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Open Access 01-12-2024 | Kaposi's Sarcoma-Associated Herpesvirus | Research

Nelfinavir inhibition of Kaposi’s sarcoma-associated herpesvirus protein expression and capsid assembly

Authors: Maggie Li, Barbara J. Smith, Jaeyeun Lee, Jennifer Petr, Nicole M. Anders, Robyn Wiseman, Michelle A. Rudek, Richard F. Ambinder, Prashant J. Desai

Published in: Infectious Agents and Cancer | Issue 1/2024

Abstract

Background

Antiviral therapies that target herpesviruses are clinically important. Nelfinavir is a protease inhibitor that targets the human immunodeficiency virus (HIV) aspartyl protease. Previous studies demonstrated that this drug could also inhibit Kaposi’s sarcoma-associated herpesvirus (KSHV) production. Our laboratory demonstrated nelfinavir can effectively inhibit herpes simplex virus type 1 (HSV-1) replication. For HSV-1 we were able to determine that virus capsids were assembled and exited the nucleus but did not mature in the cytoplasm indicating the drug inhibited secondary envelopment of virions.

Methods

For KSHV, we recently derived a tractable cell culture system that allowed us to analyze the virus replication cycle in greater detail. We used this system to further define the stage at which nelfinavir inhibits KSHV replication.

Results

We discovered that nelfinavir inhibits KSHV extracellular virus production. This was seen when the drug was incubated with the cells for 3 days and when we pulsed the cells with the drug for 1–5 min. When KSHV infected cells exposed to the drug were examined using ultrastructural methods there was an absence of mature capsids in the nucleus indicating a defect in capsid assembly. Because nelfinavir influences the integrated stress response (ISR), we examined the expression of viral proteins in the presence of the drug. We observed that the expression of many were significantly changed in the presence of drug. The accumulation of the capsid triplex protein, ORF26, was markedly reduced. This is an essential protein required for herpesvirus capsid assembly.

Conclusions

Our studies confirm that nelfinavir inhibits KSHV virion production by disrupting virus assembly and maturation. This is likely because of the effect of nelfinavir on the ISR and thus protein synthesis and accumulation of the essential triplex capsid protein, ORF26. Of interest is that inhibition requires only a short exposure to drug. The source of infectious virus in saliva has not been defined in detail but may well be lymphocytes or other cells in the oral mucosa. Thus, it might be that a “swish and spit” exposure rather than systemic administration would prevent virion production.

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Title: Nelfinavir inhibition of Kaposi’s sarcoma-associated herpesvirus protein expression and capsid assembly
Authors: Maggie Li
Barbara J. Smith
Jaeyeun Lee
Jennifer Petr
Nicole M. Anders
Robyn Wiseman
Michelle A. Rudek
Richard F. Ambinder
Prashant J. Desai
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Kaposi's Sarcoma-Associated Herpesvirus
Doxycycline
Published in: Infectious Agents and Cancer / Issue 1/2024
Electronic ISSN: 1750-9378
DOI: https://doi.org/10.1186/s13027-024-00566-7

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Abstract

Background

Methods

Results

Conclusions

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