Document Detail

Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance.
MedLine Citation:
PMID:  21030679     Owner:  NLM     Status:  MEDLINE    
The development of HIV integrase (IN) strand transfer inhibitors (INSTIs) and our understanding of viral resistance to these molecules have been hampered by a paucity of available structural data. We recently reported cocrystal structures of the prototype foamy virus (PFV) intasome with raltegravir and elvitegravir, establishing the general INSTI binding mode. We now present an expanded set of cocrystal structures containing PFV intasomes complexed with first- and second-generation INSTIs at resolutions of up to 2.5 Å. Importantly, the improved resolution allowed us to refine the complete coordination spheres of the catalytic metal cations within the INSTI-bound intasome active site. We show that like the Q148H/G140S and N155H HIV-1 IN variants, the analogous S217H and N224H PFV INs display reduced sensitivity to raltegravir in vitro. Crystal structures of the mutant PFV intasomes in INSTI-free and -bound forms revealed that the amino acid substitutions necessitate considerable conformational rearrangements within the IN active site to accommodate an INSTI, thus explaining their adverse effects on raltegravir antiviral activity. Furthermore, our structures predict physical proximity and an interaction between HIV-1 IN mutant residues His148 and Ser/Ala140, rationalizing the coevolution of Q148H and G140S/A mutations in drug-resistant viral strains.
Stephen Hare; Ann M Vos; Reginald F Clayton; Jan W Thuring; Maxwell D Cummings; Peter Cherepanov
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-28
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-18     Completed Date:  2010-12-21     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20057-62     Citation Subset:  IM    
Division of Infectious Diseases, Imperial College London, London W2 1PG, United Kingdom.
Data Bank Information
Bank Name/Acc. No.:
PDB/3OY9;  3OYA;  3OYB;  3OYC;  3OYD;  3OYE;  3OYF;  3OYG;  3OYH;  3OYI;  3OYJ;  3OYK;  3OYL;  3OYM;  3OYN
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MeSH Terms
Amino Acid Substitution / genetics
Catalytic Domain
Drug Resistance, Viral / genetics*
Evolution, Molecular*
HIV Integrase Inhibitors / chemistry,  metabolism,  pharmacology*
HIV-1 / enzymology,  genetics
Inhibitory Concentration 50
Integrases / metabolism*
Mutation / genetics
Pyrrolidinones / chemistry,  pharmacology
Retroviridae / enzymology*
Grant Support
G0900116//Medical Research Council
Reg. No./Substance:
0/HIV Integrase Inhibitors; 0/Pyrrolidinones; 22VKV8053U/raltegravir; EC 2.7.7.-/Integrases

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

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