Premature Activation of the HIV-1 Protease Is Influenced by Polymorphisms in the Hinge Region

HIV-1 protease inhibitors are an essential component of antiretroviral therapy. However, drug resistance is a pervasive issue motivating a persistent search for novel therapies. Recent reports found that when protease activates within the host cell's cytosol, it facilitates the pyroptotic killi...

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Bibliographic Details
Published in:Viruses 2024-05, Vol.16 (6), p.849
Main Authors: Tabler, Caroline O, Wegman, Sarah J, Alhusaini, Najwa, Lee, Nicole F, Tilton, John C
Format: Article
Language:English
Subjects:
Acquired immune deficiency syndrome
AIDS
Antiretroviral therapy
Care and treatment
Cell activation
Cytosol
Development and progression
Drug resistance
Drug Resistance, Viral - genetics
Flow cytometry
flow virometry
Genetic aspects
Genetic polymorphisms
Health aspects
HIV
HIV infection
HIV Infections - drug therapy
HIV Infections - genetics
HIV Infections - virology
HIV Protease - genetics
HIV Protease - metabolism
HIV Protease Inhibitors - pharmacology
HIV-1 - drug effects
HIV-1 - enzymology
HIV-1 - genetics
HIV-1 protease
Host-virus relationships
Human immunodeficiency virus
Humans
Mutation
nanoscale flow cytometry
Polymorphism, Genetic
premature protease activation
protease inhibitor
Proteases
Proteinase inhibitors
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Summary:HIV-1 protease inhibitors are an essential component of antiretroviral therapy. However, drug resistance is a pervasive issue motivating a persistent search for novel therapies. Recent reports found that when protease activates within the host cell's cytosol, it facilitates the pyroptotic killing of infected cells. This has led to speculation that promoting protease activation, rather than inhibiting it, could help to eradicate infected cells and potentially cure HIV-1 infection. Here, we used a nanoscale flow cytometry-based assay to characterize protease resistance mutations and polymorphisms. We quantified protease activity, viral concentration, and premature protease activation and confirmed previous findings that major resistance mutations generally destabilize the protease structure. Intriguingly, we found evidence that common polymorphisms in the hinge domain of protease can influence its susceptibility to premature activation. This suggests that viral heterogeneity could pose a considerable challenge for therapeutic strategies aimed at inducing premature protease activation in the future.
ISSN:1999-4915
1999-4915
DOI:10.3390/v16060849