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Glycoprotein G of Herpes simplex virus type 2. Antigenicity and genetic variability

Doctoral thesis
Authors Jan-Åke Liljeqvist
Date of public defense 2000-10-06
ISBN 91-628-4359-1
Place of publication Göteborg
Publication year 2000
Published at Institute of Laboratory Medicine, Dept of Clinical Virology
Language en
Keywords Herpes simplex virus type 2, glycoprotein G, antigenic regions, sequence variability
Subject categories Medical and Health Sciences

Abstract

Herpes simplex virus type 2 (HSV-2) causes genital lesions, meningitis and occasionally, severe neonatal infections. Globally HSV-2 infection is one of the most common sexually transmitted diseases. As HSV-2 is frequently acquired and sustained asymptomatically, diagnosis during this phase of infection is essential both for the patient, and for preventive and epidemiological work. Type-specific serology is the diagnostic method of choice for this situation. The viral envelope glycoprotein G-2 (gG-2) exhibits two features unique in HSV-2 proteins. First, precursor gG-2 is cleaved to a secreted portion (sgG-2) and to a cell- and virion-associated, highly O-glycosylated mature portion (mgG-2). Second, mgG-2 is the only known HSV-2 glycoprotein which can be used as an antigen for type-discriminating serodiagnosis. In the present work we produced monoclonal antibodies (MAbs) against sgG-2 and mgG-2, and localized linear epitopes to the carboxy-terminal part of both proteins by a pepscan technique. Human anti-mgG-2 antibodies also recognized linear epitopes within mgG-2, localized to three regions of the protein of which one was found to be immunodominant. A synthetic peptide representing the immunodominant region was used successfully as antigen for detection of human anti-mgG-2 antibodies. The anti-mgG-2 MAbs as well as the human anti-mgG-2 antibodies identified type-specific epitopes and showed no cross-reactivity to HSV-1 antigen.One of the anti-mgG-2 MAbs was used for typing of 2,400 clinical HSV-2 isolates. The antibody was reactive with all except 13 of the HSV-2 isolates, and displayed no reactivity with clinical HSV-1 isolates indicating that the MAb was suitable for typing of HSV-2. Five of these 13 isolates presented a single frameshift mutation within the gG-2 gene with subsequent inactivation of the protein expression in four of the five isolates. The other eight isolates harbored a single missense mutation localized within the epitope which explained the loss of binding. These mutations did not diminish the antibody response to mgG-2 in the respective patients. Nucleotide sequencing of the gG-2 gene segment coding for mgG-2 among clinical HSV-2 isolates revealed that the epitope regions in mgG-2 were highly conserved.In conclusion, we have shown that mgG-2 is highly immunogenic for the human host and is a suitable antigen for type-discriminating serology, as well as for typing of HSV-2 isolates. The sgG-2 protein exhibited exclusively type-specific epitopes and may prove to be a novel antigen with serodiagnostic potential. The anti-gG-2 MAbs and HSV-2 mutants described here provide promising tools for further study on the function of the gG-2 proteins.

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