Evidence map›Paper›PMID 38439055›Full record

ArticleInfectious agents and cancer2024

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

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

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Infectious agents and cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.8field-weighted citation impact, top 29% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 2 citations in OpenAlex.

  1. Review
  2. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 2 countries.

Maggie LiDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Barbara J SmithDepartment of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jaeyeun LeeDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jennifer PetrDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nicole M AndersDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Robyn WisemanDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Michelle A RudekDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Richard F AmbinderDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rambind1@jhmi.edu.
Prashant J DesaiDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. pdesai@jhmi.edu.
Johns Hopkins Medicine · USJohns Hopkins University · US

Funding

Translational Research Central ServicesP30CA006973 · NCI · JOHNS HOPKINS UNIVERSITY · PI WILLIAM George NELSON · 1985 to 2026
$208.6M
Pharmacology and Molecular Sciences Training Program: Enhancing Inclusivity Through Universal Design for Learning in Graduate CoursesT32GM135083 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI Caren L. Freel Meyers · 2020 to 2026
$3.3M
Elucidation of genetic networks of HSV-1 virion proteins and discovery of their functions in the morphogenesis of the infectious virus particleR01AI137365 · NIAID · JOHNS HOPKINS UNIVERSITY · PI DESAI, PRASHANT J, VASHEE, SANJAY · 2019 to 2024
$3.2M
Investigating the EBV methylome in PLWH: Discovery and Development of Novel EBV Diagnostics in Plasma and SalivaU01CA284811 · NCI · JOHNS HOPKINS UNIVERSITY · PI RICHARD Frederick AMBINDER, Rena Xian · 2023 to 2026
$2.7M
Synthetic Genomics Approach to Assemble Infectious Clones of KSHVR03AI146632 · NIAID · JOHNS HOPKINS UNIVERSITY · PI DESAI, PRASHANT J, VASHEE, SANJAY · 2019 to 2020
$195k
NCI NIH HHS P30 CA006973NCI NIH HHS U01 CA284811NIAID NIH HHS R01 AI137365NIAID NIH HHS R03 AI146632NIGMS NIH HHS T32 GM135083NIH HHS P30CA006973NIH HHS R03AI146632NIH HHS U01CA284811
6 · The paper itself

Abstract

backgroundAntiviral 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.

methodsFor 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.

resultsWe 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.

conclusionsOur 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.

Indexed as

Integrated stress responseKaposi’s sarcoma-associated herpesvirusNelfinavirVirus assemblyVirus inhibition

Identifiers

PMID38439055
PMCPMC10913605
OpenAlexW4392382309

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.