scholarly journals Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1275
Author(s):  
Zhanglong Liu ◽  
Trang T. Tran ◽  
Linh Pham ◽  
Lingna Hu ◽  
Kyle Bentz ◽  
...  

Multidrug resistance continues to be a barrier to the effectiveness of highly active antiretroviral therapy in the treatment of human immunodeficiency virus 1 (HIV-1) infection. Darunavir (DRV) is a highly potent protease inhibitor (PI) that is oftentimes effective when drug resistance has emerged against first-generation inhibitors. Resistance to darunavir does evolve and requires 10–20 amino acid substitutions. The conformational landscapes of six highly characterized HIV-1 protease (PR) constructs that harbor up to 19 DRV-associated mutations were characterized by distance measurements with pulsed electron double resonance (PELDOR) paramagnetic resonance spectroscopy, namely double electron–electron resonance (DEER). The results show that the accumulated substitutions alter the conformational landscape compared to PI-naïve protease where the semi-open conformation is destabilized as the dominant population with open-like states becoming prevalent in many cases. A linear correlation is found between values of the DRV inhibition parameter Ki and the open-like to closed-state population ratio determined from DEER. The nearly 50% decrease in occupancy of the semi-open conformation is associated with reduced enzymatic activity, characterized previously in the literature.

Intervirology ◽  
2014 ◽  
Vol 57 (5) ◽  
pp. 270-276 ◽  
Author(s):  
Guojian Li ◽  
Shujia Liang ◽  
Tim J. Harrison ◽  
Zhenzhu Tang ◽  
Zhiyong Shen ◽  
...  

2013 ◽  
Vol 14 (1) ◽  
pp. 34-44 ◽  
Author(s):  
Quang Duy Pham ◽  
Thu Khanh Hoang Huynh ◽  
Tram Thu Luong ◽  
Ton Tran ◽  
Thinh Xuan Vu ◽  
...  

2020 ◽  
Author(s):  
Le Chang ◽  
Junpeng Zhao ◽  
Lu Zhang ◽  
Huimin Ji ◽  
Xinyi Jiang ◽  
...  

Abstract Background: Human immunodeficiency virus (HIV) increasing molecular diversity and emergence of drug resistant mutants remain a major concern in Southern China, enfuvirtide (ENF/T-20) is the first entry inhibitor used in patients failing highly active antiretroviral therapy (HAART). However, data on HIV-1 gp41genetic diversity and primary ENF resistance-associated mutations among treatment-naïve patients in southern China is limited. The objective was to identify molecular diversity and ENF resistance patterns of HIV-1 in southern China, using envelop (env) gp41 sequences and bioinformatics tools, which may help optimize ART. Methods: From December 2018 to January 2019, 439 blood plasma samples from ENF-naïve HIV-1 patients were collected from Shenzhen, Wuhan and Chongqing, of which, 396 HIV env regions were sequenced and subtyped, and were performed the analysis of drug resistance-associated mutations (DRMs). Results: The main subtypes were circulating recombinant form (CRF) 01_AE (30.6%) and CRF07_BC (48.7%), CRF55_01B had been the fourth subtype in our work, many rare CRFs were observed. Notably, CRF02_AG and CRF_BF strains typically found in Africa and US respectively were identified amongst Chinese HIV-1 patients. Known DRMs were detected in 27.5% (109/396) of ENF treatment-naïve patients. One major DRM (L44M), many secondary DRMs including (N126K, E137K, S138A) and lots of polymorphisms were found in the study, which have been proved to elevate resistance to ENF. Conclusion: HIV-1 molecular diversity among people in southern China observed in the work indicates that HIV-1 variability is becoming increasingly complex in the south of China. A diverse set of primary DRMs discovered in this study described the serious threat to ART, which remind us the urgent need of timely surveillance of HIV-1 viral diversity and drug resistance in China.


2013 ◽  
Vol 06 (03) ◽  
pp. 1350018 ◽  
Author(s):  
GUANGYU HUANG ◽  
AIJUN FAN ◽  
KAIFA WANG

To study the transition dynamics of resistant-type human immunodeficiency virus 1 (HIV-1) in highly active antiretroviral therapy (HAART) and the affect of neutral mutation in the evolution of HIV-1, a mathematical model is proposed when mutation occurs mainly during reproduction. The derived results show that the resistant-type will certainly colonize in patients once mutation occurs. Furthermore, a neutral mutation is closely related to the colonized pattern of resistant-type HIV-1 quasispecies and there are some changes in the pattern of transmission dynamics when mutation occurs mainly during reproduction or in the absence of reproduction, which may lead to significant strategies for predicting or checking HIV-1 drug resistance in HAART.


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