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

Autor: Caroline O. Tabler, Sarah J. Wegman, Najwa Alhusaini, Nicole F. Lee, John C. Tilton
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Viruses, Vol 16, Iss 6, p 849 (2024)
Druh dokumentu: article
ISSN: 16060849
1999-4915
DOI: 10.3390/v16060849
Popis: 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.
Databáze: Directory of Open Access Journals
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