Structural analyses of 2015-updated drug-resistant mutations in HIV-1 protease: an implication of protease inhibitor cross-resistance

BMC Bioinformatics

Research

Yu-Xuan Haw¹  Wei-Li Ling¹  Chinh Tran-To Su¹  Wai-Heng Lua¹  Samuel Ken-En Gan² 

[1] Bioinformatics Institute, Agency for Science, Technology, and Research (A*STAR), 138671, Singapore, Singapore;Bioinformatics Institute, Agency for Science, Technology, and Research (A*STAR), 138671, Singapore, Singapore;p53 Laboratory, Agency for Science, Technology, and Research (A*STAR), 138648, Singapore, Singapore;

关键词: Human Immunodeficiency Virus;    Protein Data Bank;    Minimum Span Tree;    Allosteric Effect;    Human Immunodeficiency Virus Protease;   

DOI  :  10.1186/s12859-016-1372-3

来源: Springer

【 摘 要 】

BackgroundStrategies to control HIV for improving the quality of patient lives have been aided by the Highly Active Anti-Retroviral Therapy (HAART), which consists of a cocktail of inhibitors targeting key viral enzymes. Numerous new drugs have been developed over the past few decades but viral resistances to these drugs in the targeted viral enzymes are increasingly reported. Nonetheless the acquired mutations often reduce viral fitness and infectivity. Viral compensatory secondary-line mutations mitigate this loss of fitness, equipping the virus with a broad spectrum of resistance against these drugs. While structural understanding of the viral protease and its drug resistance mutations have been well established, the interconnectivity and development of structural cross-resistance remain unclear. This paper reports the structural analyses of recent clinical mutations on the drug cross-resistance effects from various protease and protease inhibitors (PIs) complexes.MethodsUsing the 2015 updated clinical HIV protease mutations, we constructed a structure-based correlation network and a minimum-spanning tree (MST) based on the following features: (i) topology of the PI-binding pocket, (ii) allosteric effects of the mutations, and (iii) protease structural stability.Results and conclusionAnalyis of the network and the MST of dominant mutations conferring resistance to the seven PIs (Atazanavir-ATV, Darunavir-DRV, Indinavir-IDV, Lopinavir-LPV, Nelfinavir-NFV, Saquinavir-SQV, and Tipranavir-TPV) showed that cross-resistance can develop easily across NFV, SQV, LPV, IDV, and DRV, but not for ATV or TPV. Through estimation of the changes in vibrational entropies caused by each reported mutation, some secondary mutations were found to destabilize protease structure. Our findings provide an insight into the mechanism of PI cross-resistance and may also be useful in guiding the selection of PI in clinical treatment to delay the onset of cross drug resistance.

【 授权许可】

CC BY   
© The Author(s). 2016