key: cord-0860189-rram4a0i
authors: Hosie, Margaret J.; Addie, Diane; Belák, Sándor; Boucraut-Baralon, Corine; Egberink, Herman; Frymus, Tadeusz; Gruffydd-Jones, Tim; Hartmann, Katrin; Lloret, Albert; Lutz, Hans; Marsilio, Fulvio; Pennisi, Maria Grazia; Radford, Alan D.; Thiry, Etienne; Truyen, Uwe; Horzinek, Marian C.
title: Feline immunodeficiency. ABCD guidelines on prevention and management
date: 2009-07-31
journal: Journal of Feline Medicine & Surgery
DOI: 10.1016/j.jfms.2009.05.006
sha: 64b06251c5c81f276a0a536dca9bf9cdd5997bf3
doc_id: 860189
cord_uid: rram4a0i

Abstract Overview Feline immunodeficiency virus (FIV) is a retrovirus closely related to human immunodeficiency virus. Most felids are susceptible to FIV, but humans are not. Feline immunodeficiency virus is endemic in domestic cat populations worldwide. The virus loses infectivity quickly outside the host and is susceptible to all disinfectants. Infection Feline immunodeficiency virus is transmitted via bites. The risk of transmission is low in households with socially well-adapted cats. Transmission from mother to kittens may occur, especially if the queen is undergoing an acute infection. Cats with FIV are persistently infected in spite of their ability to mount antibody and cell-mediated immune responses. Disease signs Infected cats generally remain free of clinical signs for several years, and some cats never develop disease, depending on the infecting isolate. Most clinical signs are the consequence of immunodeficiency and secondary infection. Typical manifestations are chronic gingivostomatitis, chronic rhinitis, lymphadenopathy, weight loss and immune-mediated glomerulonephritis. Diagnosis Positive in-practice ELISA results obtained in a low-prevalence or low-risk population should always be confirmed by a laboratory. Western blot is the ‘gold standard’ laboratory test for FIV serology. PCR-based assays vary in performance. Disease management Cats should never be euthanased solely on the basis of an FIV-positive test result. Cats infected with FIV may live as long as uninfected cats, with appropriate management. Asymptomatic FIV-infected cats should be neutered to avoid fighting and virus transmission. Infected cats should receive regular veterinary health checks. They can be housed in the same ward as other patients, but should be kept in individual cages. Vaccination recommendations At present, there is no FIV vaccine commercially available in Europe. Potential benefits and risks of vaccinating FIV-infected cats should be assessed on an individual cat basis. Needles and surgical instruments used on FIV-positive cats may transmit the virus to other cats, so strict hygiene is essential.

Since FIV was discovered in 1986, serological studies have demonstrated that it is endemic in domestic cat populations worldwide; the seroprevalence of FIV is highly variable between regions, with estimates of 1-14% in cats with no clinical signs and up to 44% in sick cats. 10, 11 Sick adult cats, male cats and free-roaming cats are most likely to be infected. 12 The major route of natural transmission is via biting. 13 Vertical transmission and transmission between cats in stable households is relatively uncommon.

Transmission from mother to kittens may occur but only some offspring become persistently infected, the proportion depending on the viral load of the queen during pregnancy and birth. If the queen is acutely infected, up to 70% of the kittens may become infected. If the seropositive queen is healthy, few kittens will be infected. 14, 15 Although neither oronasal nor venereal spread has been documented in nature, cats can be infected experimentally by virus inoculation into the nose, mouth, vagina and rectum, and virus can be recovered from semen after natural and experimental infection. 16, 17 Queens may be infected at mating if bitten by an infected tom cat.

The major targets for FIV infection are activated CD4+ T lymphocytes. These cells typically function as T helper cells, which have a central role in immune function, facilitating the development of humoral and cell-mediated immunity. The FIV envelope glycoprotein gp120 binds to a primary receptor on the cell surface, the CD134 molecule. 18, 19 The viral reverse transcriptase that mediates transcription of the RNA genome into a DNA copy (or provirus) is error-prone and lacks a proofreading function; thus FIV mutates rapidly and displays great genetic diversity. Viral variants may evade immune detection and hamper the development of molecular diagnostic techniques and vaccines.

Infections become latent when a cell has integrated a provirus copy but does not produce virus particles -unless the cell becomes activated. Latently infected cells represent a 'reservoir' of infection that is not reached by neutralising antibodies, posing an obstacle for effective vaccination.

In the first few days after experimental infection, FIV replicates in dendritic cells, macrophages and CD4+ T lymphocytes, and within 2 weeks appears in the plasma. Both the virus levels in plasma and proviral DNA in the blood mononuclear cells increase, reaching a peak 8-12 weeks after infection. During this period, mild to moderate clinical signs such as anorexia, depression and fever may be observed. These conditions usually subside rapidly; in contrast, signs such as generalised lymphadenopathy, due to increased numbers and size of active germinal centres in the lymph nodes, may persist for weeks or months. The decrease in plasma viral load marks the beginning of the so-called 'asymptomatic' phase that can last for years (and may be lifelong). It is assumed that viral replication is controlled by the immune response, and during this phase the infected cat remains free of clinical signs.

The final outcome following FIV infection is variable. During the asymptomatic phase the plasma virus load is stable, but there is a progressive decline in CD4+ T lymphocyte numbers, resulting in a decreased CD4:CD8 T lymphocyte ratio. 20 In a proportion of infected cats this leads to a functional immunodeficiency, clinical signs of acquired immunodeficiency syndrome (AIDS) and death.

If the queen is acutely infected, up to 70% of the kittens may become infected. If the seropositive queen is healthy, few kittens will be infected. 

In natural infections, the efficacy of colostral immunity is not known. Experimentally, susceptible kittens have been protected after passive transfer of antibody in response to challenge with laboratory-adapted isolates of FIV. 21 However, this may not apply to challenge with virulent field strains, and indeed enhanced infection was seen after transfer of antibodies from cats immunised with an experimental vaccine, indicating a fine balance between neutralising and infectionenhancing antibodies. 22 Active immune response Cats infected with FIV remain persistently infected despite mounting antibody and cellmediated immune responses. Feline immunodeficiency virusspecific CD8+ cytotoxic T cells are detected in the blood within 1 week of infection. 23 Coincident with the peak of viraemia, anti-FIV antibodies, including virus neutralising antibodies, appear in the plasma. 24 They generally appear from 2-4 weeks after infection, but seroconversion may be delayed in cats exposed to low virus doses. 25 Antibodies recognising Env appear earlier than those against the Gag protein p24. 26 

Most clinical signs are not directly caused by FIV, so it is vital to check for the underlying cause of the presenting clinical signs. In many cases, clinical signs will be the result of a secondary infection that should be identified and treated (see later). The virus itself is responsible for immunodeficiency (making the cat more susceptible to secondary infections and neoplasia) or immune stimulation (resulting in immune-mediated disease). In rare cases, FIV can cause neurological disease.

In the first weeks to months after infection, clinical signs lasting for a few days to a few weeks may be seen. These may include mild fever, lethargy and peripheral lymphadenopathy. 27 Haematology may reveal a neutropenia. 28 Infected cats then generally remain healthy before problems associated with immunodeficiency develop; 29 this asymptomatic period will last for years in most cases, and some cats will never develop FIV-related clinical signs. 30 Disease is often not seen until later in lifegenerally 4-6 years of age or older.

Immunodeficiency and/or immunostimulation most frequently appear in the form of chronic gingivostomatitis, chronic rhinitis, lymph adenopathy, immune-mediated glomerulo nephritis and weight loss (Fig 2) .

Many concurrent viral, bacterial, fungal and protozoal infections have been reported in FIV-infected cats. 31,32 Unusual or severe parasitic skin disease (eg, demodicosis, pediculosis) or tumours should alert the clinician to the possibility of FIV infection. Various neoplastic conditions, such as B cell lymphosarcomas, myeloproliferative disease and squamous cell carcinoma, have been reported in association with FIV infection. 33 Chronic gingivostomatitis is one of the most common presenting signs in FIV-infected cats, and impairs the cat's quality of life (Fig 3) . 34 As confirmed by experimental infections with neurovirulent strains, central nervous system involvement and peripheral neuropathy are early subclinical events, often associated only with altered forebrain or peripheral nerve electrical activity. 35 In contrast, immunochromatography tests detect only antibodies recognising short peptides from the transmembrane protein.

In Western blots, purified FIV is first separated by gel electrophoresis into its constituent proteins, and the individual FIV proteins are detected by antibodies. 45 Both ELISA and immunochromatography tests are generally appropriate, but have limitations (see box on page 579). ✜ CD4+ and CD8+ lymphocytes It is possible to stage the level of immune dysfunction by determining the CD4+ and CD8+ lymphocyte counts. However, due to the complexity of these assays, and the fact that in a clinical situation pre-infection values are not available, these tests are not clinically useful.

disrupted sleep patterns, impaired learning and paresis have also been reported. 37 Reproductive failure occurs in infected cats and is associated with PCR-positive placental and fetal tissues. 38 Renal involvement arising from glomerular and tubulointerstitial lesions associated with severe proteinuria is frequent in FIV-infected cats. Renal damage is caused possibly by the virus, together with renal immune deposits. 39 Polyclonal B cell activation sustains hyperglobulinaemia and high levels of circulating immune complexes and autoantibodies. 40 

The asymptomatic period will last for years in most cases, and some cats will never develop FIV-related clinical signs.

As well as strain variation leading to discrepant results (see text), discrepancies may arise when serology and PCR are compared: ✜ Seropositive/PCR negative results may be explained by the presence of an FIV subtype not recognised by the PCR, rather than by the absence of FIV infection. This aspect is important if a cat has been vaccinated against FIV abroad.

✜ Seronegative/PCR positive results may also be found when cats living in close contact with FIVinfected seropositive cats become provirus positive without developing antibodies or disease. 44 Such cats are infected and will usually seroconvert weeks to months later. 

If FIV-infected cats are sick, prompt and accurate diagnosis is important to allow early intervention. Many respond well to appropriate medication, although a longer or more aggressive course of therapy (eg, with antibiotics) may be needed than in uninfected cats. Some clinicians report benefits with corticosteroids and other immunosuppressive drugs in FIVinfected cats with chronic stomatitis, but their use is controversial because of side effects. Griseo fulvin has caused bone marrow suppression and should not be used. 51 Filgastrim (granulocyte colony-stimulation factor), a recombinant human cytokine (rHuG-CSF), has been used in cats with profound neutropenia. It can increase neutrophil counts, but may also lead to an increase in virus load [EBM grade III]. 52, 53 Erythropoietin is available as the recombinant human product and is used effectively in cats with non-regenerative anaemia due to endogenous erythropoietin deficiency in chronic renal failure. Cats with FIV treated with human erythropoietin (100 IU/kg SC q48h) showed a gradual increase in red and white blood cell counts [EBM grade IV]. 53 No increase in virus loads was observed, indicating that human erythropoietin can be used safely.

Insulin-like growth factor-1 is marketed as a recombinant human product and induces thymic growth and stimulates T cell function. Treatment resulted in a significant increase in thymus size and thymic cortical regeneration, replenishing the peripheral T cell pool in experimentally FIV-infected cats [EBM grade III]. 54 It could be considered in young FIVinfected cats, but there have been no studies to demonstrate efficacy in field cases.

Most of the antiviral drugs that are discussed here are licensed for treating HIV infection in humans. Unfortunately, many of the antivirals used in humans are toxic to cats or ineffective.

AZT AZT (3'-azido-2',3'-dideoxythymidine) is a nucleoside analogue (thymidine derivative) that blocks the retroviral reverse transcriptase. AZT inhibits FIV replication in vitro and in vivo; it can reduce plasma virus load, enhance cats' immunological and clinical status, and improve quality of life. In a placebo-controlled trial, AZT improved stomatitis in naturally infected cats [EBM grade I]. 55 The appropriate dosage is 5-10 mg/kg q12h PO or SC. The higher dose should be used carefully as side effects can develop. For SC injection, the 580 JFMS CLINICAL PRACTICE lyophilised product should be diluted in isotonic sodium chloride solution to prevent local irritation. For PO application, syrup or gelatine capsules (dosage/weight calculated individually for each cat) can be given.

During treatment, a complete blood count should be performed weekly for the first month, because non-regenerative anaemia is common, especially at higher doses. If the values are stable, monthly checks are sufficient. Cats with bone marrow suppression should not be treated. Studies of FIV-infected cats treated for 2 years showed that AZT is well tolerated. Some cats may develop a mild decrease in haematocrit in the first 3 weeks, which resolves even if treatment is continued. If haematocrit drops below 20%, treatment should be discontinued, and anaemia then usually resolves within a few days. As in HIV, AZT-resistant mutants of FIV can arise as early as 6 months after the start of treatment.

AMD3100 belongs to the new class of bicyclams that act as selective antagonists of the chemokine receptor CXCR4. This molecule is the main co-receptor for T cell lineadapted HIV strains and, when blocked with AMD3100, virus entry is inhibited. Feline immunodeficiency virus also uses CXCR4 for virus entry. 56,57 AMD3100 is not licensed as an antiviral compound but it is effective against FIV in vitro. In a placebo-controlled doubleblind study, in which naturally FIV-infected cats were treated (0.5 mg/kg q12h SC for 6 weeks), the drug caused a statistically significant improvement in clinical signs and a decreased proviral load. Side effects were not noted [EBM grade I]. 58 Interferons Feline interferon-omega was recently licensed for veterinary use in some European countries and Japan. Interferons are antiviral, immunomodulatory and anti-tumour cyto kines, which are species-specific; feline interferonomega can therefore be used for the duration of a cat's life without inducing antibody. Also, in contrast to the experience in human subjects, side effects have not been reported in cats. This cytokine is active against FIV in vitro, but in the only controlled study performed in field cats, no significantly improved survival rates were evident [EBM grade 1]. 59 Human interferon-alpha induces an antiviral state in cells and also has immunomodulatory effects. 60 Two treatment regimens have been published for the treatment of retroviral infections in cats [EBM grade III]. 61, 62 Whereas feline interferon-omega is available commercially and would be the appropriate cytokine to use, it is rather human interferon-alpha that

The ABCD recommends that cats should never be euthanased solely on the basis of an FIV-positive test result. Some FIVinfected cats may live as long as uninfected cats [EBM grade III]; 30 however, they have a higher risk of developing clinical signs, principally due to secondary infection, immune-mediated disease or neoplasia. 12, 30, 48 The duration of the asymptomatic stage varies according to the infecting variant. 49 

Immune modulators and interferon inducers are widely used medications in FIV-infected cats. There is no conclusive evidence from controlled studies that they have any beneficial effects on health or survival. Rather, a non-specific immune stimulation can lead to increased viral loads via the activation of latently infected cells, and hence disease progression. These products should not be used in FIV-infected cats.

The risk of FIV transmission is low in households with socially well-adapted cats. If one cat is diagnosed with FIV infection, all cats in that household should be tested. The virus is transmitted mainly during biting and fighting, and if no aggression occurs due to the stability of social and territorial structures, the probability of transmission is low. In followup studies, few additional cats seroconverted over many years. All cats should be neutered, and no new cats introduced, as this might disrupt the harmony, even between cats that have lived peacefully together for a long time.

If other infectious diseases are spreading in a multi-cat community, the risk of FIV transmission may also be higher. In that situation, isolation of seropositive cats should be considered.

Feline immunodeficiency virus is an important consideration in rescue shelters as the prevalence of infection is particularly high in populations with a feral background and in male cats. The prevalence may be lower in pre-owned cats that have recently been relinquished, compared with sheltered stray cats.

The ABCD recommends that all cats should be tested. If this cannot be achieved, at least all sick cats should be tested, and euthanasia considered when the clinical problems relate to an advanced stage of FIV infection.

Serological tests do not reliably identify infected kittens under 6 months of age. A positive result does not confirm that the kitten is infected and it must be emphasised that it is not an indication for euthanasia. In this situation, diagnosis by PCR may be considered.

The ABCD recommends that in rescue shelters, seropositive cats should be housed individually (unless from the same household); as an absolute minimum, FIV-positive cats should be segregated from FIV-negative cats. Some shelters will home FIV-positive healthy cats to selected adopters who offer living environments where the risk of infection for other cats is minimal. Detailed counselling is required.

Usually, cats in breeding catteries are kept indoors and are tested annually, and hence FIV is rare. New cats should be tested before being introduced, and breeders using an external stud or allowing an external queen to visit their stud should request proof of FIV-negative status. Cats that have escaped and returned should be quarantined for 3 months, tested and returned to their group only if found to be seronegative.

The European Advisory Board on Cat Diseases (ABCD) is indebted to Dr Karin de Lange for her judicious assistance in organising this special issue, her efforts at coordination, and her friendly deadline-keeping. The tireless editorial assistance of Christina Espert-Sanchez is gratefully acknowledged. The groundwork for this series of guidelines would not have been possible without financial support from Merial. The ABCD particularly appreciates the support of Dr Jean-Christophe Thibault, who respected the team's insistence on scientific independence.

There is no FIV vaccine commercially available in Europe. Experimentally, protection has been achieved by using several immunogens, including inactivated virus or infected cells, canarypox-based antigen expression in combination with inactivated cells and naked DNA. 63 The most successful so far have been whole inactivated virus preparations; one such vaccine has been on the market in the USA since 2002 and in Australia and New Zealand since 2004.

However, this vaccine's efficacy has not been tested against challenge with European field isolates and did not protect cats against a virulent UK primary FIV isolate [EBM grade III]. 64 Imported vaccinated cats might therefore not be protected against naturally occurring European isolates of FIV.

The ABCD does not recommend the use of the FIV vaccine in Europe, because it invalidates the serological diagnosis of infections and may not protect against European isolates. 

✜ Surgery is well tolerated by asymptomatic FIV-infected cats, but perioperative antibiotic treatment should be used in all cases.

✜ Needles and surgical instruments used on FIV-positive cats may transmit the virus to other cats, so strict hygiene is essential.

Human immunodeficiency virus and AIDS: insights from animal lentiviruses

Proviral organization and sequence analysis of feline immunodeficiency virus isolated from a pallas cat

A lion lentivirus related to feline immunodeficiency virus -epidemiologic and phylogenetic aspects

Genetic and phylogenetic divergence of feline immunodeficiency virus in the puma (Puma concolor)

Worldwide prevalence of lentivirus infection in wild feline species: Epidemiologic and phylogenetic aspects

Nucleotide sequence analysis of feline immunodeficiency virus: genome organization and relationship to other lentiviruses

Identification of three feline immunodeficiency virus (FIV) env gene subtypes and comparison of the FIV and human immunodeficiency virus type 1 evolutionary patterns

Genetic diversity of feline immunodeficiency virus: dual infection, recombination and distinct evolutionary rates among envelope sequence clades

Molecular subtyping of feline immunodeficiency virus from domestic cats in Australia

Isolation of a T-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome

Feline immunodeficiency virus infection: an overview

Prevalence of feline leukaemia virus and antibodies to feline immunodeficiency virus in cats in the United Kingdom

Epidemiologic and clinical aspects of feline immunodeficiency virus infection in cats from the Continental United States and Canada and possible mode of transmission

Vertical transmission of feline immunodeficiency virus

Frequent perinatal transmission of feline immunodeficiency virus by chronically infected cats

The cat/feline immunodeficiency virus model for transmucosal transmission of AIDS: nonoxynol-9 contraceptive jelly blocks transmission by an infected cell inoculum

Feline immunodeficiency virus is shed in semen from experimentally and naturally infected cats

Use of CD134 as a primary receptor by the feline immunodeficiency virus

Differential utilization of CD134 as a functional receptor by diverse strains of feline immunodeficiency virus

Progressive immune dysfunction in cats experimentally infected with feline immunodeficiency virus

Protection of neonatal kittens against feline immunodeficiency virus infection with passive maternal antiviral antibodies

Enhancement of feline immunodeficiency virus infection after immunizaion with envelope glycoprotein subunit vaccines

A longitudinal study of feline immunodeficiency virusspecific cytotoxic T lymphocytes in experimentally infected cats, using antigen-specific induction

Characterization of two monoclonal antibodies against feline immunodeficiency virus gag gene products and their application in an assay to evaluate neutralizing antibody activity

Serological responses of cats to feline immunodeficiency virus

Gag and env-specific serum antibodies in cats after natural and experimental infection with feline immunodeficiency virus

Quantification of lymphadenopathy in experimentally induced feline immunodeficiency virus infection in domestic cats

Feline immunodeficiency virus infection

Long-term clinical observations on feline immunodeficiency virus infected asymptomatic carriers

Long-term impact on a closed household of pet cats of natural infection with feline coronavirus, feline leukaemia virus and feline immunodeficiency virus

Disseminated Mycobacterium genavense infection in a FIV-positive cat

A high prevalence of feline leishmaniasis in southern Italy

Histologic classification and immunophenotype of lymphosarcomas in cats with naturally and experimentally acquired feline immunodeficiency virus infections

Chronic oral infections of cats and their relationship to persistent oral carriage of feline calici-, immunodeficiency, or leukemia viruses

Neuropathology associated with feline immunodeficiency virus infection highlights prominent lymphocyte trafficking through both the blood-brain and blood-choroid plexus barriers

Peripheral neuropathy in lentivirus infection: evidence of inflammation and axonal injury

Neurologic dysfunctions caused by a molecular clone of feline immunodeficiency virus, FIV-PPR

Placental immunopathology and pregnancy failure in the FIV-infected cat

Circulating immune complexes and analysis of renal immune deposits in feline immunodeficiency virus-infected cats

Serum concentration of circulating immune complexes in cats infected with feline immunodeficiency virus detected by immune adherence hemagglutination method

Presenza di anticorpi anti-nucleo in gatti FIV positivi

The variability of serological and molecular diagnosis of feline immunodeficiency virus infection

New challenges for the diagnosis of feline immunodeficiency virus infection

Detection of feline immunodeficiency virus (FIV) nucleicacids in FIV-seronegative cats

Specificity assessment of feline T-lymphotropic lentivirus serology

Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Retrovirus Testing and Management

Feline immunodeficiency virus vaccine: implications for diagnostic testing and disease management

Felines Tlymphotropes lentivirus (FTLV): experimentelle infektion und vorkommen in einigen Ländern Europas

Virulence differences between two field isolates of feline immunodeficiency virus (FIV-A Petaluma and FIV-CP Gammar) in young adult specific pathogen free cats

The effect of age on the course of experimental feline immunodeficiency virus infection in cats

Severe neutropenia associated with griseofulvin in cats with FIV infection

FIV-infected cats respond to short-term rHuG-CSF treatment which results in anti-GCSF neutralizing antibody production that inactivates drug activity

The use of human hematopoietic growth factors (rhGM-CSF and rhEPO) as a supportive therapy for FIV-infected cats

Investigation of recombinant human insulin-like growth factor type I in thymus regeneration in the acute stage of experimental FIV infection in juvenile cats

AZT in the treatment of feline immunodeficiency virus infection. Part 2

Common mechanism of infection by lentiviruses

Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication

Efficacy of the chemokine receptor inhibitor 1,1'-bis-1,4,8,11-tetraazacyclotetradekan against feline immunodeficiency virus infection [abstract

Therapeutic effects of recombinant feline interferon-omega on feline leukemia virus (FeLV)-infected and FeLV/feline immunodeficiency virus (FIV)-coinfected symptomatic cats

Immunomodulation and therapeutic effects of the oral use of interferon-alpha: mechanism of action

Alpha interferon (2b) in combination with zidovudine for the treatment of presymptomatic feline leukemia virusinduced immunodeficiency syndrome

Low-dose interferon-alpha treatment for feline immunodeficiency virus infection

Vaccine protection against feline immunodeficiency virus -setting the challenge

Limited efficacy of an inactivated feline immunodeficiency virus vaccine