Validation of Baboon Papiine Herpesvirus 2 As a Model for Macaque Macacine Herpesvirus 1 Drug Sensitivity
Abstract
Macacine herpesvirus 1 (Monkey B virus; BV) is a macaque alpha‐herpesvirus that is usually fatal when transmitted to humans, with a mortality rate close to 80%. Current antiviral treatments for BV infection are not fully effective and complete recovery is rare; surviving patients are often left with permanent neurological impairment and/or progressive neurological deterioration. Consequently, BV is a Risk Group 4 virus and until December 2012 was listed as a Select Agent by the CDC, making work with BV both dangerous and expensive. These limitations have led to little BV research being accomplished. A related Risk Group 2 baboon virus (Papiine herpesvirus 2; HVP2), represents a potential model for BV that does not have these limitations.The ability of the HVP2 model to predict sensitivity of BV to antiviral drugs was tested by comparing the drug sensitivity of HVP2 and BV in vitro (cell culture) and in vivo (BALB/c mice). Five commonly used nucleoside analogs were tested: acyclovir (ACV), penciclovir (PCV), ganciclovir (GCV), cidofovir (CDV), and 5-ethyl-2-deoxyuridine (EDU) were tested in vitro and in vivo. Additionally, seven other antivirals were tested in vitro: iododeoxyuridine (IDU), trisodium phosphonoformate (PFA), trifluorothymidine (TFT), brivudin (BVDU), adenine arabinoside (AraA), 5-bromo-deoxyuridine (BUdR) and 9-(4-hydroxybutyl)-N2-phenylguanine (HBPG). In plaque assays the drugs CDV, EDU, GCV and PCV were most effective. In mice, GCV and CDV showed efficacy, while PCV, ACV and EDU were not effective. For all but one of the twenty-four HVP2 in vitro tests, drug efficacy in vitro and in vivo against HVP2 paralleled that of BV. These results indicate that drug sensitivity of HVP2 is predictive of BV drug sensitivity.Delaying initiation of drug therapy, which mimics a human exposure to BV where seeking of medical attention can often be delayed by days, further tested the predictive nature of GCV and CDV treatment. In both drug therapy onset studies, as the time treatment delay increased so did the neurological involvement. There was however a temporally abrupt break in protection from death, with HVP2 paralleling that of BV.With all testing done, results for HVP2 paralleled those of BV. This work serves to validate the accuracy of HVP2 as a predictive model for BV drug sensitivity. This validation of the HVP2 model represents a unique and safe alternative to screen or discover anti-BV drugs.
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- OSU Theses [15752]