Efficient establishment of reactivatable latency by an acyclovir-resistant herpes simplex virus 1 thymidine kinase substitution mutant with reduced neuronal replication

Herpes simplex virus 1 causes recurrent diseases by reactivating from latency, which requires the viral thymidine kinase (TK) gene. An acyclovir-resistant mutation in TK, V204G, was previously repeatedly identified in a patient with recurrent herpetic keratitis. We found that compared with its paren...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2021-04, Vol.556, p.140-148
Main Authors: Wang, Shuaishuai, Hou, Fujun, Yao, Yu-Feng, Pan, Dongli
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Chlorocebus aethiops
Drug resistance
Epithelial Cells
Herpesvirus 1, Human - genetics
Herpesvirus 1, Human - pathogenicity
HSV-1
Humans
Keratitis, Herpetic - virology
Latent infection
Mice
Neurons - virology
Reactivation
Thymidine kinase
Vero Cells
Virus Activation
Virus Replication
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Summary:Herpes simplex virus 1 causes recurrent diseases by reactivating from latency, which requires the viral thymidine kinase (TK) gene. An acyclovir-resistant mutation in TK, V204G, was previously repeatedly identified in a patient with recurrent herpetic keratitis. We found that compared with its parental strain KOS, a laboratory-derived V204G mutant virus was impaired in replication in cultured neurons despite little defect in non-neuronal cells. After corneal inoculation of mice, V204G exhibited defects in ocular replication that were modest over the first three days but severe afterward. Acute replication of V204G in trigeminal ganglia was significantly impaired. However, V204G established latency with viral loads as high as KOS and reactivated with high frequency albeit reduced kinetics. Acyclovir treatment that drastically decreased ocular and ganglionic replication of KOS had little effect on V204G. Thus, despite reduced neuronal replication due to impaired TK activity, this clinically relevant drug-resistant mutant can efficiently establish reactivatable latency. •Acyclovir resistance by HSV-1 TK mutant V204G was confirmed in vivo.•Replication of V204G was impaired in neuronal cells and tissues.•V204G established latency in mouse ganglia as efficiently as wild-type virus.•V204G reactivated from latency with high frequency but reduced kinetics.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2021.01.016