While FeLV-infected cats are 62-times more likely to develop lymphoma or leukemia than non-infected cats and FeLV plays a direct role in tumorgenesis, FIV-infected cats have about a five-fold increased risk of tumor development, and the role of FIV is usually indirect. Lymphomas are the most common tumors in FeLV- and FIV-infected cats. While FeLV-infected cats have most commonly T-cell lymphomas, lymphomas in FIV are mostly of B-cell origin [26,27].

FeLV is a major oncogene that causes different tumors in cats, most commonly lymphoma and leukemia, less often other hematopoietic tumors and rarely other malignancies (including neuroblastoma, osteochondroma, and others). The association between FeLV and lymphomas has been clearly established in several ways. First, these malignancies can be induced in kittens by experimental FeLV infection [28,29,30]. Second, cats naturally infected with FeLV have a higher risk of developing lymphoma than uninfected cats [29,31]. Third, 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. Previously, up to 80% of feline lymphomas and leukemias were reported to be FeLV-related [32,33,34,35,36,37,38]. However, since the 1980s a reduction in the prevalence of viremia has been noted in cats with lymphoma [39,40,41]. The decrease in prevalence of FeLV infection in cats with lymphoma or leukemia also indicates a shift in tumor causation in recent years. Whereas 59% of all cats with lymphoma or leukemia were FeLV antigen-positive in one German study from 1980 to 1995, only 20% of the cats were FeLV antigen-positive in the years 1996 to 1999 in the same University Teaching Hospital [41]. In a recent study in the Netherlands, only four of 71 cats with lymphoma were FeLV-positive, although 22 of these cats had mediastinal lymphoma, which previously was strongly associated with FeLV infection [42]. A greater prevalence of lymphoma in older-age cats in now observed. 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. However, prevalence of lymphomas caused by FeLV may be higher than indicated by conventional antigen testing of blood [43]. Cats from FeLV cluster households had a 40-fold higher rate of development of FeLV-negative lymphoma than did those from the general population. FeLV-negative lymphomas have also occurred in laboratory cats known to have been infected previously with FeLV [44]. FeLV proviral DNA was detected in lymphomas of cats that tested negative for FeLV antigen [43], also suggesting that the virus may be associated with a larger proportion of lymphomas than previously thought. FeLV has been shown to incorporate cellular genes; several such transducted genes also present in regressively infected cells have been implicated in viral oncogenesis [44,45,46]. It is still unclear, how common regressive FeLV infection is responsible for FeLV-associated tumors in the field as study results have been controversial. Proviral DNA was detected in formalin-fixed, paraffin-embedded tumor tissue in 7/11 FeLV-negative cats with lymphoma [43]. However, other groups found evidence of provirus in only 1/22 [45] and in 0/50 FeLV antigen-negative lymphomas [47].

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), resulting in activation and over-expression of that gene. These effects lead to uncontrolled proliferation of these cells (clone). A malignancy results in the absence of an appropriate immune response. FeLV may also incorporate the oncogene to form a recombinant virus (e.g., FeLV-B, FeSV) containing cellular oncogene sequences that are then rearranged and activated. When they enter a new cell, these recombinant viruses are oncogenic. In a study of 119 cats with lymphomas, transduction or insertion of the myc locus had occurred in 38 cats (32%) [48]. Thus, FeLV-induced neoplasms are caused, at least in part, by somatically acquired insertional mutagenesis in which the integrated provirus may activate a proto-oncogene or disrupt a tumor suppressor gene. 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]. Twelve common integration sites for FeLV associated with lymphoma development have been identified in six loci: c-myc, flvi-1, flvi-2 (contains bmi-1), fit-1, pim-1, and flit-1. Oncogenic association of the loci is based on the fact that c-myc is known as a proto-oncogene, bmi-1 and pim-1 have been recognized as myc-collaborators, fit-1 appears to be closely linked to myb, and flit-1 insertion was shown to be associated with over-expression of cellular genes, e.g., activin-A receptor type II-like 1 (ACVRL1). [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. Among 35 FeLV-related tumors, 5/25 thymic lymphomas demonstrated proviral insertion within flit-1 locus, whereas 0/4 alimentary lymphomas, 5/5 multicentric lymphomas, and 1/1 T-lymphoid leukemia examined had rearrangements in this region. Expression of ACVRL1 mRNA was detected in the two thymic lymphomas with flit-1 rearrangement, whereas normal thymuses and seven lymphoid tumors without flit-1 rearrangement had no detectable ACVRL1 mRNA expression [51].

Fibrosarcomas that are associated with FeLV are caused by FeSV, a recombinant virus that develops de novo in FeLV-A-infected cats by recombination of the FeLV-A genome with cellular oncogenes. Through a process of genetic recombination, FeSV acquires one of several oncogenes, such as fes, fms, or fgr. As a result, FeSV is an acutely transforming (tumor-causing) virus, leading to a polyclonal malignancy with multifocal tumors arising simultaneously after a short incubation period. With the decrease in FeLV prevalence, FeSV also has become less common. FeSV-induced fibrosarcomas are multicentric and usually occur in young cats. 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. Fibrosarcomas caused by FeSV tend to grow rapidly, often with multiple cutaneous or subcutaneous nodules that are locally invasive and metastasize to the lung and other sites. Solitary fibrosarcomas in older cats are not caused by FeSV. These tumors are slower growing, locally invasive, slower metastasizing, and only occasionally curable by excision combined with radiation and/or gene therapy. They usually are classified as feline injection site sarcomas (FISS) caused by the granulomatous inflammatory reaction at the injection site, commonly occurring after inoculation of adjuvant-containing vaccines. It has been demonstrated that neither FeSV nor FeLV play any role in the development of FISS [52].

A few other tumors have been found in FeLV-infected cats; some of them might have an association with FeLV, others likely have just been observed by chance simultaneously in an infected cat. Iris melanomas, for example, are not associated with FeLV infections, although in one study three of 18 eyes tested positive for FeLV/FeSV proviral DNA [53]. In a more recent study, however, immunohistochemical staining and PCR did not find FeLV or FeSV in the ocular tissues of any cat with this disorder [54]. Multiple osteochondromas (cartilaginous exostoses on flat bones of unknown pathogenesis) have been described in FeLV-infected cats. Although histologically benign, 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 [55,56]. In spontaneous feline olfactory neuroblastomas (aggressive, histologically inhomogenous tumors of the tasting and smelling epithelium of nose and pharynx with high metastasis rates), budding FeLV particles were found in the tumors and lymph node metastases, and FeLV DNA was detected in tumor tissue [57]. The exact role of FeLV in the genesis of these tumors is uncertain. Cutaneous horns are a benign hyperplasia of keratinocytes that have been described in FeLV-infected cats [58], but the role of FeLV is also unclear.

FIV-infected cats are about five times more likely to develop lymphoma or leukemia than non-infected cats [26,27]. Lymphomas (mostly B-cell lymphomas) [26,27,59,60], leukemias, but also several other tumors have been described in association with FIV infection [26,61,62,63,64,65,66], including squamous cell carcinoma, fibrosarcoma, and mast cell tumor. FIV provirus, however, is only occasionally detected in tumor cells [67,68,69,70], suggesting a more indirect role in lymphoma formation, such as decreased cell-mediated immune surveillance or chronic B-cell hyperplasia [68,71]. However, clonally integrated FIV DNA was found in lymphoma cells from one cat that had been experimentally infected six years earlier, indicating the possibility of an occasional direct oncogenic role of FIV [67,70,72]. The prevalence of FIV infection in one cohort of cats with lymphoma was 50% [60], much higher than the FIV prevalence in the population of cats without lymphomas, which is also supportive of a cause and effect relationship. FIV could alternatively increase tumor incidence by decreasing tumor immunosurveillance mechanisms. It also could promote tumor development through the immunostimulatory effects of replicating in lymphocytes.

Myelosupression and other hematopoietic disorders can occur in both, FeLV and FIV infection. It is, however, much more common and more severe in FeLV-infected cats.

Hematologic changes described in association with FeLV include anemia (non-regenerative or regenerative), persistent, transient, or cyclic neutropenia, platelet abnormalities (thrombocytopenia and platelet function abnormalities), aplastic anemia (pancytopenia), and panleukopenia-like syndrome. For the majority of pathogenic mechanisms in which FeLV causes bone marrow suppression, active virus replication is required. However, it has been demonstrated that in some FeLV antigen-negative cats, regressive FeLV infection without viremia may be responsible for bone marrow suppression. In a recent study including 37 cats with myelosuppression that tested FeLV antigen-negative in peripheral blood, 2/37 cats (5%) were found regressively infected with FeLV by bone marrow PCR (both had non-regenerative anemia) [73]. In these regressively infected cats, FeLV provirus may interrupt or inactivate cellular genes in the infected cells, or regulatory features of viral DNA may alter expression of neighboring genes. Additionally, cell function of provirus-containing myelomonocytic progenitor and stromal fibroblasts that provide bone marrow microenvironment may be altered. Alternatively, FeLV provirus may cause bone marrow disorders by inducing the expression of antigens on the cell surface, resulting in an immune-mediated destruction of the cell. Anemia is a major non-neoplastic complication that occurs in a majority of FeLV-infected cats [4]. Anemia in FeLV-infected cats may have various causes. Approximately 10% of FeLV-associated anemias are regenerative [74], most FeLV-associated anemias, however, are non-regenerative and are caused by the bone marrow 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. In vitro exposure of normal feline bone marrow to some strains of FeLV caused suppression of erythrogenesis [6]. In addition to the direct effect of the virus on erythropoiesis, other factors can cause non-regenerative anemia in FeLV-infected cats (e.g., anemia of chronic inflammation promoted by high concentration of cytokines). FeLV infection can cause decreased platelet counts. It also can be responsible for platelet function deficits, and the lifespan of platelets is shortened in some FeLV-infected cats. Thrombocytopenia (resulting in bleeding disorders) can occur secondary to decreased platelet production from FeLV-induced bone marrow suppression or leukemic infiltration. Platelets harbor FeLV, and megakaryocytes are frequent targets of progressive FeLV infection. Immune-mediated thrombocytopenia, which rarely occurs as a single disease entity in cats, often accompanies immune-mediated hemolytic anemia (IMHA) in cats with underlying FeLV infection. FeLV infection also can cause decreased neutrophil or lymphocyte counts. Neutropenia is common in FeLV-infected cats [75] and generally occurs alone or in conjunction with other cytopenias. In some cases, myeloid hypoplasia of all granulocytic stages is observed, suggesting infection on neutrophil precursors. In some neutropenic FeLV-infected cats, an arrest in bone marrow maturation can occur at the myelocyte and metamyelocyte stages. It has been hypothesized that an immune-mediated mechanism is responsible in cases in which neutrophil counts recover with glucocorticoid treatment (“glucocorticoid-responsive neutropenia”).

Hematopoietic neoplasia (“myeloprolifertaive disorders”), including leukemia, can also cause bone marrow suppression syndromes by crowding out. Myelodysplastic syndrome (MDS), characterized by peripheral blood cytopenias and dysplastic changes in the bone marrow, is a pre-stage of acute myeloic 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]. Myelofibrosis, another cause of bone marrow suppression, is a condition characterized by abnormal proliferation of fibroblasts resulting from chronic stimulation of the bone marrow, such as chronic bone marrow activity from hyperplastic or neoplastic regeneration caused by FeLV. In severe cases, the entire endosteum within the medullary cavity can be obliterated.

Feline panleukopenia-like syndrome (FPLS), also known as FeLV-associated enteritis (FAE) or myeloblastopenia, 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. However, FPV antigen has been demonstrated by IFA in intestinal sections of cats that died from this syndrome after being experimentally infected with FeLV [77]. FPV was also demonstrated by electron microscopy despite negative FPV antigen tests. It appears that this syndrome might actually not be caused by FeLV itself, as previously thought, but by co-infection with FPV. The syndrome also has been referred to as FAE in cats with progressive FeLV infection because the clinical signs observed are usually gastrointestinal, including hemorrhagic diarrhea, vomiting, oral ulceration or gingivitis, anorexia, and weight loss [78,79]. 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].

Although cytopenias caused by bone marrow suppression are a common finding in FeLV infection, these are rather uncommon in FIV-infected cats. During the acute phase of infection, FIV-infected cats can exhibit mild neutropenia, which resolves as the cat progresses to the asymptomatic phase of infection. Clinically ill FIV-infected cats in a later phase of infection may have a variety of cytopenias, with lymphopenia being most common. Lymphopenia is caused by direct replication of the virus in CD4⁺ lymphocytes. Anemia and neutropenia (usually mild) may also be seen [4,51], although these abnormalities may be as much a reflection of concurrent disease as direct effects of FIV itself. A recent study in a high number (3784) of client-owned field cats compared hematologic parameters in FIV-infected, FeLV-infected and uninfected cats [4]. Anemia and thrombocytopenia were not significantly more common in FIV-infected versus uninfected cats. Only neutropenia was significantly more often present, in about 25% of FIV-infected cats. Soluble factors have been shown to inhibit bone marrow function in FIV-infected cats, 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 dysfunction may be present in FeLV- and in FIV-infected cats and is one of the few syndromes directly caused by the retrovirus. However, mechanisms of neurologic dysfunction are different with both viruses.

In FeLV-infected cats, most neurologic signs are caused by lymphoma and lymphocytic infiltrations in brain or spinal cord leading to compression, but in some cases, no tumor is detectable with diagnostic imaging methods or at necropsy. In these cats, FeLV-induced neurotoxicity is suspected. Anisocoria, mydriasis, central blindness, or Horner’s syndrome have been described in FeLV-infected cats without morphologic changes. In some regions (such as the southeastern United States), urinary incontinence caused by neuropathies in FeLV-infected cats has been described [80]. Direct neurotoxic effects of FeLV have been discussed as pathogenetic mechanisms. 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). A polypeptide of the FeLV envelope was found to cause dose-dependent neurotoxicity associated with alterations in intracellular calcium ion concentration, neuronal survival, and neurite outgrowth. The polypeptide from a FeLV-C strain was significantly more neurotoxic than the same peptide derived from a FeLV-A strain [81,82]. Neurologic signs in 16 cats with progressive FeLV infection consisted of abnormal vocalization, hyperesthesia, and paresis progressing to paralysis. Some cats developed anisocoria or urinary incontinence during the course of their illness. Others had concurrent FeLV-related problems such as myelodysplastic disease. The clinical course of affected cats involved gradually progressive neurologic dysfunction. Microscopically, white-matter degeneration with dilation of myelin sheaths and swollen axons was identified in the spinal cord and brain stem of affected animals [80]. Immunohistochemical staining of affected tissues revealed consistent expression of FeLV p27 antigens in neurons, endothelial cells, and glial cells, and proviral DNA was amplified from multiple sections of the spinal cord [80]. These findings suggest that in some FeLV-infected cats, the virus may directly affect CNS cells cytopathically.

Neurologic signs also have been described in both natural and experimental FIV infections [83,84,85,86,87,88]. About 5% of symptomatic FIV-infected cats have a neurological disease as a predominant clinical feature. Neurologic disorders in FIV infection seem to be strain-dependent [89]. Both central and peripheral neurologic manifestations have been described, comparable to the changes in HIV-infected human beings. Dementia in human patients with AIDS is often characterized by a slight decline in cognitive ability or behavior, changes that may be too subtle to be recognized in cats. Neurological abnormalities seen in naturally infected cats tend to be more behavioral than motor. Psychotic behavior, twitching movements of the face and tongue, compulsive roaming, dementia, loss of bladder and rectal control, and disturbed sleep patterns have been observed. Other signs described include nystagmus, ataxia, seizures, and intention tremors [90,91,92]. Abnormal forebrain electrical activity and abnormal visual and auditory-evoked potentials have also been documented in cats that appeared otherwise normal [24,66,93,94]. Although the majority of FIV-infected cats do not show clinically overt neurologic signs, a much higher proportion of infected cats have microscopic CNS lesions. Brain lesions may occur in the absence of massive infection, and abnormal neurologic function has been documented in FIV-infected cats with only mild to moderate histologic evidence of inflammation [8]. Pathologic findings include the presence of perivascular infiltrates of mononuclear cells, diffuse gliosis, glial nodules, and white matter pallor. These lesions are usually located in the caudate nucleus, midbrain, and rostral brain stem [8]. Mostly, abnormal neurologic function is the result of a direct effect of the virus on CNS cells. Neurologic signs upon FIV infection are highly strain-dependent. The virus infects the brain early, with virus-induced CNS lesions sometimes developing within two months of experimental infection [8]. Microglia and astrocytes are infected by FIV, but the virus does not infect neurons. However, neuronal death has been associated with FIV infection; in particular, forebrain signs are often a result of direct neuronal injury from the virus. The exact mechanism of neuronal damage by FIV is unclear but may include neuronal apoptosis, effects on the neuron supportive functions of astrocytes, toxic products released from infected microglia, or cytokines produced in response to viral infection. In vitro studies support the hypothesis that FIV infection may impair normal metabolism in CNS cells, particularly astrocytes [8]. Documented abnormalities of astrocyte function include altered intercellular communication, abnormal glutathione reductase activity that could render cells more susceptible to oxidative injury, and alterations in mitochondrial membrane potential that disrupt the energy-producing capacities of the cell [95]. Astrocytes are by far the most common cell type of the brain and are important in maintaining CNS neuronal vascular microenvironment. One of the most important functions of astrocytes is to regulate the level of extracellular glutamate, a major excitatory neurotransmitter that accumulates as a consequence of neuronal activity. Excessive extracellular glutamate often results in neuronal toxicity and death. FIV infection of feline astrocytes can significantly inhibit their glutamate-scavenging ability, potentially resulting in neuronal damage [95,96]. Sometimes, neurologic signs may also be caused by opportunistic infections such as toxoplasmosis, cryptococcosis, or FIP.

The most clinically important consequence of both retrovirus infections is immunosuppression. Immunosuppression can lead to secondary infectious diseases accounting for most clinical signs, but also can lead to decreased tumor surveillance mechanisms causing an increased risk of tumor development. It is important to realize that many of these secondary diseases in FeLV- and FIV-infected cats are treatable. The mechanisms that cause the immunosuppression are different for the two infections.

Many FeLV-infected cats have concurrent bacterial, viral, protozoal, and fungal infections, but few controlled studies exist proving that these cats have a higher rate of infection than FeLV-negative cats. Thus, although FeLV certainly can suppress immune function, it should not be assumed that all concurrent infections are a direct consequence of FeLV infection. Progressively FeLV-infected cats develop immunosuppression similar to that in HIV-infected people. The exact mechanisms of how the virus destroys the immune system are poorly understood, as is why different animals have such varying degrees of immunosuppression. Immunosuppression has been associated with non-integrated viral DNA from replication-defective viral variants [97]. These pathogenic immunosuppressive variants, such as FeLV-T, require a membrane-spanning receptor molecule (Pit1) and a second co-receptor protein (FeLIX) to infect T lymphocytes [98]. The latter protein is an endogenously expressed protein encoded by an endogenous provirus arising from FeLV-A, which is similar to the FeLV receptor-binding protein of FeLV-B [99].

FeLV-infected cats may develop thymic atrophy and depletion of lymph node paracortical zones following infection. Lymphopenia and neutropenia are common. In addition, neutrophils of viremic cats have decreased chemotactic and phagocytic function compared with those of normal cats. In some cats, lymphopenia may be characterized by preferential loss of CD4⁺ helper T cells, resulting in an inverted CD4/CD8 ratio (as typically seen in FIV infection) [100,101], but more commonly, substantial losses of helper cells and cytotoxic suppressor cells (CD8⁺ cells) occur [101]. Many immune function tests of naturally FeLV-infected cats are abnormal, including decreased response to T-cell mitogens, prolonged allograft reaction, reduced immunoglobulin production, depressed neutrophil function, and complement depletion. IL-2 and IL-4 are decreased in some cats [7,102], but FeLV does not appear to suppress IL-1 production from infected macrophages. IFN-γ may be deficient or increased. Increased TNF-α has been observed in serum of infected cats and in infected cells in culture. Each cytokine plays a vital role in the generation of a normal immune response, and the excess production of certain cytokines, such as TNF-α, can also cause illness. T-cells of FeLV-infected produce significantly lower levels of B-cell stimulatory factors than do those of normal cats (this defect becomes progressively more severe over time) [72], but when B-cells of FeLV-infected cats are stimulated in vitro by uninfected T-cells, their function remains normal. Primary and secondary humoral antibody responses to specific antigens are decreased and may occur delayed in FeLV-infected cats. In vaccination studies, FeLV-infected cats were not able to mount an adequate immune response to vaccines, such as rabies. Therefore, protection in a FeLV-infected cat after vaccination is not complete and not comparable to that in a healthy cat;thus, more frequent vaccinations (e.g., every six months) have to be considered.

In FIV-infected cats, immunosuppression usually occurs in later stages of the infection, and leads to predisposition for secondary infections. In a survey study of 826 naturally FIV-infected cats examined at North American Veterinary Teaching Hospitals, the most common disease syndromes were stomatitis, neoplasia (especially lymphoma and cutaneous squamous cell carcinoma), ocular disease (uveitis and chorioretinitis), anemia and leukopenia, opportunistic infections, renal insufficiency, lower urinary tract disease, and endocrinopathies, such as hyperthyroidism and diabetes mellitus [78]. Some of these problems, however, are most likely associated rather with the older age at which these cats presented (e.g., endocrinopathies, renal insufficiency) than with their FIV infection. Infections with many different “opportunistic” pathogens of viral, bacterial, protozoal, and fungal origin have been reported in FIV-infected cats. Few studies, however, have compared the prevalence of most of these infections in FIV-infected and non-infected cats, and thus, their relevancy as true secondary invaders is unclear.

The most important immunologic abnormality shown in experimental [104,105,106] as well as in natural [107,108] 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]. Loss of CD4⁺ cells leads to inversion of the CD4/CD8 ratio. In addition, an increase in the proportion of CD8⁺ cells also contributes to the inversion [104,108,110], in particular a population referred to as “CD8⁺ alpha-hi, beta-low cells” [111,112,113], a subset of CD8⁺ cells that may contribute to suppression of viremia in FIV-infected cats. Causes of CD4⁺ cell loss include decreased production secondary to bone marrow or thymic infection, lysis of infected cells induced by FIV itself (cytopathic effects), destruction of virus-infected cells by the immune system, or death by apoptosis (cell death that follows receipt of a membrane signal initiating a series of programmed intracellular events) [114,115,116,117,118,119,120,121,122,123,124,125,126]. The degree of apoptosis correlates inversely with the CD4⁺ numbers and the CD4/CD8 ratio [127]. FIV env proteins are capable of inducing apoptosis in mononuclear cells by a mechanism that requires CXCR4 binding [128]. Ultimately, loss of CD4+ cells impairs immune responses, because CD4⁺ cells have critical roles in promoting and maintaining both humoral and cell-mediated immunity. A certain subset of CD4⁺ cells, the “Treg” (for T-regulatory cells), also seems to play an important role, and Treg cells with suppressive activity have been documented during early [129] and chronic FIV infection [130]. In FIV-infected cats, increased activity of Treg cells could thus play a role in suppressing immune responses to foreign antigens or pathogens. In addition, Treg cells are themselves targets for FIV infection [129,131], and may serve as a FIV reservoir during the latent stage of infection and be capable of stimulating virus production [132]. In addition, other immunologic abnormalities can be found. Lymphocytes may lose the ability to proliferate in response to stimulation with mitogens or antigens, and priming of lymphocytes by immunogens may be impaired [105,133,134,135,136,137,138,139]. Lymphocyte function may be reduced by altered expression of cell surface molecules, such as CD4, major histocompatibility complex II antigens, or cytokines and cytokine receptors [140,141,142,143,144], or through over-expression of abnormal molecules, such as receptors [145], leading to disrupted production of cytokines or receptor function. Impaired neutrophil adhesion and emigration in response to bacterial products have been described in FIV-infected cats [146,147,148]. Natural killer cell activity may be diminished [149] or increased [150], in acutely or asymptomatically infected cats, respectively. Changes in cytokine pattern include increased production of IFN-γ, TNF-α, IL-4, IL-6, IL-10, and IL-12 [151,152,153,154], but also differences in cytokine ratios (e.g., IL-10/IL-12 ratio) [155,156].

In addition to a dysregulation of the immune system leading to immunosuppression, retrovirus-infected cats can also develop immune-mediated diseases caused by an overactive immune response. The most commonly seen immune-mediated response is a hypergammaglobulinemia which is caused by an excessive antibody response against the chronic persistent infection. The produced antibodies are not neutralizing and thus, may lead to antigen antibody complex formation. These immune complexes can deposit, usually in narrow capillary beds, leading to glomerulonephritis, polyarthritis, uveitis, and vasculitis. Secondary immune-mediated diseases are more commonly seen in FIV- than in FeLV-infected cats. When comparing plasma electrophoretograms, FeLV-infected cats do not show hypergammaglobulinemia and hyperproteinemia significantly more often than non-infected cats, whereas in FIV-infection, hypergammaglobulinemia and hyperproteinemia occur significantly more commonly [4,157].

Nevertheless, immune-mediated diseases have been described in FeLV-infected cats as well. While humoral immunity to specific stimulation decreases during the course of FeLV infection, nonspecific increases of IgG and IgM have been noted. The loss of T-cell activity in combination with the formation of antigen antibody complexes promotes immune dysregulation [158]. Immune-mediated diseases described in FeLV-infected cats include IMHA [159], glomerulonephritis [160], uveitis with immune complex deposition in iris and ciliary body [161], as well as polyarthritis [58]. Chronic progressive polyarthritis can be triggered by FeLV; in about 20% of cats with polyarthritis, FeLV seems to be an associated agent [58]. Measurement of FeLV antigen has shown that cats with glomerulonephritis have more circulating viral proteins than do other FeLV-infected cats. Antigens that can lead to antigen antibody complex formation include not only whole virus particles, but also free gp70, p27, or p15E proteins [162,163].

Immune-mediated diseases observed in FIV-infected cats are caused by an excessive immune response leading to hypergammaglobulinemia [4,104,164]. Hypergammaglobulinemia reflects polyclonal B-cell stimulation and is a direct consequence of FIV infection, because experimentally FIV-infected specific pathogen-free (SPF) healthy cats also develop hypergammaglobulinemia [164]. Increased IgG as well as circulating immune complexes have been detected in FIV-infected cats [165].

Chronic ulcero-proliferative gingivostomatitis is very common in retrovirus-infected cats, especially in those with FIV infection. In cats naturally infected with FIV, it is the most common syndrome (affecting up to 50%). It characteristically originates in the fauces and spreads rostrally, especially along the maxillary teeth. Histologically, the mucosa is invaded by plasma cells and lymphocytes, accompanied by variable degrees of neutrophilic and eosinophilic inflammation. Lesions are often painful, and tooth loss is common. Severe stomatitis can lead to anorexia and emaciation. The cause of this syndrome is unclear, but the histologic findings suggest an immune response to chronic antigenic stimulation or immune dysregulation. Circulating lymphocytes of cats with stomatitis have increased expression of inflammatory cytokines [103], further implicating immune activation in the pathogenesis of this condition. This type of stomatitis is not always correlated with FeLV or FIV infection [166], and is usually not seen in SPF cats experimentally infected with FeLV or FIV, suggesting that exposure to other infectious agents also plays a role [167]. Concurrent feline calicivirus (FCV) infection is often identified in the oral cavity of these cats, and experimental and naturally occurring co-infection of FIV and FCV infection results in more severe disease [168,169].