Abstract:
UNLABELLED:Protease is essential for retroviral replication, and protease inhibitors (PI) are important for treating HIV infection. HIV-2 exhibits intrinsic resistance to most FDA-approved HIV-1 PI, retaining clinically useful susceptibility only to lopinavir, darunavir, and saquinavir. The mechanisms for this resistance are unclear; although HIV-1 and HIV-2 proteases share just 38 to 49% sequence identity, all critical structural features of proteases are conserved. Structural studies have implicated four amino acids in the ligand-binding pocket (positions 32, 47, 76, and 82). We constructed HIV-2ROD9 molecular clones encoding the corresponding wild-type HIV-1 amino acids (I32V, V47I, M76L, and I82V) either individually or together (clone PRΔ4) and compared the phenotypic sensitivities (50% effective concentration [EC50]) of mutant and wild-type viruses to nine FDA-approved PI. Single amino acid replacements I32V, V47I, and M76L increased the susceptibility of HIV-2 to multiple PI, but no single change conferred class-wide sensitivity. In contrast, clone PRΔ4 showed PI susceptibility equivalent to or greater than that of HIV-1 for all PI. We also compared crystallographic structures of wild-type HIV-1 and HIV-2 proteases complexed with amprenavir and darunavir to models of the PRΔ4 enzyme. These models suggest that the amprenavir sensitivity of PRΔ4 is attributable to stabilizing enzyme-inhibitor interactions in the P2 and P2' pockets of the protease dimer. Together, our results show that the combination of four amino acid changes in HIV-2 protease confer a pattern of PI susceptibility comparable to that of HIV-1, providing a structural rationale for intrinsic HIV-2 PI resistance and resolving long-standing questions regarding the determinants of differential PI susceptibility in HIV-1 and HIV-2. IMPORTANCE:Proteases are essential for retroviral replication, and HIV-1 and HIV-2 proteases share a great deal of structural similarity. However, only three of nine FDA-approved HIV-1 protease inhibitors (PI) are active against HIV-2. The underlying reasons for intrinsic PI resistance in HIV-2 are not known. We examined the contributions of four amino acids in the ligand-binding pocket of the enzyme that differ between HIV-1 and HIV-2 by constructing HIV-2 clones encoding the corresponding HIV-1 amino acids and testing the PI susceptibilities of the resulting viruses. We found that the HIV-2 clone containing all four changes (PRΔ4) was as susceptible as HIV-1 to all nine PI. We also modeled the PRΔ4 enzyme structure and compared it to existing crystallographic structures of HIV-1 and HIV-2 proteases complexed with amprenavir and darunavir. Our findings demonstrate that four positions in the ligand-binding cleft of protease are the primary cause of HIV-2 PI resistance.
journal_name
J Viroljournal_title
Journal of virologyauthors
Raugi DN,Smith RA,Gottlieb GS,University of Washington-Dakar HIV-2 Study Group.doi
10.1128/JVI.01772-15subject
Has Abstractpub_date
2015-11-11 00:00:00pages
1062-9issue
2eissn
0022-538Xissn
1098-5514pii
JVI.01772-15journal_volume
90pub_type
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pub_type: 杂志文章
doi:10.1128/JVI.73.8.6293-6298.1999
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journal_title:Journal of virology
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doi:10.1128/JVI.11.1.46-53.1973
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pub_type: 杂志文章
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journal_title:Journal of virology
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abstract::This article has been retracted. ...
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.28.1.344-351.1978
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.4.3357-3362.1997
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.21.3.1128-1139.1977
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pub_type: 杂志文章
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journal_title:Journal of virology
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doi:10.1128/jvi.77.9.5378-5388.2003
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.61.9.2857-2863.1987
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00218-12
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.8.3605-3614.2002
更新日期:2002-04-01 00:00:00
abstract::Transfection of an Epstein-Barr virus (EBV)-encoded plasmid containing EBER caused a substantial decrease in the level of plasmid containing EBV in Akata and Mutu Burkitt's lymphoma (BL) lines, but failed to do so in other BL lines. The results suggest that EBER could replace the role of EBV, but other EBV products al...
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pub_type: 杂志文章
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journal_title:Journal of virology
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doi:10.1128/JVI.40.3.848-860.1981
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doi:10.1128/JVI.57.1.275-284.1986
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journal_title:Journal of virology
pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.8.3811-3818.2001
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journal_title:Journal of virology
pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.63.10.4303-4310.1989
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journal_title:Journal of virology
pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.62.12.4439-4444.1988
更新日期:1988-12-01 00:00:00
abstract::The E2 gene products of papillomavirus play key roles in viral replication, both as regulators of viral transcription and as auxiliary factors that act with E1 in viral DNA replication. We have carried out a detailed structure-function analysis of conserved amino acids within the N-terminal domain of the human papillo...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.3.1602-1611.1996
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