title: Effect of mutations in the human immunodeficiency virus type 1 protease on cleavage of the gp41 cytoplasmic tail.
abstract: We previously reported that human immunodeficiency virus type 1 (HIV-1) develops resistance to the cholesterol-binding compound amphotericin B methyl ester (AME) by acquiring mutations (P203L and S205L) in the cytoplasmic tail of the transmembrane envelope glycoprotein gp41 that create cleavage sites for the viral protease (PR). In the present study, we observed that a PR inhibitor-resistant (PIR) HIV-1 mutant is unable to efficiently cleave the gp41 cytoplasmic tail in P203L and S205L virions, resulting in loss of AME resistance. To define the pathway to AME resistance in the context of the PIR PR, we selected for resistance with an HIV-1 isolate expressing the mutant enzyme. We identified a new gp41 mutation, R236L, that results in cleavage of the gp41 tail by the PIR PR. These results highlight the central role of gp41 cleavage as the primary mechanism of AME resistance.
authors.affiliation: Virus-Cell Interaction Section, HIV Drug Resistance Program, NCI-Frederick, Bldg. 535, Rm.108, Frederick, MD 21702-1201, USA. awaheed@ncifcrf.gov
authors.forename: Abdul A
authors.initials: AA
authors.lastname: Waheed
authors.forename: Sherimay D
authors.initials: SD
authors.lastname: Ablan
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Sowder
authors.forename: James D
authors.initials: JD
authors.lastname: Roser
authors.forename: Carl P
authors.initials: CP
authors.lastname: Schaffner
authors.forename: Elena
authors.initials: E
authors.lastname: Chertova
authors.forename: Eric O
authors.initials: EO
authors.lastname: Freed
mesh_terms: D000666:Amphotericin B / Q000031:analogs & derivatives / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D009154:Mutation; D014771:Virion / Q000235:genetics / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D015700:HIV Envelope Protein gp41; D017320:HIV Protease Inhibitors; C017501:methylamphotericin B; D000666:Amphotericin B; D016333:HIV Protease