The effect of clade-specific sequence polymorphisms on HIV-1 protease activity and inhibitor resistance pathways
Authors
Bandaranayake, Rajintha M.Kolli, Madhavi
King, Nancy M.
Nalivaika, Ellen A.
Heroux, Annie
Kakizawa, Junko
Sugiura, Wataru
Schiffer, Celia A.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2010-10-28Keywords
Amino Acid SequenceAmino Acid Substitution
Catalytic Domain
Crystallography, X-Ray
Drug Resistance, Viral
Genes, Viral
HIV Protease
HIV Protease Inhibitors
HIV-1
Humans
Kinetics
Models, Molecular
Molecular Sequence Data
Mutation, Missense
Nelfinavir
Polymorphism, Genetic
Protein Conformation
Sequence Homology, Amino Acid
Sulfonamides
Thermodynamics
Biochemistry, Biophysics, and Structural Biology
Microbiology
Metadata
Show full item recordAbstract
The majority of HIV-1 infections around the world result from non-B clade HIV-1 strains. The CRF01_AE (AE) strain is seen principally in Southeast Asia. AE protease differs by approximately 10% in amino acid sequence from clade B protease and carries several naturally occurring polymorphisms that are associated with drug resistance in clade B. AE protease has been observed to develop resistance through a nonactive-site N88S mutation in response to nelfinavir (NFV) therapy, whereas clade B protease develops both the active-site mutation D30N and the nonactive-site mutation N88D. Structural and biochemical studies were carried out with wild-type and NFV-resistant clade B and AE protease variants. The relationship between clade-specific sequence variations and pathways to inhibitor resistance was also assessed. AE protease has a lower catalytic turnover rate than clade B protease, and it also has weaker affinity for both NFV and darunavir (DRV). This weaker affinity may lead to the nonactive-site N88S variant in AE, which exhibits significantly decreased affinity for both NFV and DRV. The D30N/N88D mutations in clade B resulted in a significant loss of affinity for NFV and, to a lesser extent, for DRV. A comparison of crystal structures of AE protease shows significant structural rearrangement in the flap hinge region compared with those of clade B protease and suggests insights into the alternative pathways to NFV resistance. In combination, our studies show that sequence polymorphisms within clades can alter protease activity and inhibitor binding and are capable of altering the pathway to inhibitor resistance.Source
J Virol. 2010 Oct;84(19):9995-10003. Epub 2010 Jul 21. Link to article on publisher's site
DOI
10.1128/JVI.00505-10Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26011PubMed ID
20660190Related Resources
ae974a485f413a2113503eed53cd6c53
10.1128/JVI.00505-10