Felipedia

FIV in felines

Feline immunodeficiency virus (FIV) is a lentivirus (subfamily Lentivirinae) that causes an acquired immunodeficiency syndrome in cats; so-called ‘Cat AIDS’.

First identified in 1986, FIV belongs to the Lentivirus group which also includes FeLV (Feline leukemia virus) and FFV (Feline foamy virus)[3]. Studies of wild cats, such as the Pallas’ cats of Mongolia, suggest FIV has probably been around for centuries, occurring as it does in that species of cats at a stable prevalence rate of about 25% of the feline population[4].

FIV is common worldwide. Although the prevalence rates for FIV infection in cats are relatively stable (based on serological testing for antibodies to FIV), infection rates vary dramatically based on geography and whether the cat is client-owned or stray; ranging from ~2% in Taiwan, 2.5% in client-owned cats and 23% of stray cats in the USA, 10% in southern Europe, 2-6% in northern Europe[5], to >24% (Australia)[6]. The highest prevalence (28.9%) is recorded in Japan.

Virology

FIV is associated with a high degree of genetic diversity, leading to the existence of five subtypes (A, B, C, D & E) based on envelope gene sequences[7]. The clinical significance of the various subtypes is currently unknown. The distribution of FIV subtypes varies geographically. Subtypes A, B, and C are found in Canada and the United States, although there are few published examples of Canadian subtypes. Subtype B has been reported in the West Indies[8]. Recombinant viruses are also known to exist.

  • Vaccines – An inactivated dual subtype (subtypes A, D) vaccine (Fel-O-Vax FIV; Fort Dodge Animal Health, Overland Park, Kansas, USA) became available worldwide in 2002[9].

The primary mode of transmission is thought to be via bite wounds, although it is possible for a queen to infect her kittens in utero, during birth, or postpartum via colostrum. There is also the potential for venereal transmission of the virus. Cats infected with FIV have low levels of viral antigens in their blood; this has prevented the use of screening assays based on antigen detection, however, FIV-infected cats produce high levels of circulating antiviral antibodies[10].

Innate immune responses have been shown to play an important role in controlling viral replication following acute mucosal infection and the role of CD4+ and CD8+ lymphocytes are critical for immune responses, which may or may not eliminate acute FIV viremia[11]. The initial event in the process of viral entry is the interaction between the virus and its cellular receptor. FIV targets CD4+ helper T cells by attachment of the envelope glycoprotein (Env) to CD134, a T cell activation and co-stimulatory molecule[12]. This induces an AIDS-like immunodeficiency in cats due to a progressive depletion of CD4+ cells[13]. A subsequent interaction with CXCR4 then facilitating the process of viral entry. As the CXCR4 binding site is not exposed until CD134-binding has occurred then the virus is protected from neutralizing antibodies targeting the CXCR4-binding site on Env. Prototypic FIV vaccines based on the FL4 strain of FIV contain a cell culture-adapted strain of FIV Petaluma, a CD134-independent strain of FIV that interacts directly with CXCR4.

In one study of 226 FIV-infected cats, 63% of patients expressed auto-antibodies to the lymphocyte binding receptor CD134, whereas cats infected with other feline RNA viruses, such as calicivirus, coronavirus, herpesvirus, and feline leukemia virus, did not. The presence of auto-antibodies to CD134 correlated with lower virus loads and a better overall health status in FIV-positive cats. The findings are consistent with a role for antireceptor antibodies in protection from virus spread and disease progression[14].

Programmed cell death due to apoptosis appears to be delayed in FIV-infected cells in cats, which may prolong the life of FIV-infected cells, thus propagating the viremia so characteristic of feline AIDS cases[15].

Clinical signs

The factors that influence whether or not and when a cat infected with FIV will develop clinical disease are not fully understood, although it is hypothesized that the presence of concurrent disease and variable pathogenicity associated with different clades (strains of the virus) may play a role. The role of immunomodulation of T-cells, primarily upon the thymus gland is an important consideration.

There are various clinical diseases associated with FIV infection in cats:

  • Acute illness – Initial symptoms usually slight, with a febrile response within the first 6 weeks, followed by intermittent diarrhea, respiratory disease or kidney disease over the subsequent 4 to 5 years. Pneumonia and sometimes diffuse alveolitis are present on radiographic examination.
  • FIV gingivitis
  • Kittens – during FIV infection, neonatal and pediatric feline patients often experience a shorter incubation tima and more rapid disease progression and death than do infected adults, with clinical signs of infection during the first year of life due to the rapid destruction of the immune system and development of opportunistic infections[16]. FIV-infected kittens develop immune dysfunction and disease similar to that in adult cats, but those infected in utero or soon after birth gave decreased viability in the postnatal and juvenile period. In young FIV-infected kittens, the thymus rapidly involutes, and CD4+ CD8+ cells are depleted, and there is decreased ability to replenish diminished and dysfunctional peripheral T cells[17]. Kittens inoculated in utero have been reported to have had acute, but transient thymic atrophy, which partially regenerated[18]. This was characterized by initially lowered thymus: body weight ratio, severe thymic cortical depletion, reduction of thymocyte numbers and decreased corticomedullary distinction, but this later began to rebound or approach normal.
  • FIV encephalitis
  • Quiescence – this period of FIV infection is correlated with varying degrees of health and intermittent illness. Although the cat appears healthy, viral loads within the body are still high and acute immune-responses persist throughout this period. A secondary illness may be seen, including diarrhea, respiratory disease and rhinitis, gingivitis and plasma cell stomatitis, plasma cell pododermatitis and plasma cell chondritis.
  • Terminal disease – long-term consequence of FIV infection are attributed to immune system collapse and can manifest in a multitude of ways. Invariably, a blood test reveals varying degrees of leukopenia, blood dyscrasias, and non-regenerative anemia. Overwhelming bacterial and fungal infections are the usual cause of mortality in cats as it is in humans[19].
  • Reproductive failure – high rates of kitten loss has been reported with queens infected with FIV virus. It was thought that the virus infects trophoblasts within the uterus, but recent studies have shown that reproductive failure in FIV-infected queens was not a direct result of viral replication in trophoblasts[20].

Diagnosis

FIV can be easily diagnosed by an in-house blood test, with accuracies approaching 100%[21]., detecting the presence of anti-FIV antibodies in the blood. This test is available at most veterinary clinics, and it is recommended that a FeLV test be performed at the same time[22].

In Australia and New Zealand, Gribbles laboratories can now perform PCR tests on cat blood to assess the presence of proviral DNA, therefore specifically testing for antigen rather than an antibody. This has allowed the differentiation of infected cats rather than antibody-positive FIV-vaccinated cats. IDEXX in the USA has also launched a similar PCR assay for clinical use.

It is recommended that all at-risk cats be tested for FIV and FeLV; cats with exposure to outdoors and history of fighting, cats presenting with abscesses or bite wounds, concurrent illness, and living in multi-cat households[23].

Treatment

Supportive therapy has been the mainstay in management of cats infected with FIV. This includes broad-spectrum antibiotics, vitamin supplements and nutritional support.

Unfortunately, there is no cure for the FIV virus itself. The use of anti-viral drugs in cats has been tested with some success but the prohibitive cost far outweighs its use. AZT has been shown to be ineffective at stopping the virus from invading the cat’s body even when given immediately after infection.

  • Antiviral therapy

FIV is susceptible to nucleoside analogs, such as Zidovudine, zalcitabine, didanosine, and lamivudine (3TC; β-d-2′,3′-dideoxy-3′-thiacytidine), in vitro at concentrations similar to those observed with HIV-1[24].

FIV is not susceptible to currently prescribed HIV-1 protease inhibitors. The sensitivities of FIV and HIV-1 to the active triphosphate forms of ZDV and 3TC are also similar. Furthermore, infected feline patients treated with ZDV show delayed the onset of viremia, reduced plasma virus loads, and clinical improvement, with normalisation of immune-endocrine interactions. 3TC has been studied in vivo only recently in this species; infected cats receiving experimental bone marrow transplants and 3TC in combination with ZDV demonstrated some clinical benefit. Because FIV is shed in semen and can be transmitted by artificial insemination, the feline system is analogous to what happens in human HIV infections.

In 2006, the United States Department of Agriculture issued a conditional license for a new treatment aid termed Lymphocyte T-Cell Immune Modulator. Lymphocyte T-Cell Immune Modulator is manufactured by T-Cyte Therapeutics, Inc., exclusively licensed by IMULAN BioTherapeutics, LLC and distributed in the United States by ProLabs Animal Health (www.prolabsanimalhealth.com).

In some cases, FIV positive cats have lived for ten years, but five years is common.

Prevention

In unvaccinated cats, the protocol for prevention is for three (3) vaccinations four weeks apart. Cats vaccinated with Fel-O-Vax® FIV develop antibodies to the inactivated virus present in the vaccine. Currently available antibody-based FIV diagnostic tests (e.g., SNAP® Feline Combo, PetChek® FIV Ab plates, and Western blot) available in the United States and Europe cannot distinguish cats vaccinated with Fel-O-Vax® FIV from FIV-infected cats or from cats that are both vaccinated and infected. Negative FIV-antibody test results remain reliable ([1]).

Kusuhara et al have found that dual-subtype vaccine (Fel-O-Vax FIV) protects cats against contact challenge with heterologous subtype B FIV infected cats. They demonstrate a 100% preventable fraction against a Subtype B where cats were housed together allowing a ‘natural’ challenge with FIV. Given the high prevalence of FIV and the availability of a differential test, the benefits of vaccination appear to outweigh the risks for any cat with outdoor access[25].

In a cattery/shelter scenario, vaccinating all the residents prior to adoption may provide some protection, but it is unrealistic to expect all vaccinates to be protected. Because infected cats—either healthy or ill—will be difficult to identify, the delivery of the specialized care they require will be significantly compromised. Kittens born to vaccinated queens will likely test positive for passively acquired FIV antibody. According to studies conducted by the manufacturer, antibody levels drop to levels that won’t interfere with test results by the time kittens reach 8 weeks-of-age. Some shelters and other facilities designed to house strays often euthanize cats with positive FIV test results, so previously vaccinated uninfected cats may needlessly undergo euthanasia. Permanently identifying cats vaccinated with Fel-O-Vax® FIV (e.g., using a microchip or tattoo) has been suggested as a means of identifying vaccinated cats, thus sparing them from euthanasia. Yet previous vaccination does not rule out infection nor prevent the subsequent placement of infected cats[26].

Vaccine efficacy

FIV is commonly classified into five different subtypes (A, B, C, D, and E) based upon genetic variation within one section of the virus envelope gene. Subtypes A and B are the predominant subtypes in the United States. Substantial genetic variation exists both within and between the various subtypes (also called genotypes or clades). Experimental FIV vaccines reported thus far in the literature have demonstrated poor cross protection between subtypes (e.g., vaccines based on subtype A virus have shown decreased protection against subtype B challenge).

As a condition of licensure, the United States Department of Agriculture (USDA) requires manufacturers to determine vaccine efficacy based upon results of laboratory studies. Accordingly, 45 eight week-old specific pathogen free kittens were randomized into two groups: 25 were vaccinated with Fel-O-Vax® FIV three times three weeks apart while 20 kittens served as non-vaccinated controls. Approximately one year later, both groups were challenged intramuscularly with a subtype A virus that differed by 10% in a portion of the envelope gene from the subtype A virus used in the vaccine. The preventable fraction (defined as the proportion of cats protected by vaccination in excess of the proportion that is naturally resistant) was calculated to be 0.82 (82%).

Challenge models that accurately reflect “real world” exposures to infectious agents are difficult to design and control, expensive, and involve large numbers of cats. In addition, they often require several years of data collection to obtain meaningful results. Laboratory challenges of the kind required by the USDA provide necessary and valuable information, but for reasons of practicality and expense, they may not reflect vaccine performance in the field. Although these efficacy figures are encouraging, it is possible that fewer than 82% of vaccinated cats will be protected from the vast array of FIV genetic variants to which they may be exposed in nature. Therefore, while reasonable to expect that some cats vaccinated with Fel-O-Vax® FIV will be protected from infection, others certainly will not[27].

The absence of tests that distinguish cats vaccinated with Fel-O-Vax® FIV from infected cats, coupled with questions regarding the vaccine’s ability to induce protection against all the subtypes and strains of FIV to which cats might be exposed, makes the decision to recommend the use of this product far from straightforward. It is crucial that clients are adequately informed about the vaccine’s impact on future test results, and their decision should be reached only after careful consideration of both positive and negative implications. If the decision ultimately falls in favour of vaccination, cats should test negative immediately prior to receiving Fel-O-Vax® FIV.

References

  1.  Yamamoto, JK et al (2006) Cellscience Review
  2.  Willett, BJ (2008) A single site for N-linked glycosylation in the envelope glycoprotein of feline immunodeficiency virus modulates the virus-receptor interaction. Retrovirology 5:77
  3.  Bendinelli, M et al (1995) Feline immunodeficiency virus: an interesting model for AIDS studies and an important cat pathogen. Clin Microbiol Rev 8:87-112
  4.  Brown MA, Munkhtsog B, Troyer JL, Ross S, Sellers R, Fine AE, Swanson WF, Roelke ME, O’Brien SJ. (2009) Feline immunodeficiency virus (FIV) in wild Pallas’ cats. Vet Immunol Immunopathol Oct 14
  5.  Gleich, SE et al (2009) Prevalence of feline immunodeficiency virus and feline leukemia virus among client-owned cats and risk factors for infection in Germany. JFMS 11:985-992
  6.  Norris, JM et al (2007) Prevalence of feline immunodeficiency virus infection to domesticated and feral cats in Eastern Australia. JFMS 9: 300-308
  7.  De Monte M et al (2002) A multivariate statistical analysis to follow the course of disease after infection of cats with different strains of the feline immunodeficiency virus (FIV). J Virol Methods103:157-170
  8.  Kelly, PJ et al (2011) Identification of feline immunodeficiency virus subtype-B on St. Kitts, West Indies by quantitative PCR. J Infect Dev Ctries 5(6):480-483
  9.  Huang C et al (2010) Dual-subtype feline immunodeficiency virus vaccine provides 12 months of protective immunity against heterologous challenge. J Feline Med Surg 12(6):451-457
  10.  Yamamoto, JK et al (1989) Epidemiologic and clinical aspects of feline immunodeficiency virus infection of cats from the continental United States and Canada and possible mode of transmission. J Am Vet Med Assoc 194:213
  11.  Howard KE, Reckling SK, Egan EA, Dean GA. (2010) Acute mucosal pathogenesis of feline immunodeficiency virus is independent of viral dose in vaginally infected cats. Retrovirology 7(1):2
  12.  Shimojima, M et al (2004) Use of CD134 as a primary receptor by the feline immunodeficiency virus. Science 303:1192-1195
  13.  English, RV et al (1993) In vivo lymphocyte tropism of feline immunodeficiency virus. J Virol 67:5175-5186
  14.  Grant CK, Fink EA, Sundstrom M, Torbett BE, Elder JH. (2009) Improved health and survival of FIV-infected cats is associated with the presence of autoantibodies to the primary receptor, CD134. Proc Natl Acad Sci, U S A 106(47):19980-19985
  15.  Folkl A, Wen X, Kuczynski E, Clark ME, Bienzle D. (2009) Feline programmed death and its ligand: Characterization and changes with feline immunodeficiency virus infection. Vet Immunol Immunopathol Oct 14
  16.  O’Neil, LL Burkhard, MJ & Hoover, EA (1996) Frequent perinatal transmission of feline immunodeficiency virus by chronically infected cats. J Virol 70:2894-2901
  17.  Power, C et al (1998) Neurovirulence of feline immunodeficiency virus-infected neonatal cats is viral strain specific and dependent on systemic immune suppression. J Virol 72:9109-9115
  18.  Johnson, CM et al (2001) Unique susceptibility of the fetal thymus to feline immunodeficiency virus infection: an animal model for HIV infection in utero. Am J Reprod Immunol 45:273-288
  19.  Murray, JK et al (2008) A study of risk factors for cat mortality in adoption centres of a UK cat charity. JFMS 10:338-345
  20.  Scott, VL et al (2011) Immunomodulator expression in trophoblasts from the feline immunodeficiency virus (FIV)-infected cat. Virol J 8(1):336
  21.  Hartmann, K et al (2001) Comparison of six in-house tests for the rapid diagnosis of feline immunodeficiency and feline leukaemia virus infection. Vet Rec 149:317
  22.  Muirden, A (2002) Prevalence of feline leukaemia virus and antibodies to feline immunodeficiency virus and feline coronavirus in stray cats sent to an RSPCA hospital. Vet Rec 150:621-625
  23.  Levy, J et al (2008) American Association of Feline Practitioners’ feline retrovirus management guidelines. J Fel Med Surg 10:300
  24.  Zislin, A (2005). Feline immunodeficiency virus vaccine: A rational paradigm for clinical decision-making. Biologicals 33: 219
  25.  Murray, JK et al (2009) Risk factors for feline immunodeficiency virus antibody test status in Cats Protection adoption centres. JFMS 11:467-473
  26.  Lin, D-S et al (1992) Immunological changes in cats with concurrent Toxoplsma gondii and feline immunodeficiency virus infections. J Clin Microbiol 30:17-24
  27.  Kusuhara, H (2007) Serological differentiation of FIV-infected cats from dual-subtype feline immunodeficiency virus vaccine (Fel-O-Vax FIV) inoculated cats. Vet Microbiol 10;120(3-4):217-25

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