Comparison of three cell-based drug screening platforms for HSV-1 infection.
Acyclovir (ACV) and its derivatives have been highly effective for treating recurrent, lytic infections with Herpes Simplex Virus, type 1 (HSV-1), but searches for additional antiviral drugs are motivated by recent reports of resistance to ACV, particularly among immunocompromised patients. In addition, the relative neurotoxicity of ACV and its inability to prevent neurological sequelae among HSV-1 encephalitis survivors compel searches for new drugs to treat HSV-1 infections of the central nervous system (CNS). Primary drug screens for neurotropic viruses like HSV-1 typically utilize non-neuronal cell lines, but they may miss drugs that have neuron specific antiviral effects. Therefore, we compared the effects of a panel of conventional and novel anti-herpetic compounds in monkey epithelial (Vero) cells, human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and hiPSC-derived neurons (N = 73 drugs). While the profiles of activity for the majority of the drugs were similar in all three tissues, Vero cells were less likely than NPCs to identify drugs with substantial inhibitory activity in hiPSC-derived neurons. We discuss the relative merits of each cell type for antiviral drug screens against neuronal infections with HSV-1.
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: daiutol@upmc.edu.
Leonardo
L
D'Aiuto
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Kelly
K
Williamson
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Chemistry and Departments of Biological Sciences, University of Pittsburgh, PA, USA.
Peter
P
Dimitrion
Department of Chemistry and Chemical-Biology, McMaster University, Canada.
James
J
McNulty
Department of Chemistry and Chemical-Biology, McMaster University, Canada.
Carla E
CE
Brown
Department of Chemistry and Chemical-Biology, McMaster University, Canada.
Chanti Babu
CB
Dokuburra
Department of Chemistry and Chemical-Biology, McMaster University, Canada.
Alexander J
AJ
Nielsen
Department of Chemistry and Chemical-Biology, McMaster University, Canada.
Wen Jing
WJ
Lin
Department of Infectious Diseases and Microbiology, University of Pittsburgh, USA.
Paolo
P
Piazza
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Mark E
ME
Schurdak
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Joel
J
Wood
Division of Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Robert H
RH
Yolken
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Molecular Genetics & Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA.
Paul R
PR
Kinchington
Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, USA.
David C
DC
Bloom
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, USA.
Vishwajit L
VL
Nimgaonkar
D000212:Acyclovir / Q000633:toxicity; D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D002490:Central Nervous System / Q000187:drug effects; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral / Q000187:drug effects; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D016867:Immunocompromised Host / Q000187:drug effects*; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D039904:Pluripotent Stem Cells / Q000187:drug effects; D014709:Vero Cells / Q000187:drug effects
D000998:Antiviral Agents; D000212:Acyclovir