title: Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS.
abstract: BACKGROUND
  Treatment of feline immunodeficiency virus (FIV) infection has been hampered by the absence of a specific combination antiretroviral treatment (ART). Integrase strand transfer inhibitors (INSTIs) are emerging as a promising new drug class for HIV-1 treatment, and we evaluated the possibility of inhibiting FIV replication using INSTIs.
  
  
  METHODS
  Phylogenetic analysis of lentiviral integrase (IN) sequences was carried out using the PAUP* software. A theoretical three-dimensional structure of the FIV IN catalytic core domain (CCD) was obtained by homology modeling based on a crystal structure of HIV-1 IN CCD. The interaction of the transferred strand of viral DNA with the catalytic cavity of FIV IN was deduced from a crystal structure of a structurally similar transposase complexed with transposable DNA. Molecular docking simulations were conducted using a genetic algorithm (GOLD). Antiviral activity was tested in feline lymphoblastoid MBM cells acutely infected with the FIV Petaluma strain. Circular and total proviral DNA was quantified by real-time PCR.
  
  
  RESULTS
  The calculated INSTI-binding sites were found to be nearly identical in FIV and HIV-1 IN CCDs. The close similarity of primate and feline lentivirus IN CCDs was also supported by phylogenetic analysis. In line with these bioinformatic analyses, FIV replication was efficiently inhibited in acutely infected cell cultures by three investigational INSTIs, designed for HIV-1 and belonging to different classes. Of note, the naphthyridine carboxamide INSTI, L-870,810 displayed an EC50 in the low nanomolar range. Inhibition of FIV integration in situ was shown by real-time PCR experiments that revealed accumulation of circular forms of FIV DNA within cells treated with L-870,810.
  
  
  CONCLUSIONS
  We report a drug class (other than nucleosidic reverse transcriptase inhibitors) that is capable of inhibiting FIV replication in vitro. The present study helped establish L-870,810, a compound successfully tested in human clinical trials, as one of the most potent anti-FIV agents ever tested in vitro. This finding may provide new avenues for treating FIV infection and contribute to the development of a small animal model mimicking the effects of ART in humans.
authors.affiliation: Dept. of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. andrea.savarino@iss.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Savarino
authors.forename: Mauro
authors.initials: M
authors.lastname: Pistello
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Ostilio
authors.forename: Elisa
authors.initials: E
authors.lastname: Zabogli
authors.forename: Fabiana
authors.initials: F
authors.lastname: Taglia
authors.forename: Fabiola
authors.initials: F
authors.lastname: Mancini
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferro
authors.forename: Donatella
authors.initials: D
authors.lastname: Matteucci
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ciervo
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
authors.forename: Massimo
authors.initials: M
authors.lastname: Ciccozzi
authors.forename: Mauro
authors.initials: M
authors.lastname: Bendinelli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002415:Cats; D045744:Cell Line, Tumor; D016181:Feline Acquired Immunodeficiency Syndrome / Q000821:virology*; D005260:Female; D016089:Immunodeficiency Virus, Feline / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D019429:Integrase Inhibitors / Q000494:pharmacology*; D019426:Integrases / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009287:Naphthyridines / Q000494:pharmacology; D016415:Sequence Alignment; D014764:Viral Proteins / Q000737:chemistry; D016662:Virus Integration / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019429:Integrase Inhibitors; C489415:L870810; D009287:Naphthyridines; D014764:Viral Proteins; D019426:Integrases