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The effects of antiviral agents on feline immunodeficiency virus infection

Meers, Joanne (1994) The effects of antiviral agents on feline immunodeficiency virus infection. PhD thesis, Murdoch University.

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Feline immunodeficiency virus (FIV) is a recently discovered lentivirus with many structural and replicative similarities to human immunodeficiency virus (HIV), and has been suggested as a useful animal model for the evaluation of anti-HIV chemotherapy. The successful use of the model is dependent on the development of techniques to accurately measure the response to antiviral treatment in FIV-infected cats.

FIV was isolated by the co-cultivation of peripheral blood mononuclear cells (PBMC) from seropositive cats with PBMC of seronegative donor cats, or with MYA-1 cells (a feline T-lymphoblastoid cell line). Propagation of FIV isolates was unsuccessful in Crandell feline kidney cells, but was successful in PBMC cultures, primary feline thymocytes, and MYA-1 cells.

The biological characteristics of 3 West Australian isolates of FIV were compared. The isolates had similar properties to each other, and to other reported isolates of FIV, including similar cytopathic effect (CPE), electron microscopic appearance, magnesium-dependent reverse transcriptase (RT) activity, FIV p26 core antigen production and the nucleotide sequence of gag and pol genes.

Tetrazolium-based colourimetric assays were used to quantify the CPE of FIV by demonstrating the loss of cell viability in FIV-infected MYA-1 cell cultures. These assays were then used for the titration of FIV, to assess the cytotoxicity of antiviral agents in vitro, and to determine the protection provided by antiviral agents against the CPE of FIV. Five of 6 agents evaluated by these assays provided protection against CPE induced by 2 isolates of FIV. These agents consisted of 4 RT inhibitors (zidovudine, ddC, ddI, foscarnet) and one inhibitor of virus binding/entry (dextran sulphate). A novel agent, acemannan, provided no protection against the CPE of FIV. The inhibition by zidovudine of RT activity and FIV p26 antigen levels in culture supernatant was also demonstrated.

The titre of FIV in PBMC and plasma was determined in 18 experimentally-infected cats and 2 naturally-infected cats, by end-point dilution cultures. The proportion of PBMC containing provirus was determined by polymerase chain reaction (PCR) on serially diluted samples of PBMC from 10 cats. It was demonstrated that following inoculation with virus, the titre of FIV in PBMC increased rapidly to a relatively high level which was then maintained for up to 8 months. In most cats, approximately 1 in 200 PBMC contained virus by 4 weeks post inoculation (p.i.). The results from PCR generally correlated with those from virus isolation, suggesting that the proportion of FIV provirus that is replication defective may be comparatively low. The titre of FIV in plasma peaked at approximately 2 weeks p.i., and then in many cats, declined to undetectable levels. Virus was not isolated from plasma of 2 naturally-infected cats. In some cats, plasma virus titres did not decline by up to 32 weeks p.i., suggesting that there is a variation in the immune response, which enables some, but not all, cats to clear virus from plasma.

The effect of treatment with cyclosporine on the virus titre in cats experimentally infected with FIV was investigated. Treatment began 24 hrs p.i., and continued for 4 weeks. Cyclosporine treatment lowered plasma virus titres at 2 weeks p.i., but at 4 weeks p.i. the plasma virus titre of cyclosporine-treated cats was significantly higher than in untreated cats. This suggested that, initially, the suppression of T-cell activation resulted in the inhibition of viral expression and lower plasma virus titres. However, the broader immunosuppressive effect of treatment eventually dominated the former effect, resulting in an inability to control viral replication and/or clear virus from plasma. Cyclosporine treatment did not influence the titre of FIV in PBMC.

The studies on virus load, combined with the cyclosporine data, suggest that the immune response plays a major role in the control of plasma virus titres in lentiviral infections, but has little influence on the level of cell virus titres.

Treatment of infected cats with zidovudine resulted in significant effects on virus load. Two different dose rates of zidovudine, administered at different times p.i. and with different durations of treatment, were assessed. Zidovudine treatment, with either dose regime, did not prevent establishment of infection with FIV. However, the plasma virus titre of zidovudine- treated cats, using either dose regime, was significantly lower than in untreated cats on at least one sampling occasion. The PBMC virus titre of cats treated with the higher dose of zidovudine was significantly lower than untreated cats at two sampling times. Treatment with the lower dose of zidovudine did not significantly influence PBMC virus titre. This suggested that while the effect of zidovudine on the level of PBMC virus titre may predominantly be the result of the inhibition of viral RT, the effect of zidovudine on plasma virus titres may be the result not only of RT inhibition, but also the result of the suppression of T-cell activation by zidovudine.

This work established methods by which the effect of antiviral or immunomodulating agents on the titres of FIV in PBMC and plasma of infected cats can be investigated and has demonstrated that FIV infection can be used as an effective animal model for the evaluation of antiviral agents against HIV. It has also contributed to the broader investigation of the immunopathogenesis of lentiviral infections.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Veterinary Studies
Notes: Note to the author: If you would like to make your thesis openly available on Murdoch University Library's Research Repository, please contact: Thank you.
Supervisor(s): Robinson, Wayne and Ellis, Trevor
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