Feline Immunodeficiency Virus

Also known as: FIV

Description

Feline immunodeficiency virus is a retrovirus that causes immunodeficiency disease in the domestic cat.

Agent

FIV is a member of the lentivirus genus of the Retroviridae family. Retrovirus virions are are sensitive to heat, lipid solvents, and detergents but are relatively resistant to damage caused by ultraviolet light¹. The Retroviridae are enveloped viruses which contain a single-stranded RNA genome within an icosahedral nucleocapsid. Glycoprotein surface spikes are located on the envelope. Unusually, Retroviruses have a diplod genome: two identical copies of their positive-sense ssRNA are found on the virion¹. During viral replication, reverse transcriptase converts the ssRNA genome to ssDNA. This process is inherently error-prone, and the high rate of mutation gives rise to a wide genetic diversity of virus¹. A dsDNA can then be made from the ssDNA template. This provirus DNA then becomes integrated into the host genome by the actions of the viral enzyme integrase, and remains latent until transcription is initiated by the host cell machinery¹. Proviral DNA then serves as a template for the production of progeny ssRNA genomes and messenger RNA. Once the proviral DNA has been transcribe and translated, the virions assemble and are release by budding through the host cell membrane. This does not always cause lysis¹.

Many Retrovirus genomes contain oncogenes which may be expressed when integrated to the host genomes. However, oncogenes are not a requirement for tumour induction, and some Retroviruses can cause tumours without carrying oncogenes. The Retroviral genome has four coding regions. The "gag" region codes for the matrix protein, nucleoprotein and capsid, and "pro" encodes a protease¹. Reverse transcriptase is coded by the "pol" region, whereas "env" gives rise to the envelope and receptor binding. An additional, specific cellular transporter RNA is required for replication and present within the virion.

FIV was first discovered in a cat rescue facility in the United States where cats had been showing similar clinical signs to people with acquired immunodeficiency syndrome². Subsequently it has been shown that FIV has been present in the cat population since the late 1960s, and that the virus is very similar to the human retrovirus, HIV. However, despite these similarities, FIV is specific to cats, and people cannot become infected with the virus.

Transmission and Epidemiology

The major route of transmission is via saliva, particularly through biting^{2, 3}. Therefore, those cats showing territorial aggression are most at risk of contracting FIV. High levels of virus are found in the saliva of infected cats, particularly those in the stages of acute or terminal infection³. Less commonly, salivary transmission can occur via shared food bowls and mutual grooming. Vertical transmission can occur, either transplacentally or via milk², but venereal transmission has not been reported. The likelihood of infected kittens being born to a FIV-infected mother depends on the stage of infection: up to 70% of kittens are born infected if thr queen suffers acute infection during pregnancy, but chronic infection of the mother rarely results in transplacental transmission⁴. The potential role of blood-sucking insects, such as fleas, in spreading infection is unknown².

It is clearly possible that horizontal transmission can occur within multi-cat households, but in some households only a single cat in a group may be FIV positive, whereas in others nearly every cat may be infected. Overall it appears that if fighting among cats housed together is rare, the prevalence of FIV is likely to be low⁴.

FIV infection is prevalent worldwide, with between 1 and 14% of healthy cats and up to 44% of sick cats harbering the virus⁴.

Pathogenesis

The pathogenicity of FIV is strain dependent, and can vary widely. For all strains, feline lymphocytes and macrophages are the preferred cells for virus replication, and so FIV disrupts the function of the immune system. FIV gains entry to the cell via feline CD134, a surface molecule, and uses various chemokine receptors as secondary receptors⁵. In acute infection, the virus spreads from the site of entry to the lymphoid tissues and thymus, where it first infects T-lymphocytes and then macrophages. Although both CD4+ and CD8+ cells can be infected by FIV and lysed in culture, the virus appears to preferentially destroy CD4+ cells. This intially results in a change in the ratio of CD4+ to CD8+ cells, from roughly 2:1 to less than 1:1⁵. After several months of infection, an absolute reduction in CD4+ is appreciable.

Approximately three weeks after infection, cats may show the "primary phase" of FIV infection with malaise, lymphadenopathy and pyrexia². Viraemia peaks at 7-8 weeks and then declines, but increases again in the terminal stages of disease¹. The host then remains asymptomatic for an indefinite period until cell-mediated immunity is disrupted by a decrease in the production of Th1 cytokines. In the advanced stages of infection, humoral immunity is also adversely affected. Although clinical signs are primarily due to changes related to T-cell populations, macrophages are the main reservoir of FIV in infected cats⁵. These cells are capable of transporting virus to various tissues of the body, and also suffer impairment of function, such as an increase in the production of TNF. Microglia and astrocytes in the brain, and megakaryocytes in the bone marrow, can become infected with FIV^{1, 5}, and co-infection with feline leukaemia virus can increase the expression of FIV in many tissues, including the kidneys, liver and brain.

Signalment

Feline immunodeficiency virus occurs frequently in cats throughout the world, and similar viruses have been recovered from wild and zoo felids¹. FIV infection increases in prevalence in older cats, and the average age at diagnosis is 5 years⁵. Male cats are more commonly infected than females as they roam more and exhibit a higher degree of territorial aggression^{2, 3, 4, 5}. There are no breed predilections⁵.

Diagnosis

The signs of feline immunodeficiency virus infection can be very variable, as signs are dependent on the secondary infections that become established. However, differential diagnoses for the immunosuppressive effects and some other primary effects of the virus include feline leukaemia virus infection, toxoplasmosis and the dry form of FIP⁶. Primary bacterial, parasitic, viral or fungal infections should also be ruled out⁵.

Clinical Signs

The clinical signs in the immunosuppressive stage of the disease are related to secondary infections and are therefore extremely variable. Clinically, the associated conditions cannot be distinguished from those occuring in feline leukaemia virus-related immunosuppression. Patients often present with vague signs, such as inappetance or weight loss, and a history of recurrent minor illness related to the gastrointestinal or upper respiratory tract is common. Disease of the oral cavity including gingivits and stomatitis is frequently seen. This can be linked to secondary pathogens such as calicivirus and oral bacteria. Calicivirus, along with other organisms such as herpesvirus, Toxoplasma gondii and Chlamydia psittaci, can cause ocular signs including conjunctivitis, keratitis, uveitis and chorioretinitis in 35% of cases. Similar microbes give rise to secondary cat flu, and diarrhoea occurs in a quarter of affected cats. Other common signs due to immunosupression include anaemia (due to Haemobartonella felis), meningoencephalitis, pneumonia, glomerulonephritis, renal failure, cystitis and pyoderma, caused by a variety of bacteria. The potentiating effects of FIV on FeLV infection can also induce neoplasia.

The virus itself may also have certain effects. Half of all cats affected display lymphomegaly, and pyrexia occurs in 30% of cases². Anaemia, neutropenia, lymphopenia and thrombocytopenia are commonly seen, as well as diarrhoea and uveitis. Neurological signs, renal disease and neoplasia may also be direct effects of feline immunodeficiency virus.

Laboratory Tests

No typical changes for FIV infection are revealed by routine haematology and biochemsitry. The haemogram may be noraml, or anaemia, lymphopenia or neutropenia can be seen, related to the direct effects of the virus. Secondary infection may result in a neutrophilia. Biochemical changes reflect the associated conditions in indvidual cases⁵.

Diagnosis of FIV is made by demonstrating the presence of antibodies against the virus. ELISA tests are available for in-house use, with some kits detecting antibody to the core protein p24 and others detect antibody to the envelope protein gp4l². Non-haemolysed plasma or serum is used for performing the in-house ELISA. Results must be interpreted with caution.

Once a cat acquires FIV infection, the antibodies created persist for life. This means that an ELISA test at any stage after infection should give a positive result. However, the test has a sensitivity of 98%, and so false positives do occur. Because of this, animals that test positive to an in-house ELISA, should be re-tested using a different test. Laboratories offer an immunoblot (Western blot) to confirm the diagnosis in cats that test ELISA-positive. The problem of using a test that detects anitbodies becomes apparent when it is neccessart to test kittens that are born to an FIV-positive queen. Antibodies against FIV are passively acquired via the milk, and can be detected when an ELISA test is used. This makes it imposible to distinguish animals that have been transplacentally infected with virus and are producing their own antibodies from those which have merely acquired pre-formed anitbodies from their mother. Maternally derived anitbodies can persist for up to 6 months², and so animals testing positive before this age should be restested at 8-12 months old⁵.

Negative results can be true negatives. Alternatively, they may arise when the cat is infected with FIV but the antibodies produced are not detectable by the test used. Conversely, the cat may be infected but antibodies are not present, for example in the first two months of infection². Therefore, if clinical signs give a strong suspicion of FIV infection, or the cat is known to be at risk (for example, recently bitten by and infected cat), animals should be retested 6-8 weeks later and use of an immunoblot should be considered. Up to 15% of cats completely fail to ever mount an antibody response against FIV infection. Virus isolation and RT-PCR tests exist that can detect virus rather than antibody, but these are not widely available outside the context of research, and RT-PCR in particular may be unreliable^{4, 5}.

Pathology

On post-mortem examination, lymphadenopathy is seen. Intestinal lesions similar to those seen in feline panleukopenia virus infection may be apparent⁵.

In early disease, lymphadenopathy is seen histologically to be due to follicular hyperplasia and infiltration of plasmacytes to surround the cortex. Later in disese, a mixutre of follicular hyperplasia and follicular depletion may exist, and in the terminal stages of FIV infection, follicular involution is the key feature⁵. Lymphoplasmacytic infiltrates are seen in the gingiva, lymphoid tissues, spleen, kidney, liver and brain. Brain lesions also include perivascular cuffing, gliosis, neuronal loss, vacuolation of the white matter and, occasionally, the presence of giant cells.

Treatment

Supportive care and management of secondary infections are essential in the sick FIV-positive cat. The nature and extent of any secondary infections should be established so that appropriate treatment can be provided. Often, much longer courses of antibiotics are needed in these immunosuppressed patients and the response to therapy is frequently much slower and less successful. Antibiotics should be broad spectrum and the treatment protocol should include antibiotics against anaerobes. In FIV-infected cats with chronic inflammatory conditions such as gingivitis/stomatitis the combined use of antibiotics with cautious use of corticosteroids may help to reduce the severity of clinical disease. Cats should not be fed raw meat and should be discouraged from hunting due to the increased risk of Toxoplasma gondii infection.

Preventive medicine is particularly important in the potentially immunosuppressed cat, as infection with other viruses is likely to be more life-threatening and refractory to treatment than in the otherwise healthy individual. Vaccination, particularly against herpesvirus, calicivirus and panleukopenia, is recommended and it may be worthwhile considering the use of killed vaccines, where available, to minimise the potential risk of an attenuated virus strain causing disease in an immunosuppressed patient. Vaccine boosters should be given according to manufacturers' instructions and, in any cats moving to a high risk situation such as a veterinary hospital or cattery, it may be advisable to give an additional booster unless the cat has received one in the previous six months. Vaccination for feline leukaemia virus should be considered according to the risk of exposure to this virus. Flea treatment is advisable to minimise the risk of H felis transmission. Routine worm treatment is also recommended.

Agents such as the reverse transcriptase inhibitor AZT (3'-azido-3'-deoxythymidine) and the immunostimulator interleukin-2 have been used in a small number of clinical trials involving FIV-infected cats with chronic gingivitis/stomatitis. Improvements in clinical and laboratory findings were reported in a proportion of these cats treated orally or subcutaneously with AZT at a dose of 5 mg/kg three times daily (Hartmann and others 1992, Hart and Nolte 1995, Hartmann and others 1995). Since anaemia is a potential adverse effect of this agent, haematology should be assessed regularly in cats receiving this treatment. It should be noted that neither AZT nor interleukin- 2 are licensed for veterinary use. Evening primrose oil, at a suggested dose rate of one 550 mg capsule daily, has also been used with beneficial effects, particularly in asymptomatic or mildly affected FIV-positive cats. Reported improvements have included increased bodyweight, haematocrit and neutrophil count.

Control

• No UK vaccine
• Healthy positive cats should have diagnose confirmed by further testing
• Isolate and castrate
• Preventative neutering of males

Prognosis

The long-term prognosis for FIV-infected cats is guarded, but some cats will survive for many years following diagnosis. A cat should therefore never be euthanased based on a positive test result for FIV⁴. Around 20% of affected cats die within the first two years after diagnosis; this equates to a 20% mortality rate in the first 4.5-6 years after the estimated time of infection^fmc. In generally, the more chronic and severe the clinical signs, the worse the prognosis is. The duration of the asymptomatic period following FIV infection varies with the infecting strain and cannot be predicted. However, cats affected at a younger age are more likely to progress to an immunodeficient state⁴.

Links

• Feline Advisory Bureau FIV Factsheet
• Cornell Feline Health Center factsheet on FIV

References

1. Wise, D J and Carter, G R (2005) A Concise Review of Veterinary Virology, IVIS.
2. Caney, S (2000) Feline immnunodeficiency virus: an update. In Practice, 22(5), 255-260.
3. Johnson, C M (2005) Transmission of Feline Immunodeficiency Virus. Proceedings of the 56th Annual Meeting of the American College of Veterinary Pathologists and 40th Annual Meeting of the American Society for Veterinary Clinical Pathology.
4. The European Advisory Board on Cat Diseases (2008) Feline Immunodeficiency Virus. Guidelines of Feline infectious Diseases.
5. Tilley, L P and Smith, F W K (2004) The 5-minute Veterinary Consult (Fourth Edition),Blackwell.
6. Rand, J (2006) Problem-based feline medicine, Elsevier Health Sciences.
7. Merck & Co (2008) The Merck Veterinary Manual (Eight Edition), Merial.
8. Morrision, W B (2002) Cancer in dogs and cats: medical and surgical management, Teton NewMedia.