An Important Feline Pathogen: Feline Immunodeficiency Virus (FIV)

An Important Feline Pathogen: Feline Immunodeficiency Virus (FIV)

 

Maigan Espinili Maruquin

 

It was on 1986 when immunodeficiency- like syndrome in a cat was discovered and was described to be of important model to study human AIDS (Pedersen, Ho et al. 1987). According to Harbour, D.A. et al. (2004), infected cats showed a variety of clinical signs of an immunodeficiency disorder but are free of feline leukemia virus or FeLV. It is in lentivirus genus of retroviruses and was then brought to nomenclature in line with that of human immunodeficiency virus (HIV), which is known to cause acquired immunodeficiency syndrome (AIDS) in people. The feline immunodeficiency virus (FIV) is of important pathogen with significant cause of disease in cats (Harbour, D.A. et al. 2004) (Hosie, Techakriengkrai et al. 2017)

 

Structure and Replication

Fig. 1. The structure of feline immunodeficiency virus. (Westman, Malik et al. 2015)

 

FIV is a member of the Lentivirus genus within the Retroviridae family.  Slightly smaller than other lentiviruses, FIV virions are 100–110 nm in diameter with a cylindrical core. It has a helical ribonucleoprotein strand which is surrounded by a membrane (virus envelope) that is derived from the outer membrane of the infected cell during the process of budding (Harbour, D.A. et al. 2004) (Miyazawa, Tomonaga et al. 1994). The env glycoproteins play important roles to include (1) receptor interactions with cells; (2) virus penetration and membrane fusion activity; and (3) the primary targets for antibodies and other effectors of immune functions (Bendinelli, Pistello et al. 1995). Transmembrane protein and surface protein, about 40 kDa and 95 kDa, respectively, composed the short spikes in its membrane wherein antibodies are directed.

 

After attaching to the cell, the virus enters, following uncoating. Once inside, the reverse transcriptase starts to make double- stranded DNA copy of the virion RNA genome, considering this component to be very important. The FIV has a Mg2- dependent reverse transcriptase, while FeLV has Mn2-dependent reverse transcriptase. The double-stranded DNA copy is being integrated into the chromosomal DNA of the host cell (known as a provirus). The replication can only take place after the provirus has been integrated, which is important for the further replication. During transcription of the provirus, viral proteins are being manufactured (Harbour, D.A. et al. 2004). FIV has been classified into five subtypes, Subtypes A-E (Sodora, Shpaer et al. 1994, Kakinuma, Motokawa et al. 1995, Pecoraro, Tomonaga et al. 1996, Perharic, Bidin et al. 2016).

 

Infection and Transmission and Clinical Signs

The FIV shares similar structure, life cycle and pathogenesis with the human immunodeficiency Virus (HIV), but not their host. The significant similarities between FIV and HIV makes FIV a remarkable model to further therapeutic studies in HIV (Elder and Phillips 1995, Miller, Cairns et al. 2000, Troyer, Pecon-Slattery et al. 2005, Perharic, Bidin et al. 2016).

 

Most clinical signs associated with FIV infection may be a direct result of the viral infection, or as a consequence of the immunodeficiency syndrome that is associated with infection and caused by the secondary and opportunistic infections (Harbour, D.A. et al. 2004) (Perharic, Bidin et al. 2016). It has been reported that majority of natural FIV infections are primarily transmitted by biting during antagonistic or mating interactions (Perharic, Bidin et al. 2016, Miller, Boegler et al. 2017). On the other hand, experiments also reported vertical transmission via colostrum and milk (Miller, Boegler et al. 2017). Mechanisms of viral excretion were detected through saliva FIV RNA, DNA or antibodies or though isolation of virus in saliva or oral tissues (Yamamoto, Sparger et al. 1988, Pedersen, Yamamoto et al. 1989, Yamamoto, Hansen et al. 1989, Poli, Giannelli et al. 1992, Matteucci, Baldinotti et al. 1993, Miller, Boegler et al. 2017)

 

Similar to HIV infection, FIV has underlying defect which causes progressive disruption of the host’s immune functions with slow manifestations of clinical signs. The prevalence of the FIV infection varies depending or the geographic locations, age and gender, and their health status (Bendinelli, Pistello et al. 1995). FIV infections, having nonspecific clinical manifestations, long incubation period and possible long-term asymptomatic phase makes it often left undiagnosed (Perharic, Bidin et al. 2016).  For lentiviruses, once established, infections usually persist for the lifetime of the infected hosts, and so with the FIV infection (Bendinelli, Pistello et al. 1995). It has been observed that as the disease progresses, the clinical signs become more persistent and more severe (Harbour, D.A. et al. 2004). The clinical manifestation of infection was however described to undergo staging.

 

During the primary infection, acute phase, it is clinically silent and commonly manifests itself as a transient illness (1 to 4 weeks). The hosts were described with lymphadenopathy, mild pyrexia, dullness, depression, anorexia transient neutropenia, acute diarrhea, and mild upper respiratory signs (Ishida and Tomoda 1990, Bendinelli, Pistello et al. 1995). However, aside from the lymphoid tissues, feline thymus was observed to be another site of viral replication during the acute stage of FIV infection wherein lesions develop about 4 weeks after infection (Harbour, D.A. et al. 2004).

 

The asymptomatic phase is when infections remained clinically inapparent for prolonged periods usually not sooner than 1.5 to 2 years post infection (Bendinelli, Pistello et al. 1995). These cats consistently positive, and are asymptomatic carriers (Ishida and Tomoda 1990). Despite the low progress of infection from the acute phase, few cats may skip an asymptomatic period and experience the subsequent symptomatic phases (Bendinelli, Pistello et al. 1995). Evidences show chronic inflammatory lesions may be present in the intestine but no significant large neuron loss (Harbour, D.A. et al. 2004).

 

In the terminal stages of FIV infection, immunodeficiency phase, microscopic lesions are more consistent, but are not specifically for FIV (Harbour, D.A. et al. 2004). The viral replication increases and clinical disease becomes apparent (Westman, Malik et al. 2019).

 

In the FIV infection, the persistent generalized lymphadenopathy (PGL) exists in a relatively short duration or in some cases, cats develop concurrent illness (Ishida and Tomoda 1990).  This stage is characterized by a long-lasting generalized enlargement of lymph nodes with symptoms of recurrent fevers, anorexia, weight loss, or nonspecific behavioral changes (Bendinelli, Pistello et al. 1995).

 

The AIDS- Related Complex (ARC) is where chronic problems start to show up. Similar to human, hosts experience weight loss without marked emaciation, lymphadenopathy, fever, stomatitis/ gingivitis, skin diseases, upper respiratory diseases, and/ or enteric disease and hematologic abnormalities. There are chronic secondary infections of the oral cavity, upper respiratory tract, and other body sites but no opportunistic infections observed. Also, cats at this stage of infection tend to develop a syndrome similar to human AIDS and eventually die in a short period of time. Usually, ARC stage progresses to FAIDS (Hopper, Sparkes et al. 1989, Ishida and Tomoda 1990, Bendinelli, Pistello et al. 1995).

 

In FAIDS, it is like the full- blown human AIDS. They suffer from severe secondary infections. They develop tumors to include high- and low-grade lymphosarcomas. There are neurologic abnormalities observed in FIV-infected cats including altered behavior and attitude, convulsions, nystagmus, ataxia, sterotypic motor behavior (repetitive, compulsive roaming), intention tremors, dementia, paralysis (rare), abnormal slow motor and sensory nerve conduction velocities, and histopathological abnormalities. With opportunistic agents, infections lead to treatment resistant and rapid worsening of the condition where survival is usually less than 1 year once diagnosed (Pedersen, N. C. 1993) (Ishida and Tomoda 1990, Bendinelli, Pistello et al. 1995).

 

Aside from clinical symptoms that the FIV- infected cats manifest, hematological changes are also observed. Similar to HIV, the FIV infection is a progressive depletion of the CD4⁺ helper inducer T-lymphocyte subset. For young adult cats, the decrease in CD4⁺ lymphocytes is from early decreases during primary infection to gradual decrease (Dua, Reubel et al. 1994, Bendinelli, Pistello et al. 1995).  Terminally ill cats show progressive anemia and hematological abnormalities have become more frequent and often more profound as the disease progresses (Harbour, D.A. et al. 2004).

 

Histopathological changes are also recorded. Changes show general pattern of exuberant follicular hyperplasia and follicular pleomorphism followed by progressive follicular exhaustion and involution.  Splenic changes show lesions similar in the lymph nodes, while the thymus may show atrophy (Beebe, Dua et al. 1994, Bendinelli, Pistello et al. 1995). Whereas, histopathological lesions are mainly evident in the advanced stages of infection in non- lymphoid tissues. Kidney shows varied abnormalities and oral lesions usually are mild or proliferative gingivitis and periodontitis (Bendinelli, Pistello et al. 1995).

 

Diagnosis

The FIV infection is a result of the integration of provirus into the cat’s genome, which leads in lifelong infection (Westman, Malik et al. 2019). Diagnosis is predominantly on serological tests, whereas the presence of antibody would indicate persistent FIV infection because the immune response to FIV does not eliminate the virus. On the other hand, maternally derived antibodies (MDAs) are usually detected by the diagnostic kits for kittens under 16 weeks old that test positive, thus, they are retested about 4 months later (Harbour, D.A. et al. 2004).

 

Rapid diagnostic kits for FIV are available, usually coupled with FeLV diagnostic kit. The Bioguard Corporation has been producing VETlabs FeLV Ag/ FIV Ab Combo Test. This is a sandwich lateral flow immunochromatographic assay for rapid and qualitative detection of both FeLV antigen and FIV antibodies. The test device has a testing window, coated by an invisible T (test) zone and C (control) zone. When sample is applied into the sample well on the device, the reagent will laterally flow on the surface of the test strip. Enough FeLV Ag/ FIV Ab in the sample will show a visible T band, while control band should always appear. Thus, the device can accurately indicate the presence of FeLV Ag/ FIV Ab in the specimen. Serum, plasma, or blood may be used as specimen for the diagnosis.

 

Aside from using rapid diagnostic test kits, other methods include virus isolation, detection of the retroviral enzyme reverse transcriptase and detection of the viral genome in infected cells by either in situ hybridisation or PCR. The use of specific monoclonal antibodies with an ELISA measures the amount of core antigen produced and is a useful alternative serological technique (Harbour, D.A. et al. 2004) (Guiot, Rigal et al. 1995) and the most commonly used. Although there are  easy-to-use ELISA kits that are commercially available,  false-positive and false-negative results have been reported (Bendinelli, Pistello et al. 1995) (Harbour, D.A. et al. 2004).  Western blotting could then be used to confirm the result and radioimmunoprecipitation assay (RIPA), followed by SDS-polyacrylamide gel electrophoresis analysis, or neutralization to detect antibodies that are present in serum or plasma (Harbour, D.A. et al. 2004; Egberink, H. F. et al. 1992; Tozzini, F et al. 1993) (Yamamoto, Hansen et al. 1989, Hosie and Jarrett 1990, Egberink, Lutz et al. 1991, Bendinelli, Pistello et al. 1995).

 

FIV can be isolated, usually reserved for research purposes because it is expensive and labor intensive and does not give a rapid result (Harbour, D.A. et al. 2004) (Bendinelli, Pistello et al. 1995). The verification of the virus presence in the culture is via immunofluorescence, electron microscopy and reverse transcriptase assay, or with a commercial antigen ELISA (Harbour, D.A. et al. 2004). Immunohistochemistry methods may also be used to locate FIV antigens in infected tissues (Matsumura, S. et al. 1993) (Toyosaki, Miyazawa et al. 1993, Dua, Reubel et al. 1994, Lombardi, Poli et al. 1994, Bendinelli, Pistello et al. 1995).

 

The PCR methods has been extensively applied to detect the viral genomes by amplification of specific sequences of DNA in the FIV provirus. There is real-time PCR which reduces the risk of cross-contamination. Whereas, in situ hybridisation uses a labelled FIV RNA or DNA probe to detect viral mRNA (Harbour, D.A. et al. 2004) (Bendinelli, Pistello et al. 1995).

 

Vaccines and Disease Management

Various trials were conducted to develop vaccine against FIV. In March 2002, licensed by Fort Dodge Animal Health is the first commercial FIV vaccine which contains two strains of FIV (one each from the USA and Asia) (Harbour, D.A. et al. 2004). Further, DNA vaccine was also put in trial (Hosie, Flynn et al. 1998). So far, whole inactivated virus/ fixed infected-cells vaccines have shown successful results (Tellier, Pu et al. 1998, Hesselink, Sondermeijer et al. 1999) (Matteucci, D. et al., 2000)(Hohdatsu, Okada et al. 1997). The similarities between FIV infection of cats and HIV infection of humans has given broader understanding of the development of potential candidate HIV vaccines (Hosie, Techakriengkrai et al. 2017).

 

The FIV, being the only lentivirus with commercial vaccine provides a unique opportunity to investigate the mechanisms and might contribute to the development of efficacious HIV vaccines (Hosie, Techakriengkrai et al. 2017).

 

Once a cat has been diagnosed with FIV, management depends on individual circumstances, including the views of the owner. For low risk of transmission other than by aggression, euthanasia may not be necessary except however if a very aggressive cat could not be confined indoors. Severely ill FIV- infected cats may be recommended for euthanasia, considering humane grounds. To minimize the transmission of FIV to other cats should always be considered in decision making (Harbour, D.A. et al. 2004).

 

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