ECTRIMS Online Library

Several 'anti-retroviral' nucleoside analogues have in-vitro efficacy against Epstein-Barr virus
ECTRIMS Online Library. Drosu N. 09/11/19; 278864; P504
Natalia Drosu
Natalia Drosu
Contributions
Abstract

Abstract: P504

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Microbiology and virology

N. Drosu1,2, E. Edelman2,3,4, D. Housman1

1Biology, Massachusetts Institute of Technology, Cambridge, 2Health Sciences and Technology, Harvard Medical School, Boston, 3Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, 4Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, United States

Introduction: Converging evidence associates Epstein Barr Virus (EBV) infection with multiple sclerosis (MS), but a direct role remains unproven. Attempts to treat MS using EBV-specific cytotoxic T-cells have reported promise, suggesting EBV could be a pharmacological target in established MS. While three small trials of acyclovir/valacyclovir in MS showed insignificant trends towards benefit, these drugs have a potential barrier to efficacy - phosphorylation by a viral kinase that is expressed late in the EBV lytic cycle. This creates a delay between viral reactivation and drug action.
Other nucleoside analogues (NAs), specifically 'anti-retroviral' NAs, are activated independently of viral kinases and therefore could act earlier on EBV reactivation. Intriguingly, some of these drugs have been associated with MS remission in case reports, but there are no systematic studies comparing their anti-EBV activity. Therefore, we aimed to assess the in-vitro efficacy of NAs against EBV.
Methods: Using an established model of EBV replication in the B-cell line HH514-16, we assayed the efficacy of 3 traditional anti-herpesviral NAs, as well as all 8 licensed anti-retroviral NAs against EBV replication. We assessed inhibition of DNA replication by qPCR, and gene expression by RNA-seq.
Results: Five 'anti-retroviral' NAs (zidovudine, stavudine, abacavir, tenofovir disoproxil fumarate, and tenofovir alafenamide) show comparable anti-viral efficacy to traditional anti-herpesvirals. The respective IC50s [µM] for zidovudine, abacavir, tenofovir alafenamide, acyclovir, penciclovir, and ganciclovir are 13.4, 9.14, 0.0972, 2.94, 2.03 and 0.163.
Although drugs from both classes of NAs can reduce EBV gene expression, anti-retroviral NAs differ from anti-herpesvirals on cellular gene expression. CHI3L1, reported to be the most upregulated cellular gene upon EBV lytic induction, and increasingly a validated biomarker for MS disease activity, decreases with anti-retrovirals but not with anti-herpesvirals. Differences between drug classes suggest they may act by alternative mechanisms.
Conclusions: The armamentarium of anti-EBV drugs includes five 'anti-retroviral' NAs. Given the potential role of EBV in MS, clinical investigation of these agents would be informative. Interventional trials or opportunistic observational studies in persons with MS taking these NAs for other indications may assess correlation of EBV viral load, CHI3L1, and clinical/radiological endpoints.
Disclosure: Natalia Drosu: nothing to disclose
Patrick Kearns: nothing to disclose
Elazer Edelman: nothing to disclose
David Housman: nothing to disclose

Abstract: P504

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Microbiology and virology

N. Drosu1,2, E. Edelman2,3,4, D. Housman1

1Biology, Massachusetts Institute of Technology, Cambridge, 2Health Sciences and Technology, Harvard Medical School, Boston, 3Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, 4Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, United States

Introduction: Converging evidence associates Epstein Barr Virus (EBV) infection with multiple sclerosis (MS), but a direct role remains unproven. Attempts to treat MS using EBV-specific cytotoxic T-cells have reported promise, suggesting EBV could be a pharmacological target in established MS. While three small trials of acyclovir/valacyclovir in MS showed insignificant trends towards benefit, these drugs have a potential barrier to efficacy - phosphorylation by a viral kinase that is expressed late in the EBV lytic cycle. This creates a delay between viral reactivation and drug action.
Other nucleoside analogues (NAs), specifically 'anti-retroviral' NAs, are activated independently of viral kinases and therefore could act earlier on EBV reactivation. Intriguingly, some of these drugs have been associated with MS remission in case reports, but there are no systematic studies comparing their anti-EBV activity. Therefore, we aimed to assess the in-vitro efficacy of NAs against EBV.
Methods: Using an established model of EBV replication in the B-cell line HH514-16, we assayed the efficacy of 3 traditional anti-herpesviral NAs, as well as all 8 licensed anti-retroviral NAs against EBV replication. We assessed inhibition of DNA replication by qPCR, and gene expression by RNA-seq.
Results: Five 'anti-retroviral' NAs (zidovudine, stavudine, abacavir, tenofovir disoproxil fumarate, and tenofovir alafenamide) show comparable anti-viral efficacy to traditional anti-herpesvirals. The respective IC50s [µM] for zidovudine, abacavir, tenofovir alafenamide, acyclovir, penciclovir, and ganciclovir are 13.4, 9.14, 0.0972, 2.94, 2.03 and 0.163.
Although drugs from both classes of NAs can reduce EBV gene expression, anti-retroviral NAs differ from anti-herpesvirals on cellular gene expression. CHI3L1, reported to be the most upregulated cellular gene upon EBV lytic induction, and increasingly a validated biomarker for MS disease activity, decreases with anti-retrovirals but not with anti-herpesvirals. Differences between drug classes suggest they may act by alternative mechanisms.
Conclusions: The armamentarium of anti-EBV drugs includes five 'anti-retroviral' NAs. Given the potential role of EBV in MS, clinical investigation of these agents would be informative. Interventional trials or opportunistic observational studies in persons with MS taking these NAs for other indications may assess correlation of EBV viral load, CHI3L1, and clinical/radiological endpoints.
Disclosure: Natalia Drosu: nothing to disclose
Patrick Kearns: nothing to disclose
Elazer Edelman: nothing to disclose
David Housman: nothing to disclose

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