Zoonotic infection by herpes B virus (BV) causes severe neurological disease, which in the absence of appropriate treatment can have a mortality rate of 80%. Long-term administration of acyclovir or ganciclovir is the recommended prophylactic treatment option for BV infections. However, emergence of acyclovir- and/or ganciclovir-resistant BV may become a major problem.
In this paper, we examined the ability of BV thymidine kinase (TK) from monkeys (mBVTK) and humans (hBVTK) to acquire resistance to acyclovir and ganciclovir. The sequences of mBVTK and hBVTK differ by two amino acids. We constructed and expressed four HSV-1-based recombinant viruses (HSV-1_mBVTK, HSV-1_hBVTK, HSV-1_VZVTK, and HSV_HSV-1TK) in which the HSV-1TK gene was deleted and the TK gene of monkey BV, human BV, varicella zoster virus, and HSV-1 was inserted, respectively. We then tested the sensitivity of these recombinant TK viruses to acyclovir, ganciclovir, penciclovir, and brivudine. HSV-1_HSV-1TK and wild-type HSV-1 were more susceptible to ganciclovir, acyclovir, and penciclovir than HSV-1_VZVTK, HSV-1_hBVTK, and HSV-1_mBVTK. Both HSV-1_hBVTK and HSV-1_mBVTK exhibited similar sensitivity profiles against all tested drugs: both were susceptible to acyclovir, ganciclovir, and penciclovir, but resistant to brivudine BVDU. In addition, we forced HSV-1_hBVTK to make replicate under selective pressure from acyclovir or ganciclovir, and then examined the ability of the BVTK gene to develop drug resistance.
Investigation of the drug-resistant HSV-1_hBVTK gene revealed the absence of amino acid substitutions in BVTK, suggesting that the development of ACV- or GCV-resistant BV through mutations in the TK gene is a rare occurrence in this experimental system.
Nguyen PHA et al., Analysis of antiviral drug properties of thymidine kinase of herpes B virus by using recombinant herpes simplex virus 1, Spectrum, 2023, DOI: https://doi.org/10.1128/spectrum.03091-23
● Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan
● Department of Developmental Medical Sciences, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Grant-in-Aid for Scientific Research from the Japan Ministry of Education, Culture, Sports, Science and Technology (Grant Numbers 20K06404, 21K05967, and 23K05585).