Treatment of FeLV-induced immunodeficiency syndrome (FeLV-FAIDS) with controlled release capsular implantation of 2',3'-dideoxycytidine.

2',3'-dideoxycytidine (ddC) inhibits replication of the immunodeficiency inducing strain of feline leukemia virus (FeLV-FAIDS) in vitro at concentrations ranging from 1-10 micrograms/ml. Additive antiviral effect is achieved when ddC is combined with either human recombinant alpha interferon (IFN alpha) or tumor necrosis factor (TNF) plus IFN alpha. Initial in vivo pharmacokinetic studies in cats, utilizing bolus intravenous administration of ddC (20 mg/kg), resulted in peak plasma concentrations of 15 micrograms/ml 1 min after administration and a half-life of approximately 1 h. These values could not be augmented with high levels of the deaminase blocker tetrahydrouridine administered prior to or concurrently with ddC. In vivo trials utilizing multiple, daily intravenous injections of ddC could not prevent the development of persistent viremia in cats infected with FeLV-FAIDS. To enhance ddC pharmacokinetics and antiviral activity, controlled release capsular implants were developed by blending ddC with a copolymer consisting of DL-lactide glycolide and hydroxypropyl cellulose, which was melt-spun into fibers and encapsulated in a sheath of polyethylene glycol for subcutaneous implantation. Pharmacokinetic studies, conducted in cats receiving an average dose of 600 mg of ddC, indicated an average peak plasma concentration of 17 micrograms/ml achieved at 6 h post implantation with 3.5 micrograms/ml noted at 48 h; and an extension of plasma half-life from 1.5 (bolus subcutaneous injection) to 20 h. sustained plasma concentrations of 1.5 to 10 micrograms/ml, equivalent to ddC levels previously shown to have anti-FeLV activity in vitro, were maintained throughout a 72 h period. Implantation devices could be replenished every 48 h and elevated plasma levels were sustained for four weeks without signs of clinical toxicity, sepsis or significant alterations in the hemogram. Initial clinical trials employing controlled release capsular ddC implants in vivo indicate significant retardation of FeLV-FAIDS replication throughout a four week treatment period.

Protection against feline leukemia virus infection by use of an inactivated virus vaccine.

The protective immunity induced by 3 experimental FeLV vaccines were evaluated: Prototype inactivated FeLV vaccine developed from a molecularly cloned FeLV isolate (FeLV-FAIDS-61E-A); a mixture of immunodominant synthetic peptides corresponding to regions of the FeLV-Gardner-Arnstein-B (FeLV-GA-B) envelope proteins; and an adjuvant-disrupted but non-activated virus prepared from a non-cloned FeLV field isolate comprised of subgroup A and B viruses (FeLV-05821-AB). Included as controls were parallel groups of cats inoculated with adjuvants alone or with an established commercial FeLV vaccine. After each inoculation and after virulent virus challenge exposure, sera from all cats were assayed for ELISA-reactive antibody against purified FeLV, FeLV neutralizing (VN) antibody, and FeLV antigenemia/viremia--viral p27 antigen in serum and within circulating leukocytes. Immunity was challenged by oral/nasal exposure of vaccinated and control cats with FeLV-FAIDS-61E-A or FeLV-05821-AB, an infective, noncloned, tissue-origin, FeLV field isolate containing subgroup-A and -B viruses. Vaccine-induced immunity was assessed by comparing the postchallenge-exposure incidence of persistent viremia and the pre- and postchallenge exposure titers of VN and ELISA antibody in cats of the control and vaccine groups. The percentage of cats, that resisted development of persistent viremia after FeLV challenge exposure and the preventable fraction (PF) for the vaccine groups (which adjusts for the severity of the challenge and the degree of innate resistance in the controls) were as follows: adjuvant controls, 26%; FeLV-FAIDS-61E-A inactivated virus vaccine, 95% (PF = 93.2%); FeLV-GA-B peptide vaccine, 5% (-28.4%); FeLV-05821-AB noninactivated vaccine, 67% (55.4%); and commercial FeLV vaccine, 35% (12.2%). The prechallenge exposure mean VN antibody titer for each group was: less than 1:8 in the adjuvant controls; 1:43 in the FeLV-FAIDS-61E-A-vaccinated cats; less than 1:8 in the peptide-vaccinated cats; 1:38 in the noninactivated virus-vaccinated cats group; and 1:12 in the cats vaccinated with the commercial vaccine. Thus, induction of VN antibody in the vaccinated cats, although modest, appeared to be correlated with induction of protective immunity as defined by resistance to FeLV challenge exposure. Results of these studies indicate that inoculation of cats with an experimental inactivated virus vaccine prepared from a molecularly cloned FeLV isolate was most effective in stimulating protective immunity against heterologous and homologous FeLV challenge exposure.

Feline leukemia virus-induced immunodeficiency syndrome in cats as a model for evaluation of antiretroviral therapy.

Severe progressive immunodeficiency syndrome can be induced experimentally with a molecularly cloned isolate of feline leukemia virus (FeLV-FAIDS). The resultant disease syndrome is characterized by persistent viremia, lymphopenia, progressive weight loss, persistent diarrhea, enteropathy, and opportunistic infections. The onset of clinical immunodeficiency disease is prefigured by the replication of the FeLV-FAIDS variant virus in bone marrow and other tissues. The FeLV-FAIDS system can be used to evaluate antiviral agents which act on steps in the replication cycle which are conserved among retroviruses (e.g. reverse transcriptase, protease, assembly). The persistence and magnitude of viremia serves as a useful parameter in antiviral studies because it can be easily measured, presages the eventual development of immunodeficiency, and provides a convenient indicator of therapeutic efficacy either in preventing de novo FeLV infection or in reversing or ameliorating established infection. We describe here the evaluation of 2',3'-dideoxycytidine (ddC) against FeLV-FAIDS infection - both in vitro in cell culture assay systems and in vivo in cats administered ddC either via intravenous bolus dosage or via controlled release subcutaneous implants. We found that, although controlled release delivery of ddC inhibited de novo FeLV-FAIDS replication and delayed onset of viremia when therapy was discontinued (after 3 weeks), an equivalent incidence and level of viremia were established rapidly in both ddC-treated and control cats. The FeLV model, therefore, can be used to assess rapidly experimental single agent or combined antiviral therapies for persistent retrovirus infection and disease.