Inhibition of B Virus (Macacine herpesvirus 1) by Conventional and Experimental Antiviral Compounds

Viral Immunology Center, Georgia State University, P.O. Box 4118, Atlanta, GA 30302, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 10/2009; 54(1):452-9. DOI: 10.1128/AAC.01435-08
Source: PubMed


B virus infection of humans results in high morbidity and mortality in as many as 80% of identified cases. The main objective of this study was to conduct a comparative analysis of conventional and experimental antiviral drug susceptibilities of B virus isolates from multiple macaque species and zoonotically infected humans. We used a plaque reduction assay to establish the effective inhibitory doses of acyclovir, ganciclovir, and vidarabine, as well as those of a group of experimental nucleoside analogs with known anti-herpes simplex virus activity. Four of the experimental drugs tested were 10- to 100-fold more potent inhibitors of B virus replication than conventional antiviral agents. Drug efficacies were similar for multiple B virus isolates tested, with variations within 2-fold of the median effective concentration (EC(50)) for each drug, and each EC(50) was considerably lower than those for B virus thymidine kinase (TK) mutants. We observed no differences in the viral TK amino acid sequence between B virus isolates from rhesus monkeys and those from human zoonoses. Differences in the TK protein sequence between cynomolgus and pigtail macaque B virus isolates did not affect drug sensitivity except in the case of one compound. Taken together, these data suggest that future B virus zoonoses will respond consistently to conventional antiviral treatment. Further, the considerably higher potency of FEAU (2'-fluoro-5-ethyl-Ara-U) than of conventional antiviral drugs argues for its compassionate use in advanced human B virus infections.

Download full-text


Available from: Raymond F Schinazi, Oct 01, 2015
34 Reads
  • Nonhuman Primates in Biomedical Research, 01/2012: pages 1-33; , ISBN: 9780123813657
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Although a number of antiviral agents are licensed for treatment of some human herpesvirus (HHV) infections, effective antiviral therapy is not available for all HHVs. Additional complications are associated with approved drugs, such as toxicity and side effects, and rise in drug-resistant strains is a driving force for new drug development. Success in HHV vaccine development is limited with only vaccines against varicella-zoster virus currently in use in the clinic. In vitro, in vivo and in silico high-throughput (HTP) approaches and innovative microfluidic systems will provide novel technologies to efficiently identify and evaluate new targets and antiherpetic compounds. Coupled with HTP strategies for manipulation of herpesvirus viral genomes, these strategies will greatly accelerate the development of future antivirals as well as candidate vaccine intervention strategies. Areas covered: The authors provide a brief overview of the herpesvirus family and associated diseases. Further, the authors discuss the approved and investigational antiherpetic drugs in the context of current HTP technologies. Expert opinion: HTP technology such as microfluidic systems is crucial for the identification and validation of novel drug targets and next-generation antivirals. Current drug development is limited by the unavailability of HTP preclinical model systems. Specific advancement in the development of HTP animal-specific technology, applied in parallel, allows a more rapid evaluation of drugs at the preclinical stage. The advancement of HTP combinatorial drug therapy, especially 'Organ-on-a-Chip' approaches, will aid in the evaluation of future antiviral compounds and intervention strategies.
    Expert Opinion on Drug Discovery 07/2014; 9(8):1-25. DOI:10.1517/17460441.2014.922538 · 3.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Monkey B virus (Macacine herpesvirus 1; BV) is endemic in macaques. BV (a BSL4 agent) is the primary zoonotic concern for persons working with macaques in research, and human BV infections frequently are fatal. We assessed the use of a BSL2 baboon herpesvirus (Papiine herpesvirus 1; HVP2) for predicting the drug sensitivity of BV by comparing the sensitivity of the 2 viruses to 12 antiherpetic drugs. Plaque reduction assays showed that 4 drugs (HBPG, BVdU, PFA, and BrdU) were ineffective against both viruses. Of the 8 effective drugs, both viruses were most sensitive to TFT, whereas sensitivity to the remaining 7 drugs varied between BV and HVP2 as well as between strains of HVP2. In addition, the efficacy of 5 drugs (ACV, PCV, GCV, CDV, and EDU) was tested by using a murine model. ACV and EDU were completely ineffective against both HVP2 and BV, and high doses of PCV only delayed death by a few days. GCV and CDV both protected mice against death, and CDV also prevented the development of neurologic symptoms. When the initiation of drug therapy was delayed until after virus gained access to the CNS, both GCV and CDV were ineffective. The similarity of the drug sensitivities of HVP2 and BV in both models validates the use of HVP2 as a BSL2 level model that can be used to predict drug sensitivity of BV. The greater efficacy of CDV relative to GCV suggests the potential for use of CDV in the treatment of zoonotic BV infections.
    Comparative medicine 10/2014; 64(5):386-93. · 0.74 Impact Factor