Feline immunodeficiency virus (FIV)

Feline immunodeficiency virus (FIV) is a lymphotropic lentivirus that causes an acquired immunodeficiency syndrome (AIDS) in domestic felidae. Although antigenically distinct, FIV is morphologically and biochemically correlated to human immunodeficiency virus (HIV). Both viruses exhibit a similar pathogenesis, characterized by a long period of clinical latency during which the functions of the immune system deteriorate progressively. At the end of the latency period AIDS may develop,  accompanied by opportunistic infections, systemic diseases directly or indirectly related to the presence of the virus and neoplasms. The correlations between HIV and FIV are so numerous that the latter is considered a very good animal model for studying the immunopathogenesis of lentiviruses in general and of HIV in particular.

FIV field isolates are divided into various subtypes based on the difference in the sequence of the hypervariable region of the  env (envelope) gene: to date, at least five subtypes (A, B, C, D, E) have been identified. The subtype is extremely important when performing polymerase chain reaction (PCR) analysis and when considering the hypothesis of vaccination. In the United States subtypes A and B are predominant, although subtype C has also been reported. In Canada most infections are caused by subtype C infections, with a lesser presence of subtype B. In Japan subtype D is prevalent, with subtypes A, B and C also present. In Australia and Africa subtype A has been reported; in South Africa subtype B has been notified and recently also a new subtype E. European cats are infected by subtypes A, B, C and D: subtype A is predominant in northern European countries (e.g. Germany and the Netherlands), while subtype B predominates in southern Europe (e.g. Italy). Naturally infected animals may, however, host more than one subtype. Superinfections following experimental sequential inoculations with different subtypes have been observed, indicating the lack of cross protection between different subtypes. The prevalence of FIV infection varies from 1% to 30%, depending on the country and on the number of free-roaming cats in a specific area.

As regards FIV replication, once the virus has bound to the receptors on the surface of  target cells, the nucleocapsid is released within the cell where it is transcribed into a proviral double helix DNA, which is then integrated within the genome of the host. New viral particles are then transcribed by the provirus and presented on the surface of the host cells. The cellular tropism of FIV is more varied and permissive than that of HIV; initially, just like HIV, the virus infects only  CD4+ (T-helper) cells; however, as the disease progresses the virus can also infect the CD8+ T-suppressor cytotoxic lymphocytes, B lymphocytes and macrophages. The pathogenesis of the infection does, therefore, have various stages (Table 1), in most cases recognizable either clinically or with adequate laboratory tests. The first laboratory alteration in the case of FIV infection is  lymphocytopenia, which can sometimes be severe. During this phase (stage 1), the numbers of both CD4+ and CD8+ cells decrease; this is followed by a marked immune response characterized by the production of anti-FIV antibodies and by an increase and return of CD8+ cell counts to pre-infection values (Tables 2a and b). Consequently, during this first stage there is an inversion of the CD4+:CD8+ ratio,  which is often persistent although not markedly evident. In the months that follow, there can be a return to pre-infection conditions although the number of lymphocytes in these animals usually remains lower than that in non-infected animals.

During the subsequent latency period, which can last for years, the number of T-helper cells (CD4+) progressively decreases, leading to the inversion of the physiological CD4+:CD8+ cell ratio.

Tables 2a and 2b. Trends in the T-cell populations according to the clinical stage of the disease. (From: Bo S, Peri E, Rocchi M, et al. Feline immunodeficiency virus (FIV) infection in cats as a model for HIV in man and for antiviral chemotherapy study for AIDS. Biotec 1994;9:152).

In humans infected by HIV the progression and clinical staging of the infection is based on the absolute number of circulating CD4+ cells: a count under 200 CD4+/µl defines the condition of AIDS. In FIV-positive cats it is more difficult to stage the disease, as FIV seems to be less pathogenic than HIV. Although chronic inflammation and opportunistic infections are common in cats with a low count of circulating CD4+ cells, many animals remain healthy. Dysregulation of other factors, specifically cytokines (interleukin [IL]-2, IL-12, IL10, tumour necrosis factor-alpha, interferon-gamma) is currently attributed a fundamental role in the immunopathogenesis of  lentivirus infections. 

TRANSMISSION

The natural transmission is mostly  horizontal and direct between adult cats, through  bites inflicted during fights (Burkhard, 1998). Epidemiological studies have shown that the prevalence of FIV is influenced by behaviour: the infection is more frequent among male cats (male:female ratio = 4:1) which either live outdoors or which can go outdoors. Seventy-eight percent of affected cats are young adults (2-5 years) at the time of the diagnosis. FIV is not highly contagious and the presence of several cats in the same domestic environment does not, therefore, increase the likelihood of contagion, provided that no territorial conflicts take place. Other routes of transmission (licking, shared bedding and bowls, nursing of kittens, transplacental) are much less important. Curiously, sexual transmission, which is the most common route of transmission in man, appears unusual in the cat, even if the semen of the cat does frequently contain some infective virus. Vertical transmission mainly takes place in queens infected in the early stages of gestation.

EPIDEMIOLOGY

Since its discovery in 1986, numerous serological studies have shown that FIV is endemic in cats throughout the world. The seroprevalence of FIV is extremely variable, being 1-14% in healthy cats and reaching peaks of 44%  in sick animals (Table on the prevalence of FIV and FeLV).

CLINICAL SIGNS

FIV is rarely a direct cause of disease. The clinical signs are often caused by an opportunistic infection and it is the fact that these clinical signs become chronic or are difficult to treat which leads the veterinarian to carry out tests to diagnose FIV. As for HIV infection in humans, FIV infection progresses through various stages (Table 1): the clinical stages which have been recognized in the cat include an acute stage, an asymptomatic stage of variable duration and a terminal stage; however in cats, as previously mentioned, a clear distinction between the three stages is difficult and not all stages always occur.

The evolution of FIV is well characterized only in experimental infections: 4-5 weeks after the inoculation of the virus, fever and neutropenia appear and persist for 1-9 weeks. A generalised lymphadenopathy, lasting 2-9 months, may also be present. Subsequently there is an asymptomatic period which, in many cats, is not followed by the development of fatal FIV-correlated diseases. These animals do, however, still show depletion of CD4+ cells and inversion of the CD4+/CD8+ cell ratio. Curiously, many of these cats develop B-cell lymphomas [6] and neurological disorders, which are quite rare in naturally infected animals.

In the natural history of FIV, the first stage, which is the primary phase of the infection, is characterized by clinical symptoms of variable severity, such as fever, diarrhoea, conjunctivitis and lymphadenopathy. These clinical manifestations very often last only a short time and may pass unobserved. Laboratory tests may, however, reveal the presence of  lymphocytopenia and a marked neutropenia.

The severity of the symptoms present during the primary stage varies with age: newly born kittens develop a more severe and persistent lymphadenopathy, while elderly cats show minimal signs of the disease although this progresses more rapidly to the next stage. Mortality is low during the initial phase. After this stage only a few cats develop a severe, generalised lymphadenopathy (Fig. 1), which can persist for a few months and be the source of diagnostic problems since, cytologically, it may be mistaken for a lymphoproliferative disorder.

Once the acute stage has finished, most cats enter into the latency period, during which nothing clinically significant takes place. This period may last for years (5-10 years) and its progression to the final stage depends on various factors which include age, the state of health of the patient during the early stages of the infection, the dose and route of inoculation of the virus and finally the immune status of the cat.

In general, progression to the terminal stage is faster in cats which have been infected as kittens than in cats infected as adults. The lifestyle of the animal as well as its possibility of being exposed to other infectious agents are also important. Such exposure may in fact cause a cyclic reactivation of the immune system, with consequent multiplication of CD4+ cells, the preferred FIV target, and reactivation of the virus. In such cases the asymptomatic period may be shortened by a few years. Laboratory tests carried out during the asymptomatic phase may sometimes show hypergammaglobulinaemia which, if present in an apparently healthy animal, can be the sign of an underlying infection.

Advanced stage (ARC or FAIDS): cats which do enter into the advanced stage of the disease have the immunodeficiency syndrome and can develop chronic or opportunistic infections. In this stage the diseases most commonly diagnosed are the stomatitis/gingivitis/faucitis syndrome (Fig. 2), bone marrow alterations such as anaemia and leukopenia (see under retroviral diseases), renal failure, haemoplasmosis, other opportunistic infections (mycoses, herpes virus infections, mange, bacterial infections, sinusitis, etc.), ocular inflammations (uveitis  and chorioretinitis) and, less frequently, neoplasms, in particular digestive tract lymphomas (Fig. 3). The likelihood of developing this type of tumour is in fact much higher (up to 10 times depending on the study) in FIV-positive cats than in FIV-negative ones. The development of severe parasitic (demodicosis, pediculosis) or fungal skin diseases  in an adult cat should ALWAYS alert the veterinarian to the possibility of dealing with an immune-depressed patient and tests for FIV and feline leukaemia virus (FeLV) should, therefore, be carried out.

Disorders of both the central and peripheral nervous systems often complicate the evolution of HIV infections in humans and the same happens in cats infected by FIV. “Dementia”, in the form known in man, is quite difficult to recognize in cats; however, patients with FIV-related neurological disorders can have seizures, behavioural alterations, anisocoria and paresis.

In cats that have been infected for a long time the most common manifestation is  chronic ulcerative stomatitis. Apparently, however, this syndrome occurs only in cats in which other infectious agents apart from FIV are present, and indeed it does not develop in experimentally infected SPF (pathogen free) cats. The concomitant infection which has been most frequently identified in patients with an FIV-associated stomatitis is that caused by calicivirus, which is, therefore, considered a co-factor for the possible induction of the syndrome, even if the underlying mechanism of the development of the disease is not entirely understood. Reproductive disorders have also been reported in FIV-infected cats and these can usually be attributed to the presence of the virus (identified by PCR) in foetal and placental tissues. Finally, an increasing number of publications have reported renal involvement associated with a more or less evident proteinuria. The renal damage in FIV-infected cats is caused by glomerular or tubulo-interstitial lesions which may be directly due to the virus or develop as a consequence of immune-mediated lesions. Other factors which contribute to renal damage are the polyclonal activation of B cells, the consequent hyperglobulinaemia  and high levels of circulating immune-mediated complexes.

DIAGNOSIS

FIV infections are usually diagnosed on the basis of a positive result of an enzyme-linked immunosorbent assay (ELISA) antibody screening test. Similarly to what happens in humans for HIV infections, tests used to diagnose FIV are based on the detection of antibodies produced against the virus, as FIV does not produce a sufficient number of viral particles to allow their detection in the blood or other fluids with routine immunological tests.

Seroconversion takes place 2-4 weeks after the infection and after this period antibodies can be detected by the tests, although in some cats the production of anti-FIV antibodies may take longer.

Most diagnostic test kits on the market use the ELISA method, which is extremely sensitive (Table 3): false negative results are rare, while false positive results can be found in  about a third of the cats, depending on the regional seroprevalence. For this reason ELISA-positive cats, especially if healthy, should be further assessed by using a western blot test. It is worth remembering that, just as for FeLV, false positive and difficult-to-interpret results are more frequent when the assay is conducted on whole blood or blood collected into EDTA, rather than on serum (Fig. 4).

Table 3. Sensitivity of the ELISA.

Although viral shedding is quite low, especially during the asymptomatic stage, the presence and the quantity of the virus can be determined by PCR analysis on whole blood. This investigation seems to be particularly useful in symptomatic cats in order to assess a possible response to antiviral therapy. In such cases quantitative PCR, if available as a routine examination, can be extremely useful because, just as in humans, it can determine the amount of circulating virus and evaluate the fall in viral load following specific therapy. The specificity and sensitivity of the PCR are, however, extremely variable (40-100%) and this analysis should, therefore, be used only in selected cases. It should also be checked that the laboratory is capable of identifying the viral strains (A, B, C, etc.) present locally. 

When doing a routine test in a kitten it is worth remembering that although a kitten born from a FIV-positive queen is unlikely to be infected, the kitten has certainly absorbed maternal antibodies against FIV with the colostrum and will, therefore, result positive in an ELISA. Such an animal is not actually infected and, if retested at the age of 6 months, will result negative. Kittens that test positive between 4 and 6 months of age are more probably infected. Kittens should in any case be tested early on, as a negative result is considered reliable. Results from early tests can be used to prevent infected kittens becoming a source of infection for other cats and the positive subjects may be retested later on. An early screening test also improves the compliance of owners, favouring an overall improved surveillance of the infection.

TREATMENT

Although a certain number of cats do still die as a consequence of FIV infection-related diseases, many infected subjects are able to enjoy a long period of good health and in some cases never develop FIV-related diseases. As most of the clinical problems are known to develop due to a dysfunction of the immune system, it is this dysfunction which must be kept under control and, if possible, treated. The presence of a retroviral infection does not, however, modify the therapeutic approach to be followed for any concomitant neoplastic or non-neoplastic diseases which the patient may have. Patients affected by lymphomas or leukaemias should undergo normal chemotherapy and radiation therapy. In the case of an infectious disease the treatment should be guided by the results of appropriate auxiliary tests such cultures of samples for bacteria and fungi and antibiograms; it should, however, be considered that there is a higher rate of uncommon bacterial and fungal infections in FIV-infected cats. A delay in initiating  the correct antibiotic therapy may result in a significantly increased morbidity and mortality. Numerous studies have shown that FIV-infected cats with diseases such as lymphosarcoma, cryptococcosis, stomatitis, anaemia and others, respond just as well to treatment as do non-infected cats.

It is well documented that clinical manifestations in humans do not appear in HIV-infected subjects if the amount of circulating virus is low, a condition that can be present spontaneously in some cases. The most effective therapy currently available for maintaining the viral level low or decreasing its level is highly active antiretroviral therapy (HAART), which allows HIV-positive patients to survive for a long time and with a good quality of life. HAART contains a cocktail of drugs which need to be administered every day. Antiviral therapy has been shown to be effective also in FIV-infected cats, although the drugs that can be used in cats are limited and only a few controlled trials have been published. Azidovudine is the anti-FIV drug which has been most studied; it has been shown to be capable of reducing the plasma levels of the virus and of increasing the number of circulating CD4+ cells. In a controlled clinical trial versus placebo azidovudine improved the degree of stomatitis in naturally infected cats.

In contrast, most of the immunomodulatory agents used in cats have not shown any real efficacy. A possible promising approach for many viral diseases, including FIV, could be the use of interferons, in particular following the launch on the market of a recombinant interferon of feline origin called feline interferon-omega (fIFNω). This is a type III interferon with marked antiviral activity, which has shown considerable efficacy on feline and canine cells and a much greater effect than interferon of human origin. Interferons are a family of cytokines with a broad range of physiological properties including antiviral, immunomodulatory and antiproliferative effects. Alpha-interferons are members of this family which play a fundamental role in the defence against viruses before specific antibodies are present. In fact, in the case of a viral infection alpha-interferons are produced during the initial hours, reaching a peak within 48 hours. Interferon-a2 is one of the many interferons which have shown a dual effect depending on the dose: at a high dose it is a direct antiviral agent, while at a low dose it has an immunomodulatory effect. Unfortunately when injected at high doses antibodies develop within 5-6 weeks. The animal origin of IFNω means that this cytokine can be administered parenterally at high doses without the problem of antibody development. The rationale for using interferon at an antiviral dose is based on the observation that if an effective level of circulating interferon can be maintained beyond the first 2 days of infection, the viral load can be inhibited, thus giving the animal’s T cells time to mount an effective and specific response. Like recombinant human interferon, fIFNω has been tried in FIV- and FeLV-infected cats, with contrasting results. The more recent trials (Hartaman and Gruffydd-Jones) have not reported adverse events with the use of IFNω; however, to date no study has shown a significant decrease of the viral load or an improvement of the CD4:CD8 ratio. In spite of this, most controlled trials have shown evident clinical effects following the use of both drugs. It is worth recalling that the effect of the two types of interferon (IFNαand IFNω) is substantially different. The first, administered per os, has an immunomodulatory effect, while IFNω may be used parenterally and its effect is strictly antiviral.

Table 4. Possible treatments of FIV infection with immunomodulatory or antiviral agents.

PREVENTION

Prophylaxis

Just as for FeLV,  the transmission of an FIV infection requires close contact with an infected subject that is actively shedding the virus. In the case of FIV, the presence of a penetrating wound is also necessary. It is, therefore, unlikely that a cat may contract the infection following a stay in an apartment or in a veterinary practice in which infected subjects are present.

The only form of prophylaxis against FIV infection is to control the cat’s habits, as there is currently only one vaccine available (but not in Italy), the real efficacy_^a of which is not yet known. A cat that lives indoors and never has a chance to go out will never be at risk of an FIV (or FeLV) infection.

_^aThe ABCD (European Advisory Board on Cat Diseases) does not recommend the use of this vaccine in Europe as it makes the serological tests to diagnose the infection useless and it cannot protect against the European viral isolates.  

On the other hand, immunization of FIV-positive cats against other agents (Feline  herpesvirus, Feline calicivirus, FeLV) is indicated when these cats are at risk of secondary or opportunistic infections. Furthermore, FIV-positive patients should be isolated so as to prevent them from having contact with other subjects. Owners should report any clinical signs that develop to the veterinarian, in order to allow early treatment of potentially severe disorders. Owners should also be capable of examining the cat’s gums (to detect jaundice or pale mucous membranes), palpating lymph nodes and monitoring the characteristics of the animal’s micturition and defecation.

Control of feline immunodeficiency virus in special conditions

Cats living in a shelter. The risk of FIV transmission is minimal in shelters in which there are socially well-adapted subjects and in which social conflicts are reduced to a minimum. In communities in which the serological status is not known, should a subject result positive all the cats present must be tested. The virus is transmitted mainly during fights and with bites, so if there are no episodes of aggression the probability of transmission is low.

In follow-up studies of cats living together in a community, after many years only very few cats (less than 2%) showed seroconversion. Clearly all subjects living together must be sterilised and no new cats should be introduced into the group, so as to avoid disrupting the harmony and consolidated behaviours. If, however, other contagious chronic infections, such as herpes virus infections, are present in the group, the risk of transmission may increase as the viraemia could be higher because of the continuous immune stimulation of the organisms living together.

The ABCD recommends that, in shelters, cats positive for FIV should be kept in individual cages until they can be managed in a community setting free of social conflicts.

Breeding centres. The prevalence of FIV is normally extremely low in breeding centres. In such centres the recommendation is to test all new cats introduced, even if the risk of introducing FIV-positive cats remains low. The situation is different if mixed breed cats are introduced into the centre. In such cases it is advisable to test the cat first and then implement a sort of a quarantine, with the subsequent introduction of the cat into the community only after at least 6 weeks have passed and  the cat has resulted negative in a second confirmatory test.

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