Tissue culture drug resistance analysis of a novel HIV-1 protease inhibitor termed PL-100 in non-B HIV-1 subtypes.
PL-100 is a novel HIV-1 protease inhibitor (PI) that maintains activity against viruses that are resistant to other PIs. To further characterize this compound, we used it to select for drug resistance in tissue culture, using two non-B HIV-1 subtypes, viz. subtype C and a CRF01_AE recombinant virus. PL-100 selected for both minor and major PI resistance mutations along either of two distinct pathways. One of these involved the V82A and L90M resistance mutations while the other involved a mutation at position T80I, with other mutations being observed at positions M46I/L, I54M, K55R, L76F, P81S and I85V. The resistance patterns in both subtype C and CRF01_AE were similar and an accumulation of at least three mutations in the flap and active sites were required in each case for high-level resistance to occur, demonstrating that PL-100 has a high genetic barrier against the development of drug resistance.
Asahchop
Eugene L
EL
McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
Oliveira
Maureen
M
Brenner
Bluma G
BG
Martinez-Cajas
Jorge L
JL
Toni
Thomas d'Aquin
Td
Ntemgwa
Michel
M
Moisi
Daniela
D
Dandache
Serge
S
Stranix
Brent
B
Tremblay
Cecile L
CL
Wainberg
Mark A
MA
D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D013449:Sulfonamides / Q000494:pharmacology*
D019380:Anti-HIV Agents; D002219:Carbamates; D017320:HIV Protease Inhibitors; C525732:PL 100; D013449:Sulfonamides; D016333:HIV Protease