Janet K. Yamamoto

Feline immunodeficiency virus infection

Feline immunodeficiency virus (FIV) (formerly feline T-lymphotropic lentivirus or FTLV) was first isolated from a group of cats in Petaluma, California in 1986. The virus is a typical lentivirus in gross and structural morphology. It replicates preferentially but not exclusively in feline T-lymphoblastoid cells, where it causes a characteristic cytopathic effect. The major structural proteins are 10, 17 (small gag), 28 (major core), 31 (endonuclease?), 41 (transmembrane?), 52 (core precursor polyprotein), 54/62 (reverse transcriptase?), and 110/130 (major envelope) kilodaltons in size. The various proteins are antigenically distinguishable from those of other lentiviruses, although serum from EIAV-infected horses will cross-react with some FIV antigens. Kittens experimentally infected with FIV manifest a transient (several days to 2 weeks) fever and neutropenia beginning 4 to 8 weeks after inoculation. This is associated with a generalized lymphadenopathy that persists for up to 9 months. Most cats recover from this initial phase of the disease and become lifelong carriers of the virus. Complete recovery does not occur to any extent in nature or in the laboratory setting. One experimentally infected cat died from a myeloproliferative disorder several months after infection. The terminal AIDS-like phase of the illness has been seen mainly in naturally infected cats. It appears a year or more following the initial infection in an unknown proportion of infected animals. FIV has been identified in cats from all parts of the world. It is most prevalent in high density populations of free roaming cats (feral and pet), and is very uncommon in closed purebred catteries. Male cats are twice as likely to become infected as females. Older male cats adopted as feral or stray animals are at the highest risk of infection, therefore. The infection rate among freely roaming cats rises throughout life, and reaches levels ranging from less than 1% to 12% or more depending on the area. Clinically affected cats tend to be 5 years or older at the time of hospitalization. Experimental and seroepidemiologic studies suggest that FIV is transmitted mainly by bites. Intimate, non-traumatic contact (mutual grooming, shared use of food, water and litter pans) is inefficient in transmitting the infection. In utero and venereal transmission could not be demonstrated in laboratory settings. There is no statistical linkage between FIV and feline leukemia virus (FeLV) infections in nature. The FeLV infection rate in FIV-infected animals is the same as it is for non-FIV-infected cats.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of IL-2-independent feline lymphoid cell lines chronically infected with feline immunodeficiency virus : importance for diagnostic reagents and vaccines

Two interleukin 2 (IL-2)-independent feline immunodeficiency virus (FIV) producer cell lines (FL-4 and FL-6) were produced by selecting cells from an IL-2-dependent culture of mixed peripheral blood lymphocytes infected with FIV. The new cell lines have been stable for over 1 year and spontaneously produce FIV with an average reverse transcriptase titer of 300,000 cpm/ml and an average sucrose gradient purified viral protein concentration of 1 mg/l. FIV produced from these cultures is highly infectious in vitro and in vivo. The FL-6 cell line was phenotyped as expressing the feline CD8 and Pan-T antigens, while the FL-4 cell line expressed the CD4, CD8, and Pan-T antigens. Both cell lines, however, express high levels of viral core and envelope proteins. Paraformaldehyde-inactivated whole virus and similarly inactivated whole-cell virus preparations induced a strong antibody response to core and envelope antigens in immunized cats. The establishment of FIV-producing feline IL-2-independent peripheral blood lymphocyte lines should be valuable for the development of FIV-diagnostic reagents and vaccines and also as a model for human acquired immunodeficiency syndrome vaccine development.

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

Abstract 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.

Dual-subtype FIV vaccine protects cats against in vivo swarms of both homologous and heterologous subtype FIV isolates

ObjectiveTo evaluate the immunogenicity and efficacy of an inactivated dual-subtype feline immunodeficiency virus (FIV) vaccine. DesignSpecific-pathogen-free cats were immunized with dual-subtype (subtype A FIVPet and subtype D FIVShi) vaccine and challenged with either in vivo- or in vitro-derived FIV inocula. MethodsDual-subtype vaccinated, single-subtype vaccinated, and placebo-immunized cats were challenged with in vivo-derived heterologous subtype B FIVBang [10–100 50% cat infectious doses (CID50)], in vivo-derived homologous FIVShi(50 CID50), and in vitro- and in vivo-derived homologous FIVPet(20–50 CID50). Dual-subtype vaccine immunogenicity and efficacy were evaluated and compared to single-subtype strain vaccines. FIV infection was determined using virus isolation and proviral PCR of peripheral blood mononuclear cells and lymphoid tissues. ResultsFour out of five dual-subtype vaccinated cats were protected against low-dose FIVBang (10 CID50) and subsequently against in vivo-derived FIVPet (50 CID50) challenge, whereas all placebo-immunized cats became infected. Furthermore, dual-subtype vaccine protected two out of five cats against high-dose FIVBang challenge (100 CID50) which infected seven out of eight single-subtype vaccinated cats. All dual-subtype vaccinated cats were protected against in vivo-derived FIVPet, but only one out of five single-subtype vaccinated cats were protected against in vivo-derived FIVPet. Dual-subtype vaccination induced broad-spectrum virus-neutralizing antibodies and FIV-specific interferon-γ responses along with elevated FIV-specific perforin mRNA levels, suggesting an increase in cytotoxic cell activities. ConclusionDual-subtype vaccinated cats developed broad-spectrum humoral and cellular immunity which protected cats against in vivo-derived inocula of homologous and heterologous FIV subtypes. Thus, multi-subtype antigen vaccines may be an effective strategy against AIDS viruses.

Dual-subtype FIV vaccine (Fel-O-Vax® FIV) protection against a heterologous subtype B FIV isolate

Vaccine trials were undertaken to determine whether the Fel-O-Vax® FIV, a commercial dual-subtype (subtypes A and D) feline immunodeficiency virus (FIV) vaccine, is effective against a subtype B FIV isolate. Current results demonstrate the Fel-O-Vax FIV to be effective against a subtype B virus, a subtype reported to be the most common in the USA.

Efficacy evaluation of prime-boost protocol : canarypoxvirus-based feline immunodeficiency virus (FIV) vaccine and inactivated FIV-infected cell vaccine against heterologous FIV challenge in cats

Objective:To evaluate the immunogenicity and prophylactic efficacy of immunization schemes employing a recombinant canarypoxvirus (‘ALVAC’)-based feline immunodeficiency virus (FIV) vaccine alone or in combination with an inactivated FIV-infected cell vaccine against homologous and heterologous FIV challenges in cats. Methods:Specific pathogen-free cats were given a total of three immunizations with subtype A vaccines and challenged 4 weeks after the final immunization with 50 median animal infectious doses (ID50) of FIV-Petaluma, a subtype A isolate. Following the initial challenge, protected cats received a second challenge with 75 ID50 of FIV-Bangston, a subtype B isolate. FIV-specific humoral and cell-mediated responses were measured to determine the immune correlates of protection. Results:Two of three cats immunized with the ALVAC-FIV recombinants alone were protected from homologous FIV challenge in the presence of FIV-specific cytotoxic T-lymphocyte (CTL) responses but in the absence of FIV-specific humoral responses. All three cats immunized with the ALVAC-FIV recombinant and boosted with FIV-infected cell vaccine were also protected from homologous FIV challenge in the presence of both FIV-specific CTL and humoral responses. Partial to full protection was observed in ALVAC-FIV/FIV-infected cell vaccine-immunized cats against a heterologous FIV challenge given 8 months after the initial challenge. Two out of three cats had transient infection and the remaining cat had no sign of FIV infection at a dose at which all three control cats were readily infected. Conclusions:Immunization schemes employing ALVAC-based FIV vaccines in combination with inactivated FIV-infected cell vaccine generate protective immune responses that can cross-react with FIV isolates that are genetically distinct from the vaccine strains.

Perspectives on FIV vaccine development

Feline immunodeficiency virus (FIV), discovered a decade ago, is the causative agent of feline immunodeficiency syndrome (FAIDS), a chronically degenerative, fatal disease in domestic cats. Our understanding of the immunopathogenesis of FIV has improved but the development of an effective therapy and prophylaxis has been slow, reflecting the remarkable adaptability of the virus to modern medical intervention. FIV vaccine development has had its successes and failures similar to those encountered in human immunodeficiency virus (HIV) vaccine research. This review summarizes the status of FIV vaccine research, including trials of conventional, recombinant subunit and recombinant vector-based vaccines, and potential mechanisms of vaccine protection. The lessons learned from the FIV model should provide new insights for the approaches toward the development of HIV vaccines.

Is AZT/3TC therapy effective against FIV infection or immunopathogenesis?

In vitro and in vivo prophylactic and therapeutic efficacy of AZT/3TC treatment was evaluated against feline immunodeficiency virus (FIV) infection. In vitro studies utilized FIV-infected peripheral blood mononuclear cells (PBMCs) or FIV-infected T-cell lines treated with AZT (azidothymidine) alone, 3TC alone, or AZT/3TC combination and tested for anti-FIV activity and drug toxicity. AZT/3TC combination had additive to synergistic anti-FIV activities in primary PBMC but not in chronically infected cell lines. In vivo studies consisted of four treatment groups (n=15) of SPF cats receiving AZT/3TC combination (5-75 mg/kg/drug PO BID for 8 or 11 weeks) and one control group (n=9) receiving oral placebo. Group I (n=6, 150 mg/kg/drug/day) was treated starting 3 days pre-FIV inoculation, whereas Group II (n=3, 150 mg/kg/drug/day) and Group III (n=3, 100 mg/kg/drug/day) treatments were simultaneous with FIV inoculation. Group IV treatment (n=3, 100 mg/kg/drug/day) was initiated 2 weeks post-FIV inoculation. All cats were monitored for drug toxicity and FIV infection. Eighty-three percent of cats in Group I and 33% of cats in Groups II and III were completely protected from FIV infection. A significant delay in infection and antibody seroconversion was observed in all unprotected cats from Groups I, II and III. Group IV cats had only a slight delay in FIV antibody seroconversion. Adverse drug reactions (anemia and neutropenia) were observed at high doses (100-150 mg/kg/drug/day) were reversible upon lowering the dose (20 mg/kg/drug/day). In contrast, AZT/3TC treatment had no anti-FIV activity in chronically infected cats. Furthermore, severe clinical symptoms caused by adverse drug reactions were observed in some of these cats. Overall, AZT/3TC treatment is effective for prophylaxis but not for therapeutic use in chronically FIV-infected cats.

Advances in FIV vaccine technology

Advances in vaccine technology are occurring in the molecular techniques used to develop vaccines and in the assessment of vaccine efficacy, allowing more complete characterization of vaccine-induced immunity correlating to protection. FIV vaccine development has closely mirrored and occasionally surpassed the development of HIV-1 vaccine, leading to first licensed technology. This review will discuss technological advances in vaccine designs, challenge infection assessment, and characterization of vaccine immunity in the context of the protection detected with prototype and commercial dual-subtype FIV vaccines and in relation to HIV-1.

Protection of neonatal kittens against feline immunodeficiency virus infection with passive maternal antiviral antibodies

Objective: Maternal antibodies from either vaccinated or feline immunodeficiency virus (FIV)‐infected female cats (queens) were evaluated for their ability to protect kittens against homologous FIV infection. Design: Kittens that received different levels of maternal antiviral antibodies from either vaccinated or infected queens were inoculated with homologous FIV at 1 week post‐parturition and monitored for FIV infection. Maternal antiviral antibodies in the kittens were also measured and compared to the level of FIV infection. Methods: Kittens at 1 week post‐parturition were inoculated intraperitoneally with five median cat infectious doses of FIVPet. FIV infection was monitored by virus isolation for infectious FIV and by nested polymerase chain reaction for proviral DNA. Virus‐neutralizing (VN) antibodies and antibodies to FIV transmembrane peptide and core protein were also monitored throughout the 25 weeks. Results: Neonatal kittens that received high levels of antiviral antibodies from either vaccinated or infected queens were protected from FIV inoculation. Kittens that received low levels of maternal antiviral antibodies were not completely protected from similar FIV inoculation. Protection correlated more closely with the level of maternal VN antibodies than the anti‐p25 antibodies transferred to the kittens. The unprotected kittens born to infected queens were not infected from vertical transmission because all littermates that were not FIV‐inoculated remained free of FIV infection. Conclusions: Maternal antiviral antibodies, including VN antibodies, from either vaccinated or infected queens protected neonatal kittens from FIV inoculation. Thus, maternal antiviral antibodies play a key role in preventing or limiting infection in neonates and such antiviral immunity can be provided by vaccinated queens.