Antiviral mechanisms in varicella-zoster virus infections

Larkin, Margot (1986) Antiviral mechanisms in varicella-zoster virus infections. University of Southampton, Doctoral Thesis.

Abstract

Six varicella-zoster virus (VZV)-infected cell surface proteins, M_{}r 170K, 105K, 93K, 81K, 53K and 45K, were identified following extrinsic radiolabelling of the cell surface, immunoprecipitation of detergent-solubilized extract of the same cell surface and fractionation of the immunoprecipitates using SDS-PAGE. All six were shown to be glycosylated by their affinity for Ricin communis agglutinin 1 lectin. The glycoprotein with M_{}r 170K in non-reduced PAGE was shown to be a disulphide bond-linked protein as under reducing conditions it was cleaved to a subunit, M_{}r 63K. The human serum IgG response to these glycoproteins during various clinical circumstances was investigated. Antibodies reactive with these glycoproteins could not be detected in acute sera from the chickenpox patients and in the majority of acute shingles cases. Antibodies reactive with glycoproteins with M_{}r 170K, 105K, 53K and 45K were identified in post-varicella sera, whilst during zoster convalescence antibodies to all six were prominent. Antibodies to the disulphide bond-linked glycoprotein persisted for many years following both the primary disease and its reactivation. Disseminated zoster was associated with significantly low levels of antibodies to these surface glycoproteins. Virological studies were carried out in 28 non-immunocompromised patients with herpes zoster who received treatment with the antiviral acyclovir (5 mg/kg) or placebo intravenously three times daily for five days. Mean duration of virus shedding was not significantly different in the two groups and all patients developed high titres of IgG antibodies to varicella-zoster virus, IgM and IgA responses were also detected. Interferon levels in sequential vesicle fluids reached a peak significantly sooner (p< 0.025) and at a lower level in eight treated patients compared with eight given placebo. Twenty-five VZV isolates from the zoster patients were tested for sensitivity to antiviral agents. ED₅₀ values were found to be 3.25-18μM for acyclovir, 5-25μM for vidarabine, 0.49-3.3μM for idoxyuridine and 0.025-0.05μM for bromovinyldeoxyuridine. The wide range of sensitivity to acyclovir lead to a recommendation that the therapeutic dosage used by increased from 5 mg/kg/dose to 10 mg/kg/dose to produce adequate levels in vitro. (D72154/87)

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