Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS.
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.
Savarino
Andrea
A
Dept. of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. andrea.savarino@iss.it
Pistello
Mauro
M
D'Ostilio
Daniela
D
Zabogli
Elisa
E
Taglia
Fabiana
F
Mancini
Fabiola
F
Ferro
Stefania
S
Matteucci
Donatella
D
De Luca
Laura
L
Barreca
Maria Letizia
ML
Ciervo
Alessandra
A
Chimirri
Alba
A
Ciccozzi
Massimo
M
Bendinelli
Mauro
M
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
D019429:Integrase Inhibitors; C489415:L870810; D009287:Naphthyridines; D014764:Viral Proteins; D019426:Integrases