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
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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

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Figure 1

Brincidofovir decreases EBV DNA in a human EBV-infected cell line and reduces viral mRNA following reactivation.

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Brincidofovir decreases EBV DNA in a human EBV-infected cell line and re...
(A) Viability of one EBV-infected SLCL, SMS2 (red triangle), and the Ramos EBV-negative cell line (black square) after 7 days in culture with BCV. (B and C) Average EBV DNA copy number ± SEM per 1 × 106 cells of the SMS2 SLCL detected by ddPCR for EBV BamHI DNA following 5 days in culture (B) and 7 days in culture (C) with BCV. (D–F) Average of EBV mRNA expression ± SEM in HC (open circles, n = 4) and MS (black circles, n = 6) SLCLs cultured with BCV and with (dark blue bars, to right of arrow) or without (light blue bars, under arrow) NaB+TPA to induce viral reactivation (arrow). (D) EBNA1 expression; (E) BZLF1 expression; (F) BFRF3 expression. Data analyzed using 1-way ANOVA with Tukey’s multiple comparisons (A–C) and the Kruskal-Wallis test with Dunn’s test for pairwise comparisons (D–F), *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. BCV, Brincidofovir; EBV, Epstein-Barr virus; HC, healthy control; SMS, stable multiple sclerosis patient.