Feline immunodeficiency virus: a brief review.

Feline immunodeficiency virus (FIV), previously known as feline T-lymphotropic lentivirus (FTLV), was first described by Pedersen et al. (1987) who isolated the virus from cats with a variety of clinical signs suggestive of immunodeficiency. Since then FIV has become one of the most studied feline viruses, not least because of its similarity to human immunodeficiency viruses (HIV) which cause acquired immunodeficiency syndrome (AIDS) in man.     

Vaccination against the feline immunodeficiency virus: the road not taken

Natural infection of domestic cats by the feline immunodeficiency virus (FIV) causes acquired immunodeficiency syndrome (AIDS). FIV is genetically related to human immunodeficiency virus (HIV), and the clinical and biological features of infections caused by feline and human viruses in their respective hosts are highly analogous. Although the obstacles to vaccinating against FIV and HIV would seem to be of comparable difficulty, a licensed vaccine against feline AIDS is already in widespread use in several countries. While this seemingly major advance in prevention of AIDS would appear to be highly instructive for HIV vaccine development, its message has not been heeded by investigators in the HIV field. This review endeavours to relate what has been learned about vaccination against feline AIDS, and to suggest what this may mean for HIV vaccine development.     

Virus–host interaction in feline immunodeficiency virus (FIV) infection

Feline immunodeficiency virus (FIV) infection has been the focus of several studies because this virus exhibits genetic and pathogenic characteristics that are similar to those of the human immunodeficiency virus (HIV). FIV causes acquired immunodeficiency syndrome (AIDS) in cats, nevertheless, a large fraction of infected cats remain asymptomatic throughout life despite of persistent chronic infection. This slow disease progression may be due to the presence of factors that are involved in the natural resistance to infection and the immune response that is mounted by the animals, as well as due to the adaptation of the virus to the host. Therefore, the study of virus–host interaction is essential to the understanding of the different patterns of disease course and the virus persistence in the host, and to help with the development of effective vaccines and perhaps the cure of FIV and HIV infections.     

Altered mitogen response of peripheral blood lymphocytes in different stages of feline immunodeficiency virus infection

To elucidate relationship between disease progress and immunologic alteration in feline immunodeficiency virus (FIV) infection, we classified naturally infected cats into clinical stage groups using the working criteria modified from those for human immunodeficiency virus (HIV) infection. Among the five distinct stages described for HIV infection, the three phases; asymptomatic carrier (AC), AIDS related complex (ARC), and acquired immunodeficiency syndrome (AIDS), were evaluated for concanavalin A (Con A)-induced lymphocyte blastogenic activities by using glucose consumption assay. There was a significant decrease of lymphocyte response in AC phase. The loss of response became marked as the disease progressed to ARC and AIDS, with an almost complete loss of mitogen response in AIDS phase. In addition to the loss of a lymphocyte function, AIDS in FIV infection was characterized by marked emaciation, anemia or pancytopenia, and postmortem evidences of opportunistic infections and lymphoid depletion.     

Altered tryptophan metabolism in FIV-positive cats

BACKGROUND: Feline immunodeficiency virus (FIV) is analogous to human immunodeficiency virus, the causative agent of human acquired immunodeficiency syndrome (AIDS). In AIDS patients, a progressive reduction in serum tryptophan concentration occurs because of activation of an inducible tryptophan degradation pathway mediated by elevated lamda-interferon production. HYPOTHESIS: Cats infected with FIV have increased tryptophan catabolism evidenced by reduced circulating concentrations of tryptophan and increased concentrations of the tryptophan catabolite kynurenine. ANIMALS: Convenience sample of 235 cats submitted for diagnostic FIV serology (115 FIV-negative and 120 FIV-positive cats). METHODS: Retrospective, cross-sectional study. Serum was assayed for tryptophan and kynurenine using a high performance liquid chromatography assay with fluorescence and ultraviolet detection, respectively. RESULTS: Tryptophan and kynurenine concentrations were log-normally distributed. Geometric mean concentrations were: tryptophan: FIV-positive 30.6 microM (95% CI: 26.8 34.8 microM), FIV-negative 48.9 [microM (95% CI: 43.6-54.9 microM) (P < .001); kynurenine: FIV-positive 22.7 microM (95% CI: 25.5-10.9 microM), FIV-negative 9.9 microM (95% CI: 20.3-9.03 microM) (P < .001). The ratio of kynurenine to tryptophan was: FIV-positive 4.93 (95% CI: 5.62-4.32), FIV-negative 1.34 (95% CI: 1.53 1.17) (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Serum tryptophan concentration was significantly lower and serum kynurenine concentration was significantly higher in FIV-positive cats. The kynurenine: tryptophan ratio was >3-fold higher in FIV-positive animals, indicating increased tryptophan catabolism in this group. Dietary or pharmacologic intervention to support serum tryptophan concentrations has been shown to be clinically useful in humans with AIDS and might be applicable to cats with FIV infection.     

FIV vaccine development and its importance to veterinary and human medicine: a review FIV vaccine 2002 update and review

Feline immunodeficiency virus (FIV) is a natural infection of domestic cats that results in acquired immunodeficiency syndrome resembling human immunodeficiency virus (HIV) infection in humans. The worldwide prevalence of FIV infection in domestic cats has been reported to range from 1 to 28%. Hence, an effective FIV vaccine will have an important impact on veterinary medicine in addition to being used as a small animal AIDS model for humans. Since the discovery of FIV reported in 1987, FIV vaccine research has pursued both molecular and conventional vaccine approaches toward the development of a commercial product. Published FIV vaccine trial results from 1998 to the present have been compiled to update the veterinary clinical and research communities on the immunologic and experimental efficacy status of these vaccines. A brief report is included on the outcome of the 10 years of collaborative work between industry and academia which led to recent USDA approval of the first animal lentivirus vaccine, the dual-subtype FIV vaccine. The immunogenicity and efficacy of the experimental prototype, dual-subtype FIV vaccine and the efficacy of the currently approved commercial, dual-subtype FIV vaccine (Fel-O-Vax FIV) are discussed. Potential cross-reactivity complications between commercial FIV diagnostic tests, Idexx Snap Combo Test and Western blot assays, and sera from previously vaccinated cats are also discussed. Finally, recommendations are made for unbiased critical testing of new FIV vaccines, the currently USDA approved vaccine, and future vaccines in development.     

Ability of CD8+ T cell anti-feline immunodeficiency virus (FIV) activity and FIV proviral DNA load in mononuclear cells in FIV-infected cats

We investigated the relationship between CD8+ T cell anti-feline immunodeficiency virus (FIV) activity and FIV proviral DNA load integrated in mononuclear cells. The anti-FIV activity and the proviral DNA load were correlated, and the number of proviral DNA copies was high in cats with decreased anti-FIV activity. Particularly, no anti-FIV activity was detected in the cats staged as having an acquired immunodeficiency syndrome (AIDS)-related complex or AIDS, and the number of proviral DNA copies was obviously increased compared to those in the cats in the asymptomatic stage. These results suggest that decreased anti-FIV activity destroys the control of in vivo FIV replication, which leads to an increased proviral DNA load with the progression of the clinical stage of disease.     

A longitudinal study of lymphocyte subsets in a cohort of cats naturally-infected with feline immunodeficiency virus

Despite the potential of feline immunodeficiency virus (FIV) as an animal model for human immunodeficiency virus (HIV) studies, the long term effects of naturally-occurring infection have not been determined. HIV infection causes an ongoing deterioration in immune function which directly correlates with disease, in particular acquired immunodefciency syndrome (AIDS). However, it is not known whether FIV-induced immunosuppression is progressive or related to the clinical condition. This study examined changes in lymphocyte subset numbers of serial samples, taken from cohorts of FIV-positive and FIV-negative cats over an 18-month period. FIV-positive cats were clinically staged as asymptomatic carriers (AC) or cats with AIDS-related complex (ARC), and FIV-negative cats matched and staged on the basis of similar diseases. During the course of the study, 4 FIV-positive cats developed AIDS, classed as the terminal stage of infection. There were no significant differences in the mean absolute numbers of any lymphocyte subset between the onset (to) and the completion (t18) of the study. Similarly there were no significant changes in subset numbers during the 18 months preceding the development of AIDS. While the study period was brief and the sample sizes small, it is postulated that FIV infection in Australia may not necessarily cause progressive immunodeficiency and that FIV-induced immunosuppression (as measured by subset analysis) may not be well correlated with the clinical status of the infected cat.     

Use of two virustatica (AZT, PMEA) in the treatment of FIV and of FeLV seropositive cats with clinical symptoms.

In the present study the therapeutic efficacy and the side effects of two antiretroviral compounds used in human acquired immunodeficiency syndrome (AIDS) research, 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine, Retrovir) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA), were investigated in the treatment of cats naturally infected with feline immunodeficiency virus (FIV) and cats naturally infected with feline leukemia virus (FeLV). AZT was administered subcutaneously at a dose of 5 mg kg-1 body weight every 12 h and PMEA was administered subcutaneously at a dose of 2.5 mg kg-1 body weight every 12 h during a 3 week hospitalization. The therapeutic efficacy of both compounds was investigated. There was a stronger potency of PMEA than of AZT on the regression of stomatitis in FIV and in FeLV infected cats. In addition, in FIV infection PMEA had a stronger effect on the improvement of the general clinical status. Both antiretroviral compounds were potent agents to improve the immunologic status of FIV infected cats by raising the CD4/CD8 ratio. In FeLV infection PMEA and AZT appeared to reduce antigenemia. The hematological side effects caused by PMEA were severe and stronger than those of AZT. Therefore the advantage of PMEA in clinical and immunologic improvement was diminished by the hematologic disorders, which do not allow long term treatment with this drug in the dose used.     

Strain-specific viral distribution and neuropathology of feline immunodeficiency virus

Feline immunodeficiency virus (FIV) is a naturally occurring lentivirus of domestic cats, and is the causative agent of feline AIDS. Similar to human immunodeficiency virus (HIV), the pathogenesis of FIV involves infection of lymphocytes and macrophages, and results in chronic progressive immune system collapse and death. Neuropathologic correlates of FIV infection have not yet been elucidated, and may be relevant to understanding HIV-associated neurologic disease (neuroAIDS). As in HIV, FIV strains have been shown to express differential tendencies towards development of clinical neuroAIDS. To interrogate viral genetic determinants that might contribute to neuropathogenicity, cats were exposed to two well-characterized FIV strains with divergent clinical phenotypes and a chimeric strain as follows: FIV(PPR) (PPR, relatively apathogenic but associated with neurologic manifestations), FIV(C36) (C36, immunopathogenic but without associated neurologic disease), and Pcenv (a chimeric virus consisting of a PPR backbone with substituted C36 env region). A sham inoculum control group was also included. Peripheral nerve conduction velocity, CNS imaging studies, viral loads and hematologic analysis were performed over a 12 month period. At termination of the study (350 days post-inoculation), brain sections were obtained from four anatomic locations known to be involved in human and primate lentiviral neuroAIDS. Histological and immunohistochemical evaluation with seven markers of inflammation revealed that Pcenv infection resulted in mild inflammation of the CNS, microglial activation, neuronal degeneration and apoptosis, while C36 and PPR strains induced minimal neuropathologic changes. Conduction velocity aberrations were noted peripherally in all three groups at 63 weeks post-infection. Pcenv viral load in this study was intermediate to the parental strains (C36 demonstrating the highest viral load and PPR the lowest). These results collectively suggest that (i) 3' C36 genomic elements contribute to viral replication characteristics, and (ii) 5' PPR genomic elements contribute to CNS manifestations. This study illustrates the potential for FIV to provide valuable information about neuroAIDS pathogenesis related to genotype and viral kinetics, as well as to identify strains useful to evaluation of therapeutic intervention.     

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

Eleven feline immunodeficiency virus (FIV) infected asymptomatic carrier (AC) cats were observed for 2 years for development of acquired immunodeficiency syndrome (AIDS). Four of the 11 (36.4%) showed progression of the clinical stage. Persistent generalized lymphadenopathy was noted in three cats as the first sign of illness after the AC phase, while the other showed lymphadenopathy with signs of AIDS-related complex. In all four cats the AIDS-related complex stage lasted for 10 months or longer, and two showed progression of the disease into AIDS. The two cats showing AIDS illnesses died within approximately 1 year after they had developed persistent generalized lymphadenopathy. Pathology confirmed the diagnosis of AIDS characterized by the presence of depletion lesions in the lymphoid organs, and of severe infections of an opportunistic nature. The overall mortality of FIV infected AC cats during a 2 year period was two out of 11 (18.2%). These cats showed decreased concanavalin A mitogen response of peripheral blood mononuclear cells as the disease progressed.     

Detection of feline immunodeficiency virus infection in bone marrow of cats.

Natural or experimental feline immunodeficiency virus (FIV) infection in cats is often associated with hematologic abnormalities which are similar to those observed in human immunodeficiency virus (HIV) infected patients. To determine if cells in bone marrow are infected with FIV and whether severity of hematopoietic disorder is correlated with the level of viral infection, bone marrow tissues from ten experimentally and two naturally FIV infected cats were examined by in situ hybridization for presence of FIV RNA. Seven of the 12 FIV infected cats were also naturally or experimentally coinfected with feline leukemia virus (FeLV). FIV RNA was detected mainly in megakaryocytes and unidentified mononuclear cells in the bone marrow of cats that were sick and had marrow hypercellularity and immaturity. These included all cats in the acute phase of FIV infection and two of seven long term FIV infected cats. One long term FIV infected cat with lymphosarcoma was also positive for FIV RNA in bone marrow cells. The other four long term FIV infected cats were relatively healthy, with normal bone marrow morphology, and were negative for FIV infected cells. Bone marrow from three non-infected and two cats infected with FeLV alone were also negative for FIV RNA by in situ hybridization. We concluded that megakaryocytes and mononuclear cells were targets of the viral infection and that the presence of FIV RNA in cells of the bone marrow correlated with marrow hypercellularity and immaturity, and severity of illness.     

Phylogenetic analysis to define feline immunodeficiency virus subtypes in 31 domestic cats in South Africa

Feline immunodeficiency virus (FIV), a lentivirus, is an important pathogen of domestic cats around the world and has many similarities to human immunodeficiency virus (HIV). A characteristic of these lentiviruses is their extensive genetic diversity, which has been an obstacle in the development of successful vaccines. Of the FIV genes, the envelope gene is the most variable and sequence differences in a portion of this gene have been used to define 5 FIV subtypes (A, B, C, D and E). In this study, the proviral DNA sequence of the V3-V5 region of the envelope gene was determined in blood samples from 31 FIV positive cats from 4 different regions of South Africa. Phylogenetic analysis demonstrated the presence of both subtypes A and C, with subtype A predominating. These findings contribute to the understanding of the genetic diversity of FIV.     

Characterization of morphologic changes and lymphocyte subset distribution in lymph nodes from cats with naturally acquired feline immunodeficiency virus infection.

Lymph nodes were collected at biopsy or necropsy from 18 cats with naturally acquired symptomatic feline immunodeficiency virus (FIV) infection and from 18 seronegative cats. Thirty-five of the cats were domestic shorthairs and one was a Persian cross. The cats ranged from 7 months to 16 years of age and were mainly obtained from California veterinary practitioners, a California cattery, and a Veterinary Teaching Hospital. Based on clinical signs present at tissue collection, ten FIV-infected cats fell into the acquired immunodeficiency syndrome (AIDS)-related complex (ARC) clinical stage and eight in the terminal (AIDS) stage of FIV disease. All cats were FeLV negative by antigen ELISA. Histologic sections of lymph nodes from each cat were examined blindly and were categorized as hyperplastic, involuting, mixed hyperplastic and involuting, depleted, or normal based upon subjective evaluation of follicles and paracortex. The relative abundance of plasma cells was evaluated in methyl green pyronin (MGP) and hematoxylin and eosin-stained sections. Similar numbers of FIV-seropositive and -seronegative cats fell into each lymph node category. The only difference evident between FIV-infected cats and control cats was in the degree of plasmacytosis present; moderate to marked plasmacytosis was present in 13/18 FIV-infected cats but in only 3/18 control cats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and safety of a feline immunodeficiency virus vaccine

Fel-O-Vax FIV is an inactivated virus vaccine designed as an aid in the prevention of infection of cats, 8 weeks or older, by feline immunodeficiency virus (FIV). It contains two genetically distinct FIV strains. The efficacy of this vaccine was demonstrated in a vaccination-challenge study designed to meet various regulatory requirements for registering the vaccine. Eight-week-old kittens were vaccinated with an immunogenicity vaccine which contained minimal release levels of FIV antigens formulated with a proprietary adjuvant system. Twelve months later, all vaccinates and controls were challenged with a heterologous FIV strain. Following the vigorous challenge exposure, cats were monitored for FIV viremia. It was found that 16% of the vaccinated cats developed viremia while 90% of the controls became persistently infected with FIV, which demonstrated that the vaccine was efficacious and the protective immunity lasted for at least 12 months. The safety of the vaccine was demonstrated by a field safety trial in which only 22 mild reactions of short duration were observed following administering 2051 doses of two pre-licensing serials of Fel-O-Vax FIV to cats of various breeds, ages and vaccination histories. Thus, Fel-O-Vax FIV is safe and efficacious for the prevention of FIV infection in cats.     

IgG from acutely infected cats blocks mucosal feline immunodeficiency virus infection

We have previously shown an absence of detectable systemic or local infection in cats exposed to an infectious (100 TCID(50)) feline immunodeficiency virus (FIV) plasma inoculum via either the rectal or vaginal mucosa. In contrast, this same plasma inoculum was infectious via parenteral inoculation. Moreover an equivalent dose of cell-free tissue culture-origin virus inoculum infected 100% of cats by either the rectal or vaginal exposure route. To evaluate this phenomena, we used a tissue culture system to identify a heat-stable factor in the plasma of cats acutely (3 weeks) infected with FIV that blocked infection of naive peripheral blood mononuclear cells (PBMC) by either cell-free or cell-associated FIV in vitro. A single application of as little as a 1:200 dilution of either heparinized or Alsevier's anticoagulated plasma effectively inhibited production of FIV p26 in culture over a 21-day co-culture period. Depletion of antibody using a protein A column abrogated the inhibitory effect of FIV plasma against in vitro FIV infection. Co-inoculation of heat-inactivated plasma with 400 TCID(50) FIV-B-2542 cell-free supernatant virus onto the vaginal mucosa of two cats resulted in complete inhibition of infection in one cat and increased time to infection in the second. Thus, antibody found in the plasma of cats acutely infected with FIV blocks cell-associated and cell-free infection, inhibits virus production in previously infected cells, and reduces mucosal transmission efficiency in vivo. Extrapolation may help explain the relatively inefficient mucosal transmission of human immunodeficiency virus-1 (HIV) and other lentiviruses.     

Lessons from the cat: development of vaccines against lentiviruses

Feline immunodeficiency virus (FIV) is a natural infection of domestic cats, which produces a disease with many similarities to human immunodeficiency virus (HIV) infection in man. The virus is an important cause of morbidity and mortality in pet cats worldwide. As such an effective vaccine is desirable both for its use in veterinary medicine and also as a model for the development of an HIV vaccine. A large number of candidate vaccines have been tested against feline immunodeficiency virus. These include inactivated virus and infected cell vaccines, DNA and viral vectored vaccines, subunit and peptide vaccines and vaccines using bacterial vectors. Ultimately, the development of inactivated virus and infected cell vaccines led to the release of the first licensed vaccine against FIV, in 2002. This review highlights some of the difficulties associated with the development of lentiviral vaccines and some of the lessons that have been learned in the FIV model that are of particular relevance to the development of HIV vaccines.     

Feline immunodeficiency. ABCD guidelines on prevention and management

OverviewFeline 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.InfectionFeline 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 signsInfected 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.DiagnosisPositive 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 managementCats 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 recommendationsAt 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.     

Quantification of viral ribonucleic acid in plasma of cats naturally infected with feline immunodeficiency virus

OBJECTIVE: To assess plasma viral RNA concentration in cats naturally infected with feline immunodeficiency virus (FIV). ANIMALS: 28 FIV-infected cats. PROCEDURE: Cats were categorized into 1 of the 3 following stages on the basis of clinical signs: asymptomatic (nonclinical) carrier (AC; n = 11), acquired immunodeficiency syndrome-related complex (ARC; 9), or acquired immunodeficiency syndrome (AIDS; 8). Concentration of viral RNA in plasma (copies per ml) was determined by use of a quantitative competitive polymerase chain reaction (QC-PCR) assay. Total lymphocyte count, CD4+ cell and CD8+ cell counts, and the CD4+ cell count-to-CD8+ cell count ratio were determined by use of flow cytometry. RESULTS: Plasma viral RNA concentration was significantly higher in cats in the AIDS stage, compared with cats in AC and ARC stages. Most (5/7) cats in the AIDS stage had low total lymphocyte, CD4+ cell, and CD8+ cell counts. CONCLUSIONS AND CLINICAL RELEVANCE: Concentration of plasma viral RNA is a good indicator of disease progression in FIV-infected cats, particularly as cats progress from the ARC to the AIDS stage. Determination of CD4+ and CD8+ cell counts can be used as supportive indicators of disease progression.