The feline AIDS model for HIV-1 treatment failed in the 1990s, due to structural features resembling protease inhibitor (PI) resistant HIV-1 variants. Widespread drug-resistance to PIs now invokes the possibility of rescuing feline immunodeficiency virus (FIV) as a model for PI treatment. We analyzed the susceptibility of FIV to second generation PIs, lopinavir (LPV), atazanavir (ATV), and the structurally unrelated non-peptidic PI tipranavir (TPV). We found that FIV protease resembles HIV-1 PR drug resistance mutations thus limiting binding of LPV, ATV but not TPV. All three PIs were found to inhibit FIV replication in a concentration-dependent manner, but only TPV showed an EC50 in a similar order of magnitude as in HIV-1 based assays. TPV inhibited FIV synergistically with ritonavir. Inhibition of protease activity was confirmed by western blot analysis. Molecular docking showed that the structure of FIV PR allows interactions with TPV which are energetically favorable as compared to drug resistant HIV-1 PR. The calculated hydrogen bond network was similar to that found in HIV-1 protease/TPV complexes and involved atoms in the protein backbone. In conclusion, TPV is the first FDA-approved non-NRTI HIV-1 drug to show anti-FIV properties. The TPV response by FIV may 1) support the idea of using FIV as a small animal model for PI-resistant HIV-1, thus expanding access to animal AIDS models; and 2) pave the way for the development of novel broad-based inhibitors for treatment of drug resistant HIV-1.

Response of feline immunodeficiency virus (FIV) to tipranavir may provide new clues for development of broad-based inhibitors of retroviral proteases acting on drug-resistant HIV-1

PISTELLO, MAURO
Writing – Review & Editing
;
2008

Abstract

The feline AIDS model for HIV-1 treatment failed in the 1990s, due to structural features resembling protease inhibitor (PI) resistant HIV-1 variants. Widespread drug-resistance to PIs now invokes the possibility of rescuing feline immunodeficiency virus (FIV) as a model for PI treatment. We analyzed the susceptibility of FIV to second generation PIs, lopinavir (LPV), atazanavir (ATV), and the structurally unrelated non-peptidic PI tipranavir (TPV). We found that FIV protease resembles HIV-1 PR drug resistance mutations thus limiting binding of LPV, ATV but not TPV. All three PIs were found to inhibit FIV replication in a concentration-dependent manner, but only TPV showed an EC50 in a similar order of magnitude as in HIV-1 based assays. TPV inhibited FIV synergistically with ritonavir. Inhibition of protease activity was confirmed by western blot analysis. Molecular docking showed that the structure of FIV PR allows interactions with TPV which are energetically favorable as compared to drug resistant HIV-1 PR. The calculated hydrogen bond network was similar to that found in HIV-1 protease/TPV complexes and involved atoms in the protein backbone. In conclusion, TPV is the first FDA-approved non-NRTI HIV-1 drug to show anti-FIV properties. The TPV response by FIV may 1) support the idea of using FIV as a small animal model for PI-resistant HIV-1, thus expanding access to animal AIDS models; and 2) pave the way for the development of novel broad-based inhibitors for treatment of drug resistant HIV-1.
Norelli, S; El Daker, S; D'Ostilio, D; Mele, F; Mancini, F; Taglia, F; Ruggieri, A; Ciccozzi, M; Cauda, R; Ciervo, A; Barreca, Ml; Pistello, Mauro; Bendinelli, M; Savarino, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/120418
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