Resolution and Prevention of Feline Immunodeficiency Virus-Induced Neurological Deficits by Treatment with the Protease Inhibitor TL-3

Abstract

In vivo tests were performed to assess the influence of the protease inhibitor TL-3 on feline immunodeficiency virus (FIV)-induced central nervous system (CNS) deficits. Twenty cats were divided into four groups of five animals each. Group 1 received no treatment, group 2 received TL-3 only, group 3 received FIV strain PPR (FIV-PPR) only, and group 4 received FIV-PPR and TL-3. Animals were monitored for immunological and virological status, along with measurements of brain stem auditory evoked potential (BAEP) changes. Groups 1 and 2 remained FIV negative, and groups 3 and 4 became virus positive and seroconverted by 3 to 5 weeks postinoculation. No adverse effects were noted with TL-3 only. The average peak viral load for the virus-only group 3 animals was 1.32 ؋ 10 6 RNA copies/ml, compared to 6.9 ؋ 10 4 copies/ml for TL-3-treated group 4 cats. Group 3 (virus-only) cats exhibited marked progressive delays in BAEPs starting at 2 weeks post virus exposure, which is typical of infection with FIV-PPR. In contrast, TL-3-treated cats of group 4 exhibited BAEPs similar to those of control and drug-only cats. At 97 days postinfection, treatments were switched; i.e., group 4 animals were taken off TL-3 and group 3 animals were treated with TL-3. BAEPs in group 3 animals returned to control levels, while BAEPs in group 4 animals remained at control levels. After 70 days on TL-3, group 3 was removed from the drug treatment regimen. Delays in BAEPs immediately increased to levels observed prior to TL-3 treatment. The findings show that early TL-3 treatment can effectively eliminate FIV-induced changes in the CNS. Furthermore, TL-3 can counteract FIV effects on the CNS of infected cats, although continued treatment is required to maintain unimpaired CNS function.

Replication Properties of Clade A/C Chimeric Feline Immunodeficiency Viruses and Evaluation of Infection Kinetics in the Domestic Cat

“…6A and B, respectively) were significantly higher than those of either wild-type FIV-PPR or chimeric clones with peak RT values two to five times greater than those of either FIV-PPR or any of the chimeras. In contrast, infection by FIV-PPR was both lower and delayed within the same timeframe, consistent with a lower replication rate for the latter virus in vivo (13). Interestingly, chimeric FIV infections of the total PBMCs were less efficient than those of 104-C1 cells, consistent with heterogeneity in cell types and cell cycle in the PBMC pool (Fig.…”

Small molecules targeting severe acute respiratory syndrome human coronavirus

“…39 and references therein). It is also active against several resistant variants in cell-based assays and effective in treatment of cats with AIDS (40). The K i value of 2 against the SARS-CoV 3CL protease is 0.6 M.…”

Generation of Infectious Feline Immunodeficiency Virus (FIV) Encoding FIV/Human Immunodeficiency Virus Chimeric Protease

“…Comparisons of the 3 dimensional structures of the two PRs led to the rational design of TL-3, a broad-based PR inhibitor capable of blocking infection by FIV, simian immunodeficiency virus (SIV), and HIV-1, as well as many drug-resistant HIV-1 variants (10,12,21,23,31,32). Similar approaches comparing the structures of FIV and drug-resistant HIV-1 PRs to that of WT HIV-1 PR have led to the development of additional PR-inhibiting compounds with broadened efficacy (8,9,19,29,41,42).…”