Heterogeneity and Evolution of Thymidine Kinase and DNA Polymerase Mutants of Herpes Simplex Virus Type 1: Implications for Antiviral Therapy

Laboratory of Virology, Rega Institute for Medical Research, KU Leuven, Belgium.
The Journal of Infectious Diseases (Impact Factor: 6). 01/2013; 207(8). DOI: 10.1093/infdis/jit019
Source: PubMed


Infections caused by acyclovir-resistant isolates of herpes simplex virus (HSV) after hematopoietic stem cell transplantation (HSCT) are an emerging concern. An understanding of the evolutionary aspects of HSV infection is crucial to the design of effective therapeutic and control strategies.

Eight sequential HSV-1 isolates were recovered from an HSCT patient who suffered from recurrent herpetic gingivostomatitis and was treated alternatively with acyclovir, ganciclovir, and foscavir. The diverse spectra and temporal changes of HSV drug resistance were determined phenotypically (drug-resistance profiling) and genotypically (sequencing of the viral thymidine kinase and DNA polymerase genes).

Analysis of 60 clones recovered from the different isolates demonstrated that most of these isolates were heterogeneous mixtures of variants, indicating the simultaneous infection with different drug-resistant viruses. The phenotype/genotype of several clones associated with resistance to acyclovir and/or foscavir were identified. Two novel mutations (E798K and I922T) in the viral DNA polymerase could be linked to drug resistance.

The heterogeneity within the viral populations and the temporal changes of drug-resistant viruses found in this HSCT recipient were remarkable, showing a rapid evolution of HSV-1. Drug-resistance surveillance is highly recommended among immunocompromised patients to manage the clinical syndrome and to avoid the emergence of multidrug-resistant isolates.

7 Reads
  • Source
    • "Resistance may be suspected when lesions persist for more than 1 week after initiating antiviral treatment or the emergence of new satellite lesions during treatment. A virological confirmation helps health care professionals choose among different treatment options while it avoids the selection of multidrug-resistant strains [63]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since the type of herpes simplex virus (HSV) infection affects prognosis and subsequent counseling, type-specific testing to distinguish HSV-1 from HSV-2 is always recommended. Although PCR has been the diagnostic standard method for HSV infections of the central nervous system, until now viral culture has been the test of choice for HSV genital infection. However, HSV PCR, with its consistently and substantially higher rate of HSV detection, could replace viral culture as the gold standard for the diagnosis of genital herpes in people with active mucocutaneous lesions, regardless of anatomic location or viral type. Alternatively, antigen detection--an immunofluorescence test or enzyme immunoassay from samples from symptomatic patients--could be employed, but HSV type determination is of importance. Type-specific serology based on glycoprotein G should be used for detecting asymptomatic individuals but widespread screening for HSV antibodies is not recommended. In conclusion, rapid and accurate laboratory diagnosis of HSV is now become a necessity, given the difficulty in making the clinical diagnosis of HSV, the growing worldwide prevalence of genital herpes and the availability of effective antiviral therapy.
    Virology Journal 05/2014; 11(1):83. DOI:10.1186/1743-422X-11-83 · 2.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A novel nucleoside analogue, 1-[(2S,4S-2-(hydroxymethyl)-1,3-dioxolan-4-yl]5-vinylpyrimidine-2,4(1H,3H)-dione or HDVD, was evaluated against a wide variety of herpesviruses and was found to be a highly selective inhibitor of gammaherpesvirus KSHV and EBV replication. HDVD had also a pronounced inhibitory activity against MHV-68 and HSV-1. In contrast, replication of HVS, HSV-2, and VZV was weakly inhibited by the compound and no antiviral activity was determined against HCMV and RRV. The HDVD-resistant virus phenotype contained point mutations in the viral thymidine kinase (TK) of HSV-1, MHV-68 and HVS isolates. These mutations conferred cross-resistance to other TK-dependent drugs, with the exception of a MHV-68 mutant (E358D) that exhibited only resistance to HDVD. HSV-1 and HVS TK-mutants isolated under selective pressure with bromovinyldeoxyuridine (BVDU) showed also reduced sensitivity to HDVD. Oral treatment with HDVD and BVDU was assessed in an intranasal model of MHV-68 infection in BALB/c mice. In contrast to BVDU, HDVD-treated animals showed a reduction in viral DNA loads and diminished viral gene expression during acute viral replication in the lungs, in comparison with untreated control. The valyl ester prodrug of HDVD (USS-02-71-44), suppressed the latent infection in the spleen to a greater extent than HDVD. In the present study, HDVD emerged as a highly potent antiviral with a unique spectrum of activity against herpesviruses, in particular gammaherpesviruses, and may be of interest in the treatment of virus-associated diseases.
    Journal of Virology 01/2013; 87(7). DOI:10.1128/JVI.03338-12 · 4.44 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fifty-nine US isolates of HSV-1 and HSV-2 obtained between 1998 and 2004 were tested for sensitivity to the helicase-primase inhibitor, pritelivir (AIC316, BAY 57-1293) by plaque-reduction assay. All isolates, which were collected prior to any clinical use of primase-helicase inhibitors, were sensitive and showed mean EC50 values of 0.026 and 0.029 μM for HSV-1 and HSV-2, respectively. Furthermore, several laboratory-selected acyclovir-resistant HSV mutants were also sensitive to pritelivir. These data provide a baseline for HSV sensitivity to pritelivir in general population before it is introduced and broadly used to treat HSV infection. The data also validate pritelivir as an appropriate therapy for nucleoside-resistant HSV infections.
    Antiviral research 09/2013; 100(2). DOI:10.1016/j.antiviral.2013.08.024 · 3.94 Impact Factor
Show more