commercial assays for FeLV infection detect the. viral group-specific Feline immunodeficiency virus and core antigen, p27. The IFA test is FeLV infections can be differentiated only available through a limited number of by appropriate laboratory tests. In most diagnostic laboratories. It identifies p27 circumstances, testing for both viruses is in leukocytes and platelets in fixed smears indicated. Certainly, cats with signs of of whole blood or buffy coat immunosuppression and cats entering preparations; a positive result indicates a multiple-cat facilities should be tested for productive FeLV infection in the bone both FIV and FeLV. marrow cells. Most (97%) IFA-positive cats remain persistently infected and Diagnostic Tests for FIV viremic for life. In many cats, p27 The diagnosis of FIV infection antigen can be detected by IFA by 4 usually depends on the detection of FIV- weeks after infection, but some cats may specific antibodies in serum, plasma or take up to 12 weeks to develop an IFA- whole blood. The presence of FIV positive test. When testing leukopenic antibodies correlates well with persistent cats, buffy coat smears provide a much FIV infection. Commercial ELISA tests better substrate for the IFA than whole are available for use in veterinary clinics, blood smears. hospitals, and diagnostic laboratories; Enzymatic detection of soluble FeLV some laboratories also offer IFA or p27 antigen is the basis of FeLV testing immunoblot (western blot) assays for in most veterinary clinics and hospitals. FIV antibodies. In general, FIV ELISAs Several com m ercial manufacturers have similar sensitivites to the IFA and produce ELISA tests for detection of immunoblot procedures; however, false- FeLV antigen in whole blood, serum, positives (decreased specificities) with plasma, saliva or tears. These tests are ELISAs may occur due to operator error more sensitive than the IFA at detecting (especially inadequate washing) or early or transient FeLV infections; nonspecific reactivity with cell culture however, a single positive ELISA test components. The likelihood of false- cannot predict which cats will be positive results increases when testing persistently viremic. A second ELISA cats at low risk for FIV infection, test is recommended in 12 weeks, and Confirmation of positive ELISA tests for many veterinarians confirm a positive test FIV antibody by IFA or immunoblot is with IFA at this point. False-positive recommended when the cat is ELISA results are more common when asymptomatic or at low risk for infection, whole blood is used rather than serum or or when euthanasia of an FIV-positive cat plasma. In addition, false-positive tests may be considered. or inconsistent results may be common The presence of maternally-derived with tests using saliva and tears; cats with HV antibody in kittens less than 4 to 5 positive results should be retested using months of age results in positive tests whole blood (IFA) or serum (ELISA). with any of the antibody assays, whether Because commercial FeLV tests detect or not the kittens are actually infected. viral antigen rather than antibody, Kittens suspected of having a positive previous vaccination does not interfere FIV test due to maternal antibody should with the ability to detect FeLV infection. be retested at 6 to 8 months of age. It is Assays for antibodies to FeLV gp70 and important to note that virus-positive FOCMA are used occasionally to evaluate kittens may become seronegative for the immune status of FeLV antigen- several weeks after the loss of maternal negative exposed cats or to evaluate a antibody and before seroconversion to response to vaccination. positive status with their own antibodies. 11 TREATMENT OF FELINE (plasmapheresis) has been used to RETROVIRAL INFECTIONS remove circulating immune complexes in AND ASSOCIATED DISEASES FeLV-positive cats. Perhaps the best strategy for Antiviral Therapeutic Agents antiretroviral therapy is use of a Safe and consistently effective combination of 2 or more of the drugs antiviral agents are not available for use in mentioned above. Until more extensive FIV- and FeLV-infected cats. Two field trials of these agents, alone and in primary approaches to antiretroviral combination, have been performed, no therapy have been used in cats: (1) single treatment can be recommended as Reverse transcriptase inhibitors have been better than the rest. Table 3 outlines administered to suppress viral replication, treatment regimens for AZT and some of and (2) Immunomodulatory drugs have the immunomodulatory drugs. been given to potentiate the cat's immune response against the retrovirus. Treatment of Diseases Associated In a small field trial, general clinical with FeLV and FIV Infections improvement of FIV-associated Management of secondary and stomatitis, gingivitis, and diarrhea was opportunistic infections is a primary observed after treatment with a reverse consideration in the treatment of cats transcriptase inhibitor, either 9- immunosuppressed by FeLV or FIV. 2[phosphonomethoxyethyl] adenine Toxoplasmosis, haemobartonellosis, and (PMEA) or 3'-azido-2', 3'- cryptococcosis are frequently associated dideoxythymidine (AZT). Thus with feline retroviral infections; suggested administration of AZT or PMEA may chemotherapies are outlined in Table 3. reduce the severity of FeLV- and FIV- Additional supportive therapy, such as associated diseases; however, the drugs parenteral fluids and nutritional (especially PMEA) are not readily supplements, may be required. Yearly available and the risks of toxicity often vaccination for respiratory and enteric outweigh the therapeutic benefits. If viruses with inactivated vaccines is these drugs are used, treated cats should recommended; MLV vaccines for rabies be monitered closely for the development should never be used in of anemia, cytopenias, and immunosuppressed cats (at present, only hepatotoxicities, and the dosage should inactivated rabies vaccines are approved be adjusted as needed. for use in all cats). The ability of some Immunomodulatory drugs may FIV- and FeLV-infected cats to respond allieviate some clinical signs associated appropriately to vaccination is with retroviral infections. Low dose, questionable; the immune response of orally administered human recombinant immunocompromised cats to vaccines, alpha interferon (IFN) has been especially rabies virus vaccines, needs successful in increasing survival rates and further evaluation. improving clinical status of FeLV- Retrovirus-related gingivitis tends to infected cats. Oral IFN treatment may act be refractory to treatment. Antibacterial by stimulating the release of soluble or antimycotic drugs may be used cytokines, such as IL1, from effectively if the primary lesions are due oropharyngeal macrophages and to overgrowth of bacteria or fungi, but lymphocytes; these cytokines then prolonged therapy or increased dosages circulate systemically and modulate may be required. Metronidazole or immune function. Additional promising clindamycin may be useful in treating im m unom odulatory drugs include anaerobic bacterial infections. Judicious acemannan, Propionibacterium acnes, but aggressive use of corticosteroids or and staphylococcal protein A (SPA). All gold salts may be helpful in controlling of these drugs induce the release of im m u n e -m e d ia te d inflammation; endogenous interferons and IL1. In however, response to therapy may addition, SPA immunoadsorption decline over time. These 12 immunosuppressive agents should be related glaucoma is the same as for restricted or avoided in cats with overt glaucoma due to other causes. signs of opportunistic bacterial or fungal Many cases of lymphosarcoma in infections. A recent report details the use FeLV-positive cats have been managed of a preactivated photoactive compound, successfully with combination merocyanine 540, in 2 cats with severe chemotherapy. Regimens using gingivitis; however, a safe and effective vincristine, cyclophosphamide, and dose range for use of this drug in cats has prednisone are most commonly used. not been adequately defined. Periods of remission average 3 to 4 Bone marrow examination is months, but some cats may remain in especially useful when evaluating severe remission for a much longer time. anemias in FeLV-infected cats. Myeloproliferative disease and leukemias Haemobartonella infection should be are more refractory to treatment. No data suspected in all cats with regenerative are available on the efficacy of hemolytic anemias; treatment consists of antineoplastic therapy in FIV-positive administration of oxytetracycline for 3 cats. Surgical removal of isolated tumors weeks with short term use of oral may be useful but care must be taken to glucocorticoids in severe cases. Blood insure proper healing of incisions. transfusions can provide emergency Established chemotherapy protocols may support when the cat's hematocrit is less be followed for the treatment of than 10%, but multiple transfusions may lymphoproliferative diseases. Combined be required. Passive antibody transfer therapy with nonspecific may help reduce the level of FeLV immunopotentiators such as antigenemia in some cats; therefore, Staphylococcus protein A or immunization of blood donor cats with Propionobacterium acnes, or IFN may FeLV vaccines is useful when blood help control FeLV- or FIV-related transfusions are required for FeLV- tumors, but experimental evidence of associated anemia. their efficacy is lacking. Management of weight loss and cachexia associated with FIV and FeLV SELECTED RECENT infections is critical. Cats with normal REFERENCES appetites should be evaluated for malabsorption and managed accordingly. Barlough JE, et al.: Acquired immune Anorexic cats may benefit from IV dysfunction in cats with experimentally administration of diazepam or oral induced feline immunodeficiency virus administration of oxazepam. Anabolic infection: Comparison of short-tenn infections. J Acq Imm Def Syndr steroids or megestrol acetate may be 4:219-227, 1991. useful for more prolonged stimulation of Barr MC, et al.: Comparison and interpretation appetite and reversal of cachexia; of diagnostic tests for feline however, controlled studies on the, immunodeficiency virus infection. J efficacy and safety of these drugs in Am Vet Med Assoc 199:1377-1381, retrovirus-infected cats are lacking. 1991. Treatment for anterior uveitis consists Beebe AM, et al.: Detection of feline of application of topical corticosteroids, immunodeficiency virus infection in but long-term response to therapy may be bone marrow of cats. Vet Immunol incomplete or poor. Pars planitis will Immunopathol 35:37-49, 1992. often regress spontaneously and may Beebe AM, et al.: Primary stage of feline recur; topical and systemic corticosteroid immunodeficiency virus infection: viral therapy may be used but may not stop the dissemination and cellular targets. J Virol 68:3080-3091,1994. progression of the lesions. Systemic Brown WC, et al.: Feline immunodeficiency corticosteroids should be used with virus infects both CD4+ and CD8+ T caution considering the potential for lymphocytes. J Virol 65:3359-3364, further immunosuppression of an already 1991. compromised cat. Management of FIV- Callanan JJ, et al.: Clinical and pathological Loar AS: Feline leukemia virus: Immunization findings in feline immunodeficiency and prevention. Vet C linics N virus experimental infection. Vet Amer: Small Anim Pract Immunol Immunopathol 35:3-13, 23:193-211, 1993. 1992. O'Connor TP,Jr., et al,: Report of the N atio n al Charreyre C and Pedersen NC: Study of feline FeLV/FIV Awareness Project. J Am leukemia virus immunity. J Am Vet Vet Med Assoc 199:1348-1353, Med Assoc 199:1316-1324, 1991. 1991. Dow SW, et al.: Feline immunodeficiency virus Olmsted RA, et al.: Worldwide prevalence of neurotropism: Evidence that astrocytes lentivirus infection in wild feline and microglia are the primary target species: Epidem iologic anl cells. Vet Immunol Immuno­ phylogenetic aspects. J Virol pathol 35:23-35, 1992. 66:6008-6018, 1992. Egberink HF, et al.: Chemotherapy of feline O'Neil SA, et al.: Clinical and epidemiological immunodeficiency virus infection. J aspects of feline immunodeficiency Am Vet Med Assoc 199:1485-1487, virus and Toxoplasma gondii 1991. coinfections in cats. JAAHA Hardy WD,Jr. and Zuckerman EE: Ten-year study 27:211-220, 1991. comparing enzyme-linked immuno­ Pedersen NC, et al.: Feline leukemia virus sorbent assay with the immuno- infection as a potentiating cofactor for fluorescent antibody test for detection of the primary and secondary stages of feline leukemia virus infection in cats. J experimentally induced feline Am Vet Med Assoc 199:1365-1373, immunodeficiency virus infection. J 1991. Virol 64(2):598-606, 1990. Hoover EA and Mullins JI: Feline leukemia Pedersen NC: Immunogenicity and efficacy of a virus infection and diseases. J Am Vet commercial feline leukemia virus Med Assoc 199:1287-1297, 1991. vaccine. J Vet Int Med 7:34-39, IshidaT and Tomodal: Clinical staging of feline 1993. imunodeficiency virus infection. Jpn J Phillips TR, et al.: Neurologic abnormalities Vet Sci 52:645-648, 1990. associated with feline immunodeficiency Ishida T, et al.: Long-term clinical observations virus infection. J Gen Virol 75:979- on feline immunodeficiency virus 987, 1994. infected asymptomatic carriers. Vet Rojko JL and Kociba GJ: Pathogenesis of Immunol Immunopathol 35:15-22, infection by the feline leukemia virus. J 1992. Am Vet Med Assoc 199:1305-1310, .Jarrett O: Overview of feline leukemia virus 1991. research. J Am Vet Med Assoc Scott FW, et al.: Panel report on the Colloquium 199:1279-1281, 1991. on Feline Leukemia Virus/Feline Jarrett O, et al.: Comparison of diagnostic Immunodeficiency Virus: Tests axl methods for feline leukemia virus and Vaccination. J Am Vet Med Assoc feline immunodeficiency virus. J Am 199:1273-1278, 1991. Vet Med Assoc 199:1362-1364, Sheets RL, et al.: Recombinant feline leukemia 1991. virus genes detected in naturally Kass PH, et al.: Epidemiologic evidence for a occurring feline lymphosarcomas. J causal relation between vaccination and Virol 67:3118-3125,1993. fibrosarcoma tumorigenesis in cats. J Shelton GH, et al.: Feline immunodeficiency Am Vet Med Assoc 203:396-405, virus and feline leukemia virus 1993. infections and their relationships to Lafrado LJ: Evaluation of a feline leu k em ia virus lymphoid malignancies in cats: A vaccine in a controlled natural retrospective study (1968-1988). J Acq transmission study. J Am Vet Med Imm Def Syndr 3:623-630, 1990. Assoc 204:914-917,1994. Shelton GH, et al.: Severe neutropenia associated Lappin MR, et al.: Effect of primary phase feline with griseofulvin therapy in cats with immunodeficiency virus infection on feline immunodeficiency virus infection. cats with chronic toxoplasmosis. Vet J Vet Internal Med 4:317-319, Immunol Immunopathol 35: 1990. 121-131, 1992. 14 Shelton GH, et al.: Hematologic abnormalities infected with feline immunodeficiency in cats seropositive for feline virus. J Virol 65:2225-2230, 1991. immunodeficiency virus. J Am Vet Wasmoen T, et al.: Transmission of feline Med Assoc 199:1353-1357, 1991. immunodeficiency virus from infected Sparger EE: Current thoughts on feline queens to kittens. Vet Immunol immunodeficiency virus infection. Vet Immunopathol 35:83-93,1992, Clinics N Amer: Small Anim Weiss RC, et al.: Low-dose orally administered Pract 23:173-191, 1993. alpha interferon treatment for feline Swango LJ: Evaluation of feline leukemia virus leukemia virus infection. J Am Vet diagnostic tests available for in-office Med Assoc 199:1477-1481, 1991. use by veterinarians. J Am Vet Med Wiggs RB, et al.: Effects of preactivated MC540 Assoc 199:1386-1389, 1991. in the treatment of lymphocytic Swenson CL, et al.: Prevalence of disease in plasmacytic stomatitis in feline nonviremic cats previously exposed to leukemia virus and feline feline leukemia virus. J Am Vet Med immunodeficiency virus positive cats. J Assoc 196:1049-1052, 1990. Vet Dent 10:9-13, 1993. TizardI: Use of immunomodulators as an aid to ZengerE, et al.: Evaluation of cofactor effect of clinical management of feline leukemia feline syncytium-forming virus on virus-infected cats. J Am Vet Med feline immunodeficiency virus infection. Assoc 199:1482-1485, 1991. Am J Vet Res 54:713-718, 1993. Torten M, et al.: Progressive immune dysfunction in cats experimentally 15

TABLE 1. DISEASES ASSOCIATED W ITH FIV AND FELV INFECTIONS Immunosuppression with opportunistic infections Gingivitis/Stomatitis (FTV>FeLV) Myeloprdiferative disease/Erythroleukemia (FeLV»FTV) Fibrosarcomas (FELV only - FeSV-related) Lymphosarcoma/Lymphoid leukemias (FeLV»FTV) Diarrhea/Panleukopenia-like syndrome Weight loss/Cachexia Chronic fever Glomerulonephritis Anterior uveitis/Pars planitis/Glaucoma (FIV»FeLV) Behavioral changes/Dementia/Peripheral neuropathies Hypergammaglobulinemia (FIV>FeLV) Hemolytic anemias/Aplastic anemias (FeLV»FTV) Lymphopenia/Neutropenia Thrombocytopenia (FeLV»FIV) Abortion/Fetal resorptions/Thymic atrophy (fading kittens) (FeLV»FIV) _^romc^rogessive^d(^arthriti£^FeSFV^associated??2______^_^

TABLE 2. FELINE LEUKEMIA VIRUS VACCINES

Product Name Manufacturer Type of Vaccine

Fel-O-Vax Lv-K Fort Dodge Laboratories, K, WV (FeLV-FAIDS strain), w/adjuvant Fevaxyn FeLV Solvay Animal Health, K, WV (subgroups A & B), w/adjuvant Shawnee, KS Geneti Vac FeLV Pitman-Moore/ Recombinant SU Coopers Animal Health, (subgroup A/gp70 + part of pl5E), Mundelein, IL w/adjuvant Leukocell 2 SmithKline Beecham Animal Health, Culture filtrate SU Exton, PA (subgroup A, B, & C/gp70, pl5E, others), w/adjuvant VacSYN/FeLV Synbiotics, K, WV (UCD-1 FeLV substrain), San Diego, CA no adjuvant

K = killed (inactivated), WV = whole virus, SU = subunit Derived from Loar, AS. Feline leukemia virus: Immunization and prevention. Vet Clinics of North America: Small Animal Practice 23:193,1993. 16 TABLE 3. DRUG APPENDIX Generic Trade Dosage Route Frequency Descriptior AZT Retrovir 5 mg/kg SQ ql2hfor Antiretroviral drug 0'-azido-2,3'- 3weeks (moniter for anemi. dideoxythidine)

Interferon-alpha Roferon 30 IU/cat PO Daily - 7 days Immunefunction (recombinant on; 7 days off modulator human IFN)

Propionibacterium Immunoregulin 0.5 ml/cat IV Once or Immune function acnes twice weekly modulator Acemannan Canisyn 100 mg/cat or POor Daily Immunefunction 2 mg/kg SQ, IV modulator Prednisilone 2 to 4 mg/kg PO Daily Corticosteroid - immunosuppressio Metronidazde Flagyl 7 to 15 mg/kg PO q8h to ql2h Antimicrobial - anaerobes Oxytetracycline Teiramycinor 15 mg/kg or POor q8hor Antimicrobial - Liquamycin 7 mg/kg IM, IV ql2h Haemobartonella Clindamycin Antirobe 11 mg/kg PO ql2h Antimicrobial - Toxoplasma Diazepam or Valium or 0.2 mg/kg or IV or Asneeded Appetite stimulant Oxazepam Serax 2.5 mg/kg PO