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.
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 here analyzed susceptibility of FIV to second generation PIs, lopinavir, atazanavir, and the structurally unrelated non-peptidic PI tipranavir. We found that FIV protease resembles HIV-1 protease drug resistance mutations limiting binding of lopinavir and atazanavir but not tipranavir. All three PIs were found to inhibit FIV replication in a concentration-dependent manner, but only tipranavir inhibited FIV similarly to HIV-1. This drug inhibited FIV synergistically with ritonavir. Inhibition of protease activity was confirmed by Western blot analysis. In molecular docking simulations, tipranavir displayed energetically favorable interactions with the catalytic cavity of the mature dimeric FIV protease. The calculated hydrogen bond network was similar to that found in HIV-1 protease/tipranavir complexes and involved atoms in the protein backbone. We also modeled the interaction of tipranavir with an immature protease monomer, suggesting that inhibition of protease dimerization may be a secondary modality for FIV inhibition by tipranavir. In conclusion, tipranavir is the first FDA-approved non-reverse transcriptase inhibitor of HIV-1 to show anti-FIV properties. The tipranavir 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 development of novel broad-based inhibitors for treatment of drug resistant HIV-1.
Norelli
Sandro
S
Department of Infectious, Parasitic and Immune-mediate Diseases, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy.
El Daker
Sary
S
D'Ostilio
Daniela
D
Mele
Federico
F
Mancini
Fabiola
F
Taglia
Fabiana
F
Ruggieri
Anna
A
Ciccozzi
Massimo
M
Cauda
Roberto
R
Ciervo
Alessandra
A
Barreca
Maria L
ML
Pistello
Mauro
M
Bendinelli
Mauro
M
Savarino
Andrea
A
D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D002415:Cats; D002460:Cell Line; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011753:Pyrones / Q000378:metabolism / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013449:Sulfonamides
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D016333:HIV Protease; C107201:tipranavir