Assessment of FIV-C infection of cats as a function of treatment with the protease inhibitor, TL-3.
BACKGROUND
The protease inhibitor, TL-3, demonstrated broad efficacy in vitro against FIV, HIV and SIV (simian immunodeficiency virus), and exhibited very strong protective effects on early neurologic alterations in the CNS of FIV-PPR infected cats. In this study, we analyzed TL-3 efficacy using a highly pathogenic FIV-C isolate, which causes a severe acute phase immunodeficiency syndrome, with high early mortality rates.


RESULTS
Twenty cats were infected with uncloned FIV-C and half were treated with TL-3 while the other half were left untreated. Two uninfected cats were used as controls. The general health and the immunological and virological status of the animals was monitored for eight weeks following infection. All infected animals became viremic independent of TL-3 treatment and seven of 20 FIV-C infected animals developed severe immunodepletive disease in conjunction with significantly (p < or = 0.05) higher viral RNA loads as compared to asymptomatic animals. A marked and progressive increase in CD8+ T lymphocytes in animals surviving acute phase infection was noted, which was not evident in symptomatic animals (p < or = 0.05). Average viral loads were lower in TL-3 treated animals and of the 6 animals requiring euthanasia, four were from the untreated cohort. At eight weeks post infection, half of the TL-3 treated animals and only one of six untreated animals had viral loads below detection limits. Analysis of protease genes in TL-3 treated animals with higher than average viral loads revealed sequence variations relative to wild type protease. In particular, one mutant, D105G, imparted 5-fold resistance against TL-3 relative to wild type protease.


CONCLUSIONS
The findings indicate that the protease inhibitor, TL-3, when administered orally as a monotherapy, did not prevent viremia in cats infected with high dose FIV-C. However, the modest lowering of viral loads with TL-3 treatment, the greater survival rate in symptomatic animals of the treated cohort, and the lower average viral load in TL-3 treated animals at eight weeks post infection is indicative of a therapeutic effect of the compound on virus infection.
de Rozières
Sohela
S
Department of Molecular Biology, The Scripps Research Institute, La Jolla, USA. sohela@scripps.edu
Swan
Christina H
CH
Sheeter
Dennis A
DA
Clingerman
Karen J
KJ
Lin
Ying-Chuan
YC
Huitron-Resendiz
Salvador
S
Henriksen
Steven
S
Torbett
Bruce E
BE
Elder
John H
JH
D000818:Animals; D001933:Brain Stem / Q000503:physiopathology; D002415:Cats; D015331:Cohort Studies; D005072:Evoked Potentials, Auditory / Q000502:physiology; D016181:Feline Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000503:physiopathology / Q000635:transmission*; D005260:Female; D016089:Immunodeficiency Virus, Feline / Q000187:drug effects / Q000302:isolation & purification / Q000472:pathogenicity*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D019562:Viral Load; D015431:Weight Loss / Q000187:drug effects
D011480:Protease Inhibitors