Broad-spectrum antiviral brincidofovir inhibits Epstein-Barr virus and related gammaherpesvirus in human and nonhuman primate cells
Abaigeal Donaldson, Madeleine R. Druker, Maria Chiara Monaco, Emily H. Stack, Paige Zimmerman, Amanda Lee, Izabela Bialuk, William Frazier, Irene Cortese, Heather Narver, Masatoshi Hazama, Fuminori Yoshida, Xiaofan Li, Laurie T. Krug, Stacey L. Piotrowski, Steven Jacobson
Abaigeal Donaldson, Madeleine R. Druker, Maria Chiara Monaco, Emily H. Stack, Paige Zimmerman, Amanda Lee, Izabela Bialuk, William Frazier, Irene Cortese, Heather Narver, Masatoshi Hazama, Fuminori Yoshida, Xiaofan Li, Laurie T. Krug, Stacey L. Piotrowski, Steven Jacobson
View: Text | PDF
Research Article Neuroscience Virology

Broad-spectrum antiviral brincidofovir inhibits Epstein-Barr virus and related gammaherpesvirus in human and nonhuman primate cells

Abstract

Epstein-Barr virus (EBV) is of growing interest for its potential role in neurodegenerative diseases such as multiple sclerosis (MS) and its possible utility as a therapeutic target in herpesvirus-associated chronic diseases. The effects of brincidofovir (BCV) on EBV reactivation were evaluated in vitro using EBV-infected spontaneous lymphoblastoid cell lines (SLCLs) and peripheral blood mononuclear cells (PBMCs) derived from patients with MS and healthy controls. In addition, a B lymphoblastoid cell line and PBMCs from common marmosets (Callithrix jacchus) naturally infected with an EBV-related gammaherpesvirus (Callitrichine herpesvirus 3, CalHV-3) were used to measure BCV efficacy in a nonhuman primate model. BCV significantly inhibited gammaherpesvirus reactivation, with decreased lytic and latent viral transcript expression. These results suggest that BCV may be a useful antiviral for inhibiting EBV activity in patients with MS. Additionally, this work further validates the utility of CalHV-3 in marmosets as a translational model for the investigation of successful EBV-targeting therapeutics.

Authors

Abaigeal Donaldson, Madeleine R. Druker, Maria Chiara Monaco, Emily H. Stack, Paige Zimmerman, Amanda Lee, Izabela Bialuk, William Frazier, Irene Cortese, Heather Narver, Masatoshi Hazama, Fuminori Yoshida, Xiaofan Li, Laurie T. Krug, Stacey L. Piotrowski, Steven Jacobson

×

Figure 3

Brincidofovir reduces EBV mRNA expression in PBMCs from an individual with stable multiple sclerosis (SMS) following viral reactivation.

Options: View larger image (or click on image) Download as PowerPoint
Brincidofovir reduces EBV mRNA expression in PBMCs from an individual wi...
(A–C) Representative ddPCR plots of EBNA1 detection from SMS6 PBMCs cultured (A) without NaB+TPA and no BCV, (B) with NaB+TPA and no BCV, and (C) with NaB+TPA and 125nM BCV. Y axis represents the FAM-MGBNFQ fluorescent amplitude, corresponding to EBNA1 detection in this plot (blue dots + orange dots, upper quadrants). X axis represents the VIC-MGBNFQ fluorescent amplitude, which corresponds to the HPRT housekeeping gene (green dots, bottom right quadrant). Lower left quadrant represents droplets negative for both EBNA1 and HPRT (gray dots). (D–F) Quantification of EBV mRNA expression in SMS6 PBMCs cultured with BCV and with or without NaB+TPA to induce viral reactivation (arrow). (D) EBNA1 expression; (E) BZLF1 expression; (F) BFRF3 expression. Open circle intersecting x-axis, mRNA expression undetected by ddPCR; BCV, Brincidofovir; EBV, Epstein-Barr virus; SMS, stable multiple sclerosis patient; Control, cells treated with only media.