Our analysis of these studies provides evidence that glycoprotein G variation is likely significant in clinical typing discrepancies and also in isolate variations. Analysis of the amino acid sequences of Y3369 and other isolates indicates that there is a shared significant variation among HSV-1 strains that alters viral antigen assay specificity. PCR analysis is likely to succeed in HSV typing where the isolate is not recognized by the monoclonal antibody. In addition to results presented here, PCR has been used to type HSV samples on other occasions. In one study, 75 HSV-positive isolates yielded two which were untypable using type-specific antibody tests, later confirmed HSV-1 by PCR. Another study yielded 1 untypable isolate of 37 tested HSV-positive isolates, which was also confirmed as HSV-1 by PCR. These represent about 2% of the HSV-positive isolates in these two studies.
We have determined the presence of two phylogenetic groups of glycoprotein G. One group was only found in Europe, and all the isolates in this group contain the epitope AFPL, which a common assay uses to type HSV-1. The other group was found in all tested regions, which include Africa, Asia and Europe. This group was characterized by the AVPL sequence. Y3369 is a member of this group. The two sequences differ by location statistically (χ2 = 142.8, p < 0.0001).
The identification of these two groups, as well as their localization to different parts of the world, may aid in developing strategies for clinical viral antigen assays for HSV typing. Although the isolates included in the meta analysis which have the AVPL sequence were not tested by us, they would likely fail to type as HSV-1 using this same test. It should be considered that tests for the viral antigen epitope AFLP be used with caution in Africa or Asia.
This variation may also alter the interaction of virus with host. The presence of the variations in the immunodominant region of the protein suggests these mutations could be a result of viral immune evasion. These mutations may also affect the functioning of glycoprotein G, which involves attachment and entry. Further tests are being performed to study what other effects this mutation has on the virus’s efficiency of infection.