# Translation initiation factor targeting by HHV-8 vIRF-1

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2020 · $213,694

## Abstract

Human herpesvirus 8 (HHV-8) encodes four interferon regulatory factor homologues (vIRFs) that interact, in
inhibitory fashion, with cellular IRFs and/or a variety of other cellular proteins involved in innate immunity and
cellular stress signaling. For vIRF-1 these proteins include CBP/p300 (required for IRF-induced transcription
and interferon signaling), p53, p53-activating ATM kinase, BH3-only proteins Bim and Bid, TGFβ-activated Smad
transcription factors, and retinoic acid and interferon induced protein 19 (GRIM19). Recent affinity precipitation
and mass spectrometry (MS) analyses undertaken in our laboratory have identified novel cellular targets of vIRF-
1. Among these are translational initiation factor eIF4A1, poly(rC)-binding proteins 1 and 2, and USP7 (which
has since been published by others). Interestingly, eIF4A1 and USP7 were detected at far higher abundance in
MS-analyzed vIRF-1 co-precipitates [from HHV-8+ BCBL-1 primary effusion lymphoma (PEL) cells] than were
previously reported interactors of vIRF-1 (e.g., CBP/p300). Interactions of vIRF-1 with eIF4A1 and PCBP1 (in
addition to other proteins) have been verified by immunoprecipitation experiments. Of note, eIF4A1 expression
has been reported to be elevated in several cancers and to enhance translation of mRNAs encoding proteins
such as cyclins, CDKs and pro-survival and angiogenic factors involved in cancer development and progression.
Regulation by eIF4A1 is through unwinding of poly-G repeat-induced G-quadruplex and other secondary
structures in long 5' untranslated regions of client mRNAs. PCBP1/2 contain hnRNP-K homology (KH) domains
and are related to hnRNP-K ATP helicase; the functions of the PCBPs are varied but include translational
regulation via enhancement of internal ribosome entry site (IRES)-dependent initiation, in addition to mRNA
stabilization and transcriptional regulation. We hypothesize that interactions of vIRF-1 with eIF4A1, PCBP1 and
PCBP2 regulate translation to promote HHV-8 infected cell survival and function during latency and/or productive
replication via enhanced expression of eIF4A1- and PCBP1/2-regulated mRNAs such as Bcl-2, Bcl-x and c-IAP
(eIF4A1) and Bag-1, XIAP and c-myc (PCBP1/2). We have identified pro-growth/survival activity of vIRF-1 in
latently infected PEL cells and pro-replication activities of vIRF-1 in lytically reactivated PEL and other cell types.
We propose here to focus follow-up experimental analysis on vIRF-1-targeted eIF4A1 and PCBPs 1 and 2 to
characterize an entirely new mechanism of vIRF-1 function, via translational regulation, which is of significance
scientifically and potentially also for future development of anti-viral and therapeutic strategies targeting these
interactions in infected cells.

## Key facts

- **NIH application ID:** 9840465
- **Project number:** 5R21CA228678-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** John Nicholas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $213,694
- **Award type:** 5
- **Project period:** 2019-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840465

## Citation

> US National Institutes of Health, RePORTER application 9840465, Translation initiation factor targeting by HHV-8 vIRF-1 (5R21CA228678-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9840465. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*