In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat).
3-O-(3',3'-dimethylsuccinyl)betulinic acid (PA-457 or bevirimat) potently inhibits human immunodeficiency virus type 1 (HIV-1) maturation by blocking a late step in the Gag processing pathway, specifically the cleavage of SP1 from the C terminus of capsid (CA). To gain insights into the mechanism(s) by which HIV-1 could evolve resistance to PA-457 and to evaluate the likelihood of such resistance arising in PA-457-treated patients, we sought to identify and characterize a broad spectrum of HIV-1 variants capable of conferring resistance to this compound. Numerous independent rounds of selection repeatedly identified six single-amino-acid substitutions that independently confer PA-457 resistance: three at or near the C terminus of CA (CA-H226Y, -L231F, and -L231M) and three at the first and third residues of SP1 (SP1-A1V, -A3T, and -A3V). We determined that mutations CA-H226Y, CA-L231F, CA-L231M, and SP1-A1V do not impose a significant replication defect on HIV-1 in culture. In contrast, mutations SP1-A3V and -A3T severely impaired virus replication and inhibited virion core condensation. The replication defect imposed by SP1-A3V was reversed by a second-site compensatory mutation in CA (CA-G225S). Intriguingly, high concentrations of PA-457 enhanced the maturation of SP1 residue 3 mutants. The different phenotypes associated with mutations that confer PA-457 resistance suggest the existence of multiple mechanisms by which HIV-1 can evolve resistance to this maturation inhibitor. These findings have implications for the ongoing development of PA-457 to treat HIV-1 infection in vivo.
Adamson
Catherine S
CS
Virus-Cell Interaction Section, HIV Drug Resistance Program, NCI-Frederick, Bldg. 535/Rm. 108, 1050 Boyles Street, Frederick, MD 21702-1201, USA.
Ablan
Sherimay D
SD
Boeras
Ioana
I
Goila-Gaur
Ritu
R
Soheilian
Ferri
F
Nagashima
Kunio
K
Li
Feng
F
Salzwedel
Karl
K
Sakalian
Michael
M
Wild
Carl T
CT
Freed
Eric O
EO
D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology*; D036022:Capsid Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D006801:Humans; D019169:Jurkat Cells; D046529:Microscopy, Electron, Transmission; D020125:Mutation, Missense; D013386:Succinates / Q000494:pharmacology*; D013489:Suppression, Genetic; D014315:Triterpenes / Q000494:pharmacology*; D014764:Viral Proteins / Q000032:analysis / Q000302:isolation & purification; D014771:Virion / Q000648:ultrastructure; D019065:Virus Assembly / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D053978:Pentacyclic Triterpenes
D019380:Anti-HIV Agents; D036022:Capsid Proteins; D013386:Succinates; D014315:Triterpenes; D014764:Viral Proteins; C479935:bevirimat; D053978:Pentacyclic Triterpenes