title: A combination of polymorphic mutations in V3 loop of HIV-1 gp120 can confer noncompetitive resistance to maraviroc.
abstract: Maraviroc binds to the pocket of extracellular loops of the cell surface CCR5 and prevents R5 HIV-1 from using CCR5 as a coreceptor for entry into CD4-positive cells. To evaluate the contribution of the V3 loop structure in gp120 to maraviroc resistance, we isolated maraviroc-resistant variants from the V3 loop library virus (HIV-1(V3Lib)) containing a set of random combinations of 0-10 polymorphic mutations in vitro. HIV-1(V3Lib) at passage 17 could not be suppressed even at 10 μM (>1400-fold resistance), while HIV-1(JR-FL) at passage 17 revealed an 8-fold resistance to maraviroc. HIV-1(V3Lib-P17) contained T199K and T275M plus 5 mutations in the V3 loop, I304V/F312W/T314A/E317D/I318V. The profile of pseudotyped virus containing I304V/F312W/T314A/E317D/I318V in V3 loop alone revealed a typical noncompetitive resistance, although T199K and/or T275M could not confer noncompetitive resistance. This type of library virus is useful for isolation of escape viruses from effective entry inhibitors.
authors: Department of Medical Virology, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8665, Japan.
authors: Yuzhe
authors: Y
authors: Yuan
authors: Yosuke
authors: Y
authors: Maeda
authors: Hiromi
authors: H
authors: Terasawa
authors: Kazuaki
authors: K
authors: Monde
authors: Shinji
authors: S
authors: Harada
authors: Keisuke
authors: K
authors: Yusa
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D000077592:Maraviroc; D009154:Mutation; D011110:Polymorphism, Genetic; D014230:Triazoles / Q000494:pharmacology*; D053586:Virus Internalization
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D014230:Triazoles; C514793:gp120 protein, Human immunodeficiency virus 1; D000077592:Maraviroc