.png){kind=icon}
.png){kind=icon}
Return
Molecular and Clinical Characterization of Protease Inhibitor Resistance in HIV-1 CRF35-AD with Virologic Failure: Implications for Treatment Optimization
.png){kind=icon}
PRE
AI
I
T
J
B
T
A
DOI：10.1142/S273741652650064X.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Background: Drug resistance driven by protease (PR) gene mutations poses a major challenge to antiretroviral therapy (ART), particularly in regions such as Iran, where the HIV-1 CRF35-AD subtype predominates. Objectives: To characterize the prevalence, structural impact, and clinical associations of protease inhibitor (PI) resistance mutations in HIV-1 CRF35-AD among Iranian patients with virological failure. Methods: In this cross-sectional study, we analyzed 44 ART-experienced patients with viral loads > 1000 copies/mL in Hamadan, Iran (2020-2022). The PR gene was amplified using nested RT-PCR and subtyped via phylogenetic analysis. Drug resistance mutations (DRMs) were identified using Stanford HIVdb. Molecular docking and molecular dynamics (MD) simulations assessed structural effects on PI binding. Chi-square tests and logistic regression evaluated associations with clinical variables. Results: All sequences were confirmed as CRF35-AD. DRMs were detected in 93% of patients. Predominant mutations included R41K (95%), L89M (91%), L10I (36%), L19Q (36%), and L63V (27%). L19Q and L63V were significantly associated with resistance to atazanavir (P = 0.03) and darunavir (P = 0.04), respectively. Molecular docking showed reduced binding affinity to these PIs, while saquinavir and amprenavir retained strong interactions (Delta G: -9.5 to -10.2 kcal/mol). Molecular dynamics simulations further suggest that resistance-associated mutations promote increased conformational flexibility and reduced structural stability in protease-inhibitor complexes relative to the wild-type enzyme. Resistance was more common in younger women with mother-to-child transmission and prolonged ART exposure (P < 0.01). Conclusions: The high DRM burden in CRF35-AD highlights the need for routine genotypic resistance testing and subtype-tailored ART regimens. Saquinavir and amprenavir may remain viable options for patients with multi-PI resistance in CRF35-AD-endemic regions.
Keywords:
HIV-1
protease inhibitors
drug resistance
CRF35-AD
molecular docking
molecular dynamics
saquinavir
amprenavir
treatment optimization
Journal
J
IF:
2.3
Papers:
98
Citations:
0
Organization
Cited Papers