In vitro characterization of FIV-pPPR, a pathogenic molecular clone of feline immunodeficiency virus, and two drug-resistant pol gene mutants

Objective-To compare in vitro replication kinetics and nucleoside analog su sceptibilities of a natural feline immunodeficiency virus (FIV) isolate (FI V-Maxam), a molecular clone of FIV (FIV-pPPR), and two (-)-beta -L-2',3'-di deoxy-3'-thiacytidine- (3TC-) resistant mutants of FIV-pPPR. Sample Population-Peripheral blood mononuclear cells (PBMC) from 4 specific -pathogenfree cats. Procedure-Two point mutations corresponding to mutations of human immunodef iciency virus type 1 (HIV-1) were engineered into the highly conserved YMDD motif of the reverse transcriptase- (RT-) encoding region of the FIV-pPPR pol gene. Replication kinetics and nucleoside analog susceptibilities of FI V-Maxam, FIV-pPPR, and the 2 mutant viruses were measured in vitro, using f eline PBMC. Results-Replication kinetics and nucleoside analog susceptibilities were si milar between FIV-Maxam and FIV-pPPR. However, FIV-Maxam was significantly more susceptible to 3TC. A methionine-to-valine mutation at codon 183 (M183 V) of the RT-encoding region of the pol gene of FIV-pPPR conferred high-lev el phenotypic resistance to 3TC and cross-resistance to the related compoun d (-)-beta -L-2',3'-dideoxy-5-fluoro-3'-thiacytidine. Conclusions and Clinical Relevance-Similarities between FIV-Maxam and FIV-p PPR suggest that results of studies performed using FIV-pPPR will have rele vance to natural FIV infection in cats. In vitro evaluation of nucleoside a nalog susceptibilities of FIV-Maxam may help determine concentrations of nu cleoside analogs required for effective treatment of FIV-infected cats. Impact for Human Medicine-3TC resistance of FIV-pPPR M183V was similar in m agnitude to that of HIV-1 M184V, a mutant described in infected humans trea ted with 3TC. Thus, FIV-pPPR M183V may be a useful model for studying the i n vivo effects of 3TC resistance on lentivirus pathogenesis.