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Clinical Aspects Feline Retroviruses-04-02684

Clinical Aspects Feline Retroviruses-04-02684

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Viruses 2012, 4, 2684-2710; doi:10.


www.mdpi.com/journal/viruses Review


ISSN 1999-4915

Clinical Aspects of Feline Retroviruses: A Review
Katrin Hartmann Medizinische Kleintierklinik, LMU University of Munich, Germany, Veterinaerstrasse 13, 80539 Munich, Germany; E-Mail: hartmann@uni-muenchen.de; Tel.: +49-89-2180-2653, Fax: +49-89-2180-16501. Received: 12 October 2012; in revised form: 24 October 2012 / Accepted: 26 October 2012 / Published: 31 October 2012

Abstract: Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) are retroviruses with global impact on the health of domestic cats. The two viruses differ in their potential to cause disease. FeLV is more pathogenic, and was long considered to be responsible for more clinical syndromes than any other agent in cats. FeLV can cause tumors (mainly lymphoma), bone marrow suppression syndromes (mainly anemia), and lead to secondary infectious diseases caused by suppressive effects of the virus on bone marrow and the immune system. Today, FeLV is less commonly diagnosed than in the previous 20 years; prevalence has been decreasing in most countries. However, FeLV importance may be underestimated as it has been shown that regressively infected cats (that are negative in routinely used FeLV tests) also can develop clinical signs. FIV can cause an acquired immunodeficiency syndrome that increases the risk of opportunistic infections, neurological diseases, and tumors. In most naturally infected cats, however, FIV itself does not cause severe clinical signs, and FIV-infected cats may live many years without any health problems. This article provides a review of clinical syndromes in progressively and regressively FeLV-infected cats as well as in FIV-infected cats. Keywords: feline leukemia virus; FeLV; feline immunodeficiency virus; FIV; clinical signs; immunosuppression; immune-mediated diseases; tumors; neurologic signs; bone marrow suppression

1. Introduction Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) belong to the most common infectious diseases in cats. Both are retroviruses, but FeLV is a γ-retrovirus, while FIV is classified as

Viruses 2012, 4


a lentivirus. Although FeLV and FIV are closely related, they differ in their potential to cause disease. In the United States, prevalence of both infections is about 2% in healthy cats and up to about 30% in high-risk or sick cats [1,2]. Risk factors for infection include male gender, adulthood, and outdoor access [3,4]. Retroviral tests can diagnose only infection, not clinical disease. FeLV is more pathogenic than FIV. For a long time, FeLV was considered to account for most disease-related deaths, and to be responsible for more clinical syndromes than any other single agent in cats. It was proposed that approximately one third of all tumor-related deaths in cats were caused by FeLV, and an even greater number of cats died of FeLV-related anemia and secondary infections caused by suppressive effects of the virus on bone marrow and the immune system. Today, these statements have to be revised, as in recent years the prevalence and consequently the importance of FeLV as a pathogen in cats have been decreasing. Still, if present in closed households with other viruses, such as feline coronavirus (FCoV), or FIV, FeLV infection has the greatest impact on survival [5]. The death rate of progressively FeLV-infected cats in multi-cat households has been estimated at approximately 50% in two years and 80% in three years [6,7], but is much lower today, at least for cats that are well taken care of and that are kept strictly indoors in single-cat households. A survey in the United States compared the survival of more than 1000 FeLV-infected cats to more than 8000 age- and sex-matched uninfected control cats and found that in FeLV-infected cats median survival was 2.4 years compared to 6.0 years for control cats [2]. Despite the fact that progressive FeLV infection is associated with a decrease in life expectancy, many owners elect to provide treatment for their cats, and with proper care, FeLV-infected cats might live for many years with good quality of life. Although FIV can cause an acquired immunodeficiency syndrome in cats (“feline AIDS”) comparable to human immunodeficiency virus (HIV) infection in humans, with increased risk for opportunistic infections, neurologic diseases, and tumors, in most naturally infected cats, FIV does not cause a severe clinical syndrome. With proper care, FIV-infected cats can live many years and, in fact, can die at older age from causes unrelated to their FIV infection. In a follow-up study in naturally FIVinfected cats, the rate of progression was variable, with death occurring in about 18% of infected cats within the first two years of observation (about five years after the estimated time of infection). An additional 18% developed increasingly severe disease, but more than 50% remained clinically asymptomatic during the two years [8]. FIV infection has little impact on a cat population and does not reduce the number of cats in a household [2]. Thus, overall survival time is not shorter than in uninfected cats, and quality of life is usually fairly high over an extended period of time. 2. Stages of Infection Both infections are chronic in nature and develop through different disease stages. Characteristically for both infections, there is a long asymptomatic phase, in which cats do not show clinical signs. FeLV infection has different stages. Recently, novel diagnostic tools, including very sensitive PCR methods providing new data on the course of FeLV infection, have questioned the traditional understanding of FeLV pathogenesis. Cats believed to be immune to FeLV after infection were found to remain provirus-positive. Antigen-negative, provirus-positive cats are frequently detected and their clinical relevance and role in FeLV epidemiology is still not fully understood. Antigen-negative, provirus-positive cats are considered FeLV carriers. Following reactivation, they can act as an infection source. As FeLV provirus is integrated into the cat’s genome, it is unlikely to be fully cleared

g.10]. viremia may persist longer than three weeks. Regressive infection can be reactivated because the information for producing complete viral particles is present and can potentially be reused when antibody production decreases (e. After initial infection. 4 2686 over time. They have high levels of neutralizing antibodies. Abortive infection is likely caused when a cat is exposed to low doses of FeLV [15]. Even if bone marrow cells become infected. Antigen-negative. and infected hematopoietic precursor cells develop into infected granulocytes and platelets that circulate in the body. In a study in Switzerland it was shown that in addition to the antigen-positive. no virus is actively produced. In regressive infection. During cell division. proviral DNA is replicated and the information given to the daughter cells. about 10% of the cat population that were negative for antigen were positive for proviral DNA in the blood [16]. Thus. cats with regressive infection have negative results in all tests that detect FeLV antigen. Sensitive PCR methods can detect provirus in the blood of cats with regressive infection that are antigen-negative. In some cats. provirus-positive cats do not shed the virus. they cannot completely eliminate the virus from the body. even if they terminate viremia because the information for virus replication (proviral DNA) is present in bone marrow stem cells. Neither FeLV antigen nor viral RNA or proviral DNA can be detected in the blood at any time. cats have positive results on tests that detect free antigen in plasma (e. . The molecular basis of latency is the integration of a copy of the viral genome (provirus) into cellular chromosomal DNA. However. a certain percentage of cats is able to clear viremia. ELISA).Viruses 2012. Based on this information. replicating FeLV spreads systemically through infected mononuclear cells (lymphocytes and monocytes). regressively infected cats do not shed FeLV and are not infectious to others. this viremia.. provirus-positive cats. Thus. This condition has been called “latent infection” (and is now a part of the regressive infection). the virus actually can still be found later in these cats when investigating tissue samples. because studies using very sensitive PCR methods have found that in many of the formerly considered “regressor cats”. In cats with regressive infection. They shed virus. It is still unknown. Therefore. Although proviral DNA remains present within the cellular genome. During this stage. is terminated within weeks or months (therefore formerly called “transient viremia”). a new classification has been proposed. Thus. Regressive infection develops following an effective immune response. and focal or atypical infection (Table 1) [11-14]. how often this situation really occurs in nature. and no infectious virus particles are produced. but reactivation with reoccurring virus shedding is possible [9. in which the stages of FeLV infection are defined as abortive infection (comparable to the former “regressor cats”). In some immunocompetent cats (formerly called “regressor cats)”. it appears likely that none or only very few cats can completely clear FeLV infection from all cells. after immunosuppression). Abortive infection. bone marrow cells become infected. proviral DNA is not translated into proteins. these cats never become viremic. regressive infection (comparable to the former “transient viremia” followed by “latent infection”). viral replication may be terminated by an effective humoral and cell-mediated immune response. mainly with saliva. After about three weeks of viremia. However.g. however.. the virus starts initially to replicate in the local lymphoid tissue in the oropharyngeal area. virus replication and viremia are contained prior to or shortly after bone marrow infection. After infection. complete cell lineages may contain FeLV proviral DNA. progressive infection (comparable to the former “persistent viremia”).

therefore. 4 2687 In cats with progressive infection. Table 1. hematopoietic disorders. extensive virus replication occurs. but are probably rare in the field. FeLV infection is not contained early in the infection. Regressive and progressive infections can be distinguished by repeated testing for viral antigen in peripheral blood. Initially both. or positive and negative results may alternate [14]. Clinical Signs Clinical signs in both retrovirus infections are variable.19]. and a terminal phase sometimes called “feline acquired immunodeficiency syndrome” (“AIDS”) [18. This replication can lead to intermittent or low-grade production of antigen. immunodeficiency. similar to HIV infection in people. followed by the bone marrow and mucosal and glandular epithelial tissues. even cats in moribund condition with severe immunosuppression and secondary infections may fully recover with appropriate care and return to an asymptomatic stage. progressive infection with high virus load [11. After a long asymptomatic phase..Viruses 2012. regressive infection is associated with low.17]. Stages of feline leukemia virus (FeLV) infection Stages of FeLV infection Progressive Regressive Abortive Focal FeLV p27 antigen in blood Positive Negative Negative Variable Virus blood culture Positive Negative Negative Variable Viral RNA in blood Positive Negative Negative Variable Viral DNA in blood Positive Positive Negative Variable Viral tissue culture Positive Negative Negative Positive FeLVassociated disease Likely Unlikely Unlikely Unlikely Viral shedding Positive Negative Negative Variable Experimental FIV infection also progresses through several stages. Moreover. regressive and progressive infections are accompanied by persistence of FeLV proviral DNA in the blood detected by PCR but later are associated with different FeLV loads when measured by quantitative PCR. Progressively infected cats remain persistently viremic. and their virus loads can even decrease dramatically. bladder. cats can develop tumors. Cats with progressive infection develop FeLV-associated diseases. in mammary glands. Focal infections or atypical infections may also be observed in natural infections. including an acute phase.g. and most of them will die within a few years. and not all stages are apparent. Focal infections are characterized by a persistent atypical local viral replication (e. However. regressively infected cats will turn negative at latest 16 weeks after infection. immune-mediated . different from HIV-infected people. Thus. these cats can have weakly positive or discordant results in antigen tests. Thus. first in the lymphoid tissues. while progressively infected cats will remain positive. a clinically asymptomatic phase of variable duration. there is no clear distinction between these stages in naturally FIV-infected cats. severe clinical signs due to secondary infection) can recover and be asymptomatic again. eyes). neurologic disorders. cats classified as being in the “AIDS phase” (high virus load. This condition has been called “persistent viremia” and is now classified as progressive infection. Focal infections or atypical infections have been reported in up to 10% of experimentally infected cats. They are infectious to other cats for the remainder of their life. the usefulness of this staging in natural FIV infection has been questioned. 3. and therefore.

they tend to have abortive or regressive infections or. 4 2688 diseases.. The duration of the following asymptomatic phase varies. to which FIV-infected cats are considered more susceptible. various co-infections (including FIV infection. Probably the most important host factor that determines the clinical outcome of cats infected with FeLV is the age of the cat at the time of infection [22]. In experimental infection. fading kitten syndrome). have at least milder signs and a more protracted period of apparent good health [7]. lethargy. Neonatal kittens develop marked thymic atrophy after infection (“fading kitten syndrome”). and stomatitis) were the most frequent findings (15%). stomatitis. such as the subgroup that determines differences in the clinical picture (e. such as infections and neoplasia. and leukemia or myeloproliferative diseases (4%) [20]. FeLV-C is primarily associated with non-regenerative anemia). signs of enteritis. FIV itself may cause some clinical features (e. and generalized lymph node enlargement [23]. including fever. after which cats will enter a period in which they appear clinically healthy. Some of the differences in outcome can be traced to properties of the virus itself. Of 8642 FeLV-infected cats presented to North American Veterinary Teaching Hospitals. hemotropic mycoplasmosis. but usually lasts many years. the clinical signs are a reflection of opportunistic infections. conjunctivitis. In the last. symptomatic phase (“AIDS phase”) of infection. wasting. The acute phase may last several days to a few weeks. hematologic disorders. and neurologic disease. immunosuppression. upper respiratory infection. leukopenia or thrombocytopenia (5%). immune-mediated diseases. FeLV-B is primarily associated with tumors. and the age of the cat at the time of infection [24. followed by anemia (11%). Although FeLV was named after a tumor that first garnered its attention. Clinical signs in naturally FIV-infected cats usually reflect secondary diseases.g. The pathomechanism of these disorders is different in both retrovirus infections (Table 2). they acquire a progressive resistance. This phase is usually not noticed by the owners in naturally infected cats. exposure to secondary pathogens. dermatitis. an initial stage is sometimes noticed usually with transient and mild clinical signs. Clinical signs associated with FeLV infection can be classified as tumors. When older cats become infected. As cats mature.. and stomatitis. feline infectious peritonitis (FIP). In contrast. and early death.g. most infected cats are presented to the veterinarian not for tumors but for anemia or immunosuppression. The outcome of FeLV infection and the clinical course are determined by a combination of viral and host factors. progressive infection with persistent viremia has been associated with a silencing of virusspecific humoral and cell-mediated immunity host effector mechanisms [21]. neurologic signs) resulting from abnormal function or inflammation of affected organs. . Factors that influence the duration of the asymptomatic phase include the pathogenicity of the infecting isolate (also depending on the FIV subtype). and other syndromes (including neuropathy.25]. lymphoma (6%).Viruses 2012. neoplasia. respiratory tract disease. if developing progressive infection. myelosuppression. reproductive disorders. resulting in severe immunosuppression. A study aiming to define dominant host immune effects or mechanisms responsible for the outcome of infection by using longitudinal changes in FeLV-specific cytotoxic T-lymphocytes (CTL) found that high levels of circulating FeLV-specific effector CTLs appear before virus-neutralizing antibodies in cats that have recovered from exposure to FeLV.

The major reason for the decreasing association of FeLV with lymphoma is the decreasing prevalence of FeLV infection in the overall cat population as a result of FeLV vaccination as well as testing and elimination programs. resulting in activation and over-expression of that gene. lymphomas in FIV are mostly of B-cell origin [26. However. several such transducted genes also present in regressively infected cells have been implicated in viral oncogenesis [44-46].Viruses 2012. only four of 71 cats with lymphoma were FeLV-positive. Proviral DNA was detected in formalin-fixed.31]. less often other hematopoietic tumors and rarely other malignancies (including neuroblastoma. Tumors 2689 While FeLV-infected cats are 62-times more likely to develop lymphoma or leukemia than noninfected cats and FeLV plays a direct role in tumorgenesis. Whereas 59% of all cats with lymphoma or leukemia were FeLV antigen-positive in one German study from 1980 to 1995. It is still unclear. 4 3. other groups found evidence of provirus in only 1/22 [45] and in 0/50 FeLV antigen-negative lymphomas [47]. cats naturally infected with FeLV have a higher risk of developing lymphoma than uninfected cats [29. since the 1980s a reduction in the prevalence of viremia has been noted in cats with lymphoma [39-41]. FeLV has been shown to incorporate cellular genes. FeLV proviral DNA was detected in lymphomas of cats that tested negative for FeLV antigen [43]. and others). and the role of FIV is usually indirect. A malignancy results in the absence of an appropriate immune response. how common regressive FeLV infection is responsible for FeLV-associated tumors in the field as study results have been controversial. FIV-infected cats have about a five-fold increased risk of tumor development. Previously. In a recent study in the Netherlands. most commonly lymphoma and leukemia. A greater prevalence of lymphoma in older-age cats in now observed. The decrease in prevalence of FeLV infection in cats with lymphoma or leukemia also indicates a shift in tumor causation in recent years. FeLV-negative lymphomas have also occurred in laboratory cats known to have been infected previously with FeLV [44]. up to 80% of feline lymphomas and leukemias were reported to be FeLV-related [32-38]. most cats with lymphoma were—at least in earlier times when prevalence of FeLV was still higher—FeLV-positive in tests that detected infectious virus or FeLV antigens. However.27]. also suggesting that the virus may be associated with a larger proportion of lymphomas than previously thought. While FeLV-infected cats have most commonly T-cell lymphomas. which previously was strongly associated with FeLV infection [42]. First. Lymphomas are the most common tumors in FeLV. Third.1. Cats from FeLV cluster households had a 40-fold higher rate of development of FeLV-negative lymphoma than did those from the general population. paraffin-embedded tumor tissue in 7/11 FeLV-negative cats with lymphoma [43]. osteochondroma. Second. However. The association between FeLV and lymphomas has been clearly established in several ways. these malignancies can be induced in kittens by experimental FeLV infection [28-30].and FIV-infected cats. prevalence of lymphomas caused by FeLV may be higher than indicated by conventional antigen testing of blood [43]. although 22 of these cats had mediastinal lymphoma. The most important mechanism by which FeLV causes malignancy is by insertion of the FeLV genome into the cellular genome near a cellular oncogene (most commonly myc). only 20% of the cats were FeLV antigen-positive in the years 1996 to 1999 in the same University Teaching Hospital [41]. These effects lead to uncontrolled proliferation of these cells (clone). FeLV is a major oncogene that causes different tumors in cats. FeLV may also .

FeSV also has become less common. Fibrosarcomas that are associated with FeLV are caused by FeSV. Multiple osteochondromas (cartilaginous exostoses on flat bones of unknown .. others likely have just been observed by chance simultaneously in an infected cat. fit1. FeSV-induced fibrosarcomas are multicentric and usually occur in young cats. Twelve common integration sites for FeLV associated with lymphoma development have been identified in six loci: c-myc. 5/25 thymic lymphomas demonstrated proviral insertion within flit-1 locus. immunohistochemical staining and PCR did not find FeLV or FeSV in the ocular tissues of any cat with this disorder [54]. fit-1 appears to be closely linked to myb.. or fgr. some of them might have an association with FeLV. 4 2690 incorporate the oncogene to form a recombinant virus (e. Thus. In a study of 119 cats with lymphomas. Fibrosarcomas caused by FeSV tend to grow rapidly. such as fes. for example. and flit-1. leading to a polyclonal malignancy with multifocal tumors arising simultaneously after a short incubation period. although in one study three of 18 eyes tested positive for FeLV/FeSV proviral DNA [53]. With the decrease in FeLV prevalence. Through a process of genetic recombination. Among 35 FeLV-related tumors. pim-1. often with multiple cutaneous or subcutaneous nodules that are locally invasive and metastasize to the lung and other sites. FeSV is an acutely transforming (tumor-causing) virus. FeSV) containing cellular oncogene sequences that are then rearranged and activated. slower metastasizing. and 1/1 T-lymphoid leukemia examined had rearrangements in this region. and only occasionally curable by excision combined with radiation and/or gene therapy. A few other tumors have been found in FeLV-infected cats. It has been demonstrated that neither FeSV nor FeLV play any role in the development of FISS [52]. e. These tumors are slower growing.Viruses 2012. fms. bmi-1 and pim-1 have been recognized as myc-collaborators.g. Oncogenic association of the loci is based on the fact that c-myc is known as a proto-oncogene. transduction or insertion of the myc locus had occurred in 38 cats (32%) [48]. flvi-1. activin-A receptor type II-like 1 (ACVRL1). FeLV-B.g. at least in part. Strains of FeSV identified from naturally occurring tumors are defective and unable to replicate without the presence of FeLV-A as a helper virus that supplies proteins (such as those coded by the env gene) to FeSV. 5/5 multicentric lymphomas. When they enter a new cell. and flit-1 insertion was shown to be associated with over-expression of cellular genes. whereas normal thymuses and seven lymphoid tumors without flit-1 rearrangement had no detectable ACVRL1 mRNA expression [51]. A recent study suggested that the U3-LTR region of FeLV transactivates cancer-related signaling pathways through production of a non-coding 104 base RNA transcript that activates NF kappaB [49]. In a more recent study. flvi-2 (contains bmi-1). commonly occurring after inoculation of adjuvant-containing vaccines. Iris melanomas. whereas 0/4 alimentary lymphomas. locally invasive. Expression of ACVRL1 mRNA was detected in the two thymic lymphomas with flit-1 rearrangement. FeSV acquires one of several oncogenes. are not associated with FeLV infections. FeLV-induced neoplasms are caused. by somatically acquired insertional mutagenesis in which the integrated provirus may activate a proto-oncogene or disrupt a tumor suppressor gene. a recombinant virus that develops de novo in FeLV-A-infected cats by recombination of the FeLV-A genome with cellular oncogenes. however. [50]. Flit-1 seems to have an important role in the development of lymphomas and appears to represent a common novel FeLV proviral integration domain that may influence lymphomagenesis by insertional mutagenesis. They usually are classified as feline injection site sarcomas (FISS) caused by the granulomatous inflammatory reaction at the injection site. As a result. these recombinant viruses are oncogenic. Solitary fibrosarcomas in older cats are not caused by FeSV.

but also several other tumors have been described in association with FIV infection [26. fibrosarcoma. suggesting a more indirect role in lymphoma formation.70. It also could promote tumor development through the immunostimulatory effects of replicating in lymphocytes. cell function of provirus-containing myelomonocytic progenitor and stromal fibroblasts that provide bone marrow microenvironment may be altered. histologically inhomogenous tumors of the tasting and smelling epithelium of nose and pharynx with high metastasis rates). FIV could alternatively increase tumor incidence by decreasing tumor immunosurveillance mechanisms.27]. In these regressively infected cats. and panleukopenia-like syndrome. which is also supportive of a cause and effect relationship. active virus replication is required. However. For the majority of pathogenic mechanisms in which FeLV causes bone marrow suppression. aplastic anemia (pancytopenia). much higher than the FIV prevalence in the population of cats without lymphomas. they may cause significant morbidity if they occur in an area such as a vertebra and put pressure on the spinal cord or nerve roots [55. Anemia is a major nonneoplastic complication that occurs in a majority of FeLV-infected cats [4]. or regulatory features of viral DNA may alter expression of neighboring genes. FIV-infected cats are about five times more likely to develop lymphoma or leukemia than noninfected cats [26. Cutaneous horns are a benign hyperplasia of keratinocytes that have been described in FeLV-infected cats [58]. FIV provirus. Approximately 10% of FeLV-associated anemias are regenerative [74]. including squamous cell carcinoma. resulting in an immune-mediated destruction of the cell. The exact role of FeLV in the genesis of these tumors is uncertain. regressive FeLV infection without viremia may be responsible for bone marrow suppression. 4 2691 pathogenesis) have been described in FeLV-infected cats. is only occasionally detected in tumor cells [67-70]. leukemias. FeLV provirus may interrupt or inactivate cellular genes in the infected cells. however. Myelosuppression Myelosupression and other hematopoietic disorders can occur in both.59. or cyclic neutropenia. budding FeLV particles were found in the tumors and lymph node metastases. It is. and FeLV DNA was detected in tumor tissue [57]. 3. In a recent study including 37 cats with myelosuppression that tested FeLV antigen-negative in peripheral blood. such as decreased cell-mediated immune surveillance or chronic B-cell hyperplasia [68.2. FeLV and FIV infection. However. 2/37 cats (5%) were found regressively infected with FeLV by bone marrow PCR (both had non-regenerative anemia) [73]. much more common and more severe in FeLV-infected cats. most FeLV-associated anemias. Anemia in FeLV-infected cats may have various causes.72]. Although histologically benign. Hematologic changes described in association with FeLV include anemia (non-regenerative or regenerative). Lymphomas (mostly B-cell lymphomas) [26. clonally integrated FIV DNA was found in lymphoma cells from one cat that had been experimentally infected six years earlier. In spontaneous feline olfactory neuroblastomas (aggressive. are non-regenerative and are caused by the bone marrow .27.Viruses 2012. FeLV provirus may cause bone marrow disorders by inducing the expression of antigens on the cell surface. Alternatively.56]. indicating the possibility of an occasional direct oncogenic role of FIV [67.71]. but the role of FeLV is also unclear. however. and mast cell tumor. it has been demonstrated that in some FeLV antigen-negative cats. however. platelet abnormalities (thrombocytopenia and platelet function abnormalities). persistent.60]. Additionally.61-66]. The prevalence of FIV infection in one cohort of cats with lymphoma was 50% [60]. transient.

In vitro exposure of normal feline bone marrow to some strains of FeLV caused suppression of erythrogenesis [6]. FPV was also demonstrated by electron microscopy despite negative FPV antigen tests. Platelets harbor FeLV. During the acute phase of infection.Viruses 2012. In severe cases. including leukemia. It was found that changes of the LTR region of the FeLV genome (presence of three tandem direct 47-bp repeats in the upstream region of the enhancer (URE)) are strongly associated with the induction of MDS [76]. characterized by peripheral blood cytopenias and dysplastic changes in the bone marrow. is a pre-stage of acute myeloic leukemia. another cause of bone marrow suppression. and the lifespan of platelets is shortened in some FeLVinfected cats. It is still unclear whether all theses syndromes have the same origin and are simply caused by co-infection with FPV (and even modified life FPV vaccines have been discussed) or if they are caused by FeLV itself [77]. anemia of chronic inflammation promoted by high concentration of cytokines). often accompanies immune-mediated hemolytic anemia (IMHA) in cats with underlying FeLV infection. these are rather uncommon in FIV-infected cats. which rarely occurs as a single disease entity in cats. FeLV infection can cause decreased platelet counts.. and megakaryocytes are frequent targets of progressive FeLV infection. an arrest in bone marrow maturation can occur at the myelocyte and metamyelocyte stages. FeLV infection also can cause decreased neutrophil or lymphocyte counts. including hemorrhagic diarrhea. FIV-infected cats . It has been hypothesized that an immune-mediated mechanism is responsible in cases in which neutrophil counts recover with glucocorticoid treatment (“glucocorticoidresponsive neutropenia”). can also cause bone marrow suppression syndromes by crowding out. Neutropenia is common in FeLV-infected cats [75] and generally occurs alone or in conjunction with other cytopenias. The syndrome also has been referred to as FAE in cats with progressive FeLV infection because the clinical signs observed are usually gastrointestinal.g. other factors can cause nonregenerative anemia in FeLV-infected cats (e. myeloid hypoplasia of all granulocytic stages is observed. suggesting infection on neutrophil precursors. Myelodysplastic syndrome (MDS). In addition to the direct effect of the virus on erythropoiesis. oral ulceration or gingivitis. and weight loss [78. However. Myelofibrosis. Thrombocytopenia (resulting in bleeding disorders) can occur secondary to decreased platelet production from FeLV-induced bone marrow suppression or leukemic infiltration. vomiting. 4 2692 suppressive effect of the virus resulting from primary infection of hematopoietic stem cells and infection of stroma cells that constitute the supporting environment for hematopoietic cells. is a condition characterized by abnormal proliferation of fibroblasts resulting from chronic stimulation of the bone marrow. consists of severe leukopenia (< 3000 cells/μl) with enteritis and destruction of intestinal crypt epithelium that mimics feline panleukopenia caused by feline panleukopenia virus (FPV) infection. such as chronic bone marrow activity from hyperplastic or neoplastic regeneration caused by FeLV. Hematopoietic neoplasia (“myeloprolifertaive disorders”). anorexia. It appears that this syndrome might actually not be caused by FeLV itself. FPV antigen has been demonstrated by IFA in intestinal sections of cats that died from this syndrome after being experimentally infected with FeLV [77]. also known as FeLV-associated enteritis (FAE) or myeloblastopenia. but by co-infection with FPV. the entire endosteum within the medullary cavity can be obliterated. Feline panleukopenia-like syndrome (FPLS). In some cases. Although cytopenias caused by bone marrow suppression are a common finding in FeLV infection. It also can be responsible for platelet function deficits.79]. In some neutropenic FeLV-infected cats. Immunemediated thrombocytopenia. as previously thought.

The polypeptide from a FeLV-C strain was significantly more neurotoxic than the same peptide derived from a FeLV-A strain [81. These findings suggest that in some FeLV-infected cats. 4 2693 can exhibit mild neutropenia. Anemia and thrombocytopenia were not significantly more common in FIV-infected versus uninfected cats. white-matter degeneration with dilation of myelin sheaths and swollen axons was identified in the spinal cord and brain stem of affected animals [80]. Neurologic signs in 16 cats with progressive FeLV infection consisted of abnormal vocalization.Viruses 2012. urinary incontinence caused by neuropathies in FeLV-infected cats has been described [80]. in about 25% of FIV-infected cats. neuronal survival. which resolves as the cat progresses to the asymptomatic phase of infection. Anemia and neutropenia (usually mild) may also be seen [4. Some cats developed anisocoria or urinary incontinence during the course of their illness. Others had concurrent FeLV-related problems such as myelodysplastic disease. mydriasis. Anisocoria. Direct neurotoxic effects of FeLV have been discussed as pathogenetic mechanisms. central blindness. Soluble factors have been shown to inhibit bone marrow function in FIV-infected cats. The clinical course of affected cats involved gradually progressive neurologic dysfunction. FeLV-infected and uninfected cats [4]. Microscopically. About 5% of symptomatic FIV-infected cats have a neurological disease as a predominant clinical feature. but in some cases. mechanisms of neurologic dysfunction are different with both viruses. no tumor is detectable with diagnostic imaging methods or at necropsy. and glial cells. FeLV envelope glycoproteins may be able to produce increased free intracellular calcium leading to neuronal death (this has also been described in HIV-infected humans). and neurite outgrowth.3. and paresis progressing to paralysis. hyperesthesia. In FeLV-infected cats. FeLV-induced neurotoxicity is suspected. A recent study in a high number (3784) of client-owned field cats compared hematologic parameters in FIVinfected. Immunohistochemical staining of affected tissues revealed consistent expression of FeLV p27 antigens in neurons. most neurologic signs are caused by lymphoma and lymphocytic infiltrations in brain or spinal cord leading to compression. 3.51].82]. In some regions (such as the southeastern United States). Neurologic disorders in FIV infection seem to be strain-dependent [89]. However. Only neutropenia was significantly more often present. Neurologic Dysfunction Neurologic dysfunction may be present in FeLV. Clinically ill FIV-infected cats in a later phase of infection may have a variety of cytopenias. A polypeptide of the FeLV envelope was found to cause dosedependent neurotoxicity associated with alterations in intracellular calcium ion concentration. In these cats. Both central and .and in FIV-infected cats and is one of the few syndromes directly caused by the retrovirus. or Horner’s syndrome have been described in FeLV-infected cats without morphologic changes. endothelial cells. Lymphopenia is caused by direct replication of the virus in CD4+ lymphocytes. the virus may directly affect CNS cells cytopathically. with lymphopenia being most common. although these abnormalities may be as much a reflection of concurrent disease as direct effects of FIV itself. and bone marrow infection has been associated with decreased ability to support hematopoietic potential in vitro or has been proposed as a mechanism underlying the development of cytopenias [51]. Neurologic signs also have been described in both natural and experimental FIV infections [83-88]. and proviral DNA was amplified from multiple sections of the spinal cord [80].

66. twitching movements of the face and tongue. effects on the neuron supportive functions of astrocytes. The exact mechanism of neuronal damage by FIV is unclear but may include neuronal apoptosis. a much higher proportion of infected cats have microscopic CNS lesions. Abnormal forebrain electrical activity and abnormal visual and auditory-evoked potentials have also been documented in cats that appeared otherwise normal [24. Psychotic behavior. toxic products released from infected microglia. and abnormal neurologic function has been documented in FIV-infected cats with only mild to moderate histologic evidence of inflammation [8]. comparable to the changes in HIV-infected human beings.93. particularly astrocytes [8]. Documented abnormalities of astrocyte function include altered intercellular communication. Pathologic findings include the presence of perivascular infiltrates of mononuclear cells. dementia. Dementia in human patients with AIDS is often characterized by a slight decline in cognitive ability or behavior. loss of bladder and rectal control. but also can lead to decreased tumor surveillance mechanisms causing an increased risk of tumor development. Although the majority of FIV-infected cats do not show clinically overt neurologic signs.4. ataxia.and FIVinfected cats are treatable.Viruses 2012. The virus infects the brain early. or cytokines produced in response to viral infection. neuronal death has been associated with FIV infection. 4 2694 peripheral neurologic manifestations have been described. and disturbed sleep patterns have been observed. diffuse gliosis. Other signs described include nystagmus. Immunodeficiency and Secondary Infections The most clinically important consequence of both retrovirus infections is immunosuppression. forebrain signs are often a result of direct neuronal injury from the virus. It is important to realize that many of these secondary diseases in FeLV. Brain lesions may occur in the absence of massive infection. The mechanisms that cause the immunosuppression are different for the two infections. neurologic signs may also be caused by opportunistic infections such as toxoplasmosis. . midbrain. Excessive extracellular glutamate often results in neuronal toxicity and death. and alterations in mitochondrial membrane potential that disrupt the energy-producing capacities of the cell [95]. These lesions are usually located in the caudate nucleus. with virus-induced CNS lesions sometimes developing within two months of experimental infection [8]. or FIP. Microglia and astrocytes are infected by FIV. FIV infection of feline astrocytes can significantly inhibit their glutamate-scavenging ability. However. Neurological abnormalities seen in naturally infected cats tend to be more behavioral than motor. abnormal neurologic function is the result of a direct effect of the virus on CNS cells. abnormal glutathione reductase activity that could render cells more susceptible to oxidative injury. cryptococcosis. Neurologic signs upon FIV infection are highly strain-dependent.96]. and rostral brain stem [8]. seizures. One of the most important functions of astrocytes is to regulate the level of extracellular glutamate. compulsive roaming. and intention tremors [90-92]. in particular. potentially resulting in neuronal damage [95. and white matter pallor. Sometimes. glial nodules. Immunosuppression can lead to secondary infectious diseases accounting for most clinical signs. a major excitatory neurotransmitter that accumulates as a consequence of neuronal activity. Mostly. 3. In vitro studies support the hypothesis that FIV infection may impair normal metabolism in CNS cells. but the virus does not infect neurons. changes that may be too subtle to be recognized in cats.94]. Astrocytes are by far the most common cell type of the brain and are important in maintaining CNS neuronal vascular microenvironment.

renal insufficiency. including decreased response to T-cell mitogens. IFN-γ may be deficient or increased. FeLV-infected cats were not able to mount an adequate immune response to vaccines. every six months) have to be considered. In addition. such as hyperthyroidism and diabetes mellitus [78]. Some of these problems. Increased TNF-α has been observed in serum of infected cats and in infected cells in culture. depressed neutrophil function. their function remains normal. These pathogenic immunosuppressive variants. Thus. protection in a FeLV-infected cat after vaccination is not complete and not comparable to that in a healthy cat. 4 2695 Many FeLV-infected cats have concurrent bacterial. and leads to predisposition for secondary infections.Viruses 2012. but more commonly. Infections with many different “opportunistic” pathogens of viral. are most likely associated rather with the older age at which these cats presented (e. and fungal origin have been . but when B-cells of FeLV-infected cats are stimulated in vitro by uninfected T-cells. prolonged allograft reaction.g. ocular disease (uveitis and chorioretinitis).. In some cats. IL-2 and IL-4 are decreased in some cats [7. In vaccination studies. although FeLV certainly can suppress immune function. anemia and leukopenia. lower urinary tract disease. Progressively FeLV-infected cats develop immunosuppression similar to that in HIV-infected people. T-cells of FeLVinfected produce significantly lower levels of B-cell stimulatory factors than do those of normal cats (this defect becomes progressively more severe over time) [72].101]..thus. but few controlled studies exist proving that these cats have a higher rate of infection than FeLV-negative cats. require a membrane-spanning receptor molecule (Pit1) and a second co-receptor protein (FeLIX) to infect T lymphocytes [98]. and endocrinopathies. as is why different animals have such varying degrees of immunosuppression. Primary and secondary humoral antibody responses to specific antigens are decreased and may occur delayed in FeLV-infected cats. such as rabies. substantial losses of helper cells and cytotoxic suppressor cells (CD8+ cells) occur [101]. Lymphopenia and neutropenia are common. but FeLV does not appear to suppress IL-1 production from infected macrophages. Therefore. and the excess production of certain cytokines. protozoal. renal insufficiency) than with their FIV infection. protozoal. endocrinopathies. immunosuppression usually occurs in later stages of the infection. can also cause illness. neutrophils of viremic cats have decreased chemotactic and phagocytic function compared with those of normal cats. In FIV-infected cats. such as FeLV-T. reduced immunoglobulin production. such as TNF-α.102]. however. Immunosuppression has been associated with non-integrated viral DNA from replication-defective viral variants [97]. more frequent vaccinations (e. viral. and fungal infections. neoplasia (especially lymphoma and cutaneous squamous cell carcinoma). In a survey study of 826 naturally FIV-infected cats examined at North American Veterinary Teaching Hospitals. FeLV-infected cats may develop thymic atrophy and depletion of lymph node paracortical zones following infection. which is similar to the FeLV receptor-binding protein of FeLV-B [99]. resulting in an inverted CD4/CD8 ratio (as typically seen in FIV infection) [100. The latter protein is an endogenously expressed protein encoded by an endogenous provirus arising from FeLV-A. the most common disease syndromes were stomatitis. Each cytokine plays a vital role in the generation of a normal immune response. Many immune function tests of naturally FeLV-infected cats are abnormal. The exact mechanisms of how the virus destroys the immune system are poorly understood. it should not be assumed that all concurrent infections are a direct consequence of FeLV infection. lymphopenia may be characterized by preferential loss of CD4+ helper T cells. opportunistic infections.g. bacterial. and complement depletion.

and Treg cells with suppressive activity have been documented during early [129] and chronic FIV infection [130]. an increase in the proportion of CD8+ cells also contributes to the inversion [104. or cytokines and cytokine receptors [140-144]. A certain subset of CD4+ cells. Causes of CD4+ cell loss include decreased production secondary to bone marrow or thymic infection. beta-low cells” [111-113]. The produced antibodies are not neutralizing and thus.108. retrovirusinfected cats can also develop immune-mediated diseases caused by an overactive immune response. loss of CD4+ cells impairs immune responses. uveitis. polyarthritis. lysis of infected cells induced by FIV itself (cytopathic effects). 3. also seems to play an important role. but also differences in cytokine ratios (e. because CD4+ cells have critical roles in promoting and maintaining both humoral and cell-mediated immunity. In addition. 4 2696 reported in FIV-infected cats. or death by apoptosis (cell death that follows receipt of a membrane signal initiating a series of programmed intracellular events) [114-126]. Changes in cytokine pattern include increased production of IFN-γ. however.133-139]. Treg cells are themselves targets for FIV infection [129. IL-10/IL-12 ratio) [155. usually in narrow capillary beds. respectively. and thus. Impaired neutrophil adhesion and emigration in response to bacterial products have been described in FIV-infected cats [146-148]. and vasculitis. IL-4. and priming of lymphocytes by immunogens may be impaired [105.Viruses 2012. In FIV-infected cats. Immune-mediated Diseases In addition to a dysregulation of the immune system leading to immunosuppression. The degree of apoptosis correlates inversely with the CD4+ numbers and the CD4/CD8 ratio [127]. or through over-expression of abnormal molecules.131]. such as receptors [145]. In addition. Loss of CD4+ cells leads to inversion of the CD4/CD8 ratio. FIV env proteins are capable of inducing apoptosis in mononuclear cells by a mechanism that requires CXCR4 binding [128]. such as CD4. Few studies. These immune complexes can deposit. in particular a population referred to as “CD8+ alpha-hi. destruction of virusinfected cells by the immune system. and IL12 [151-154]. IL-10. The most important immunologic abnormality shown in experimental [104-106] as well as in natural [107. IL-6. in acutely or asymptomatically infected cats.g.108] infection is a decrease in the number and relative proportion of CD4+ cells in the peripheral blood as well as in most primary lymphoid tissues [109]. Secondary immune-mediated diseases are more commonly seen in FIV.156]. a subset of CD8+ cells that may contribute to suppression of viremia in FIVinfected cats. Lymphocyte function may be reduced by altered expression of cell surface molecules. leading to disrupted production of cytokines or receptor function. other immunologic abnormalities can be found. increased activity of Treg cells could thus play a role in suppressing immune responses to foreign antigens or pathogens.5..than in FeLV- . may lead to antigen antibody complex formation. Lymphocytes may lose the ability to proliferate in response to stimulation with mitogens or antigens.110]. leading to glomerulonephritis. The most commonly seen immune-mediated response is a hypergammaglobulinemia which is caused by an excessive antibody response against the chronic persistent infection. TNF-α. and may serve as a FIV reservoir during the latent stage of infection and be capable of stimulating virus production [132]. the “Treg” (for T-regulatory cells). Ultimately. In addition. Natural killer cell activity may be diminished [149] or increased [150]. major histocompatibility complex II antigens. their relevancy as true secondary invaders is unclear. have compared the prevalence of most of these infections in FIV-infected and non-infected cats.

glomerulonephritis [160]. The cause of this syndrome is unclear. In cats naturally infected with FIV. especially along the maxillary teeth. Measurement of FeLV antigen has shown that cats with glomerulonephritis have more circulating viral proteins than do other FeLV-infected cats. and experimental and naturally occurring co-infection of FIV and FCV infection results in more severe disease [168. Immunemediated diseases described in FeLV-infected cats include IMHA [159]. especially in those with FIV infection. nonspecific increases of IgG and IgM have been noted. hypergammaglobulinemia and hyperproteinemia occur significantly more commonly [4.Viruses 2012.169]. FeLV seems to be an associated agent [58].164]. Immune-mediated diseases observed in FIV-infected cats are caused by an excessive immune response leading to hypergammaglobulinemia [4.163].157]. Circulating lymphocytes of cats with stomatitis have increased expression of inflammatory cytokines [103]. Nevertheless. Histologically. and is usually not seen in SPF cats experimentally infected with FeLV or FIV. Increased IgG as well as circulating immune complexes have been detected in FIV-infected cats [165]. While humoral immunity to specific stimulation decreases during the course of FeLV infection. It characteristically originates in the fauces and spreads rostrally. especially in indoor-only households. Still. but the histologic findings suggest an immune response to chronic antigenic stimulation or immune dysregulation. the mucosa is invaded by plasma cells and lymphocytes. suggesting that exposure to other infectious agents also plays a role [167]. and tooth loss is common. or p15E proteins [162. further implicating immune activation in the pathogenesis of this condition. it is the most common syndrome (affecting up to 50%). uveitis with immune complex deposition in iris and ciliary body [161].104. many owners still elect to provide therapy for their FeLV-infected cats. Conclusions FeLV can cause severe clinical syndromes. Lesions are often painful. Antigens that can lead to antigen antibody complex formation include not only whole virus particles. Chronic progressive polyarthritis can be triggered by FeLV. but also free gp70. accompanied by variable degrees of neutrophilic and eosinophilic inflammation. Hypergammaglobulinemia reflects polyclonal B-cell stimulation and is a direct consequence of FIV infection. in about 20% of cats with polyarthritis. because experimentally FIV-infected specific pathogen-free (SPF) healthy cats also develop hypergammaglobulinemia [164]. may live for . as well as polyarthritis [58]. whereas in FIV-infection. FeLV-infected cats do not show hypergammaglobulinemia and hyperproteinemia significantly more often than non-infected cats. Stomatitis Chronic ulcero-proliferative gingivostomatitis is very common in retrovirus-infected cats. Severe stomatitis can lead to anorexia and emaciation. and with proper treatment. When comparing plasma electrophoretograms. 4. FeLV-infected cats. p27. This type of stomatitis is not always correlated with FeLV or FIV infection [166]. immune-mediated diseases have been described in FeLV-infected cats as well. 4 2697 infected cats. The loss of T-cell activity in combination with the formation of antigen antibody complexes promotes immune dysregulation [158]. and progressive FeLV infection is associated with a decrease in life expectancy. Concurrent feline calicivirus (FCV) infection is often identified in the oral cavity of these cats.6. 3.

direct influence of the virus (specific FIV strains). lymphoma and neurotoxic effects (of FeLV envelope glycoprotein) common. While long-term studies describing clinical outcomes of naturally occurring FeLV and FIV infection are lacking. multi-factorial disease FIV 5-times as likely as in noninfected cats. changes in cytokine pattern rare. several mechanisms..g. pancytopenia. commonly die at an old age from causes unrelated to their FIV infection. direct role of FeLV. glomerulonephritis and uveitis very common. primary infection of bone marrow precursor cells and stroma cells rare. decrease in CD4+ cells. FIV-infected cats can live many years and. Diseases secondary to immunosuppression account for a large portion of the syndromes seen in FeLV-infected cats... thrombocytopenia. Most clinical signs in FIV-infected cats reflect secondary diseases. hyperglobulinemia common with immune complex deposition leading to e. With proper care.and FIVinfected animals can be significantly improved.g. soluble factors inhibiting bone marrow function rare. mainly neutropenia. such as infections and neoplasia. several mechanisms. . e. multi-factorial disease Bone marrow suppression Neurologic disorders Immunodeficiency Immune-mediated diseases Stomatitis Acknowledgments Many doctoral students have contributed to various parts of the author’s publications cited in this paper and are acknowledged for all their hard work. replication of virus in all bone marrow cells (including neutrophils). indirect role of FIV..g. 4 2698 many years with good quality of life. direct influence of the virus. changes in cytokine pattern sometimes. e. and it is important to realize that many of these secondary diseases are treatable. mainly B-cell lymphoma rare.g. Comparison of clinical signs and their main pathomechanism in feline leukemia virus-(FeLV-) infected and feline immunodeficiency virus-(FIV-) infected cats Clinical syndrome Tumors FeLV 62-times as likely as in noninfected cats. the life expectancy and quality of life of FeLV. impairment of astrocyte function common. and by treating these symptomatically. modalities for treatment of secondary infections or other co-incident diseases are available. to which FIV-infected cats are more susceptible. e.Viruses 2012. in fact. mainly T-cell lymphoma common. immune-mediated hemolytic anemia common. neutropenia. In most naturally infected cats. Table 2. anemia. FIV does not cause a severe clinical syndrome.

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