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Publication Abstract from PubMed

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 non-active site N88S mutation in response to nelfinavir (NFV) therapy, whereas clade B protease develops both the active site mutation D30N and the non-active site mutation N88D. Structural and biochemical studies were carried out on 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 when compared to clade B, and also has weaker affinity for both NFV and darunavir (DRV). This weaker affinity may lead to the non-active site N88S variant in AE, which exhibits significantly decreased affinity for both NFV and DRV. The D30N/N88D in clade B resulted in a significant loss of affinity for NFV and to a lesser extent for DRV. Comparison of crystal structures of AE protease shows significant structural rearrangement in the flap hinge region compared with clade B 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.

The Effect of Clade Specific Sequence Polymorphisms on HIV-1 Protease Activity and Inhibitor Resistance Pathways.,Bandaranayake RM, Kolli M, King NM, Nalivaika E, Heroux A, Kakizawa J, Sugiura W, Schiffer CA J Virol. 2010 Jul 21. PMID:20660190^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.