Molecular analyses and phylogeny of the herpes simplex virus 2 US9 and glycoproteins gE/gI obtained from infected subjects during the Herpevac Trial for Women.

Kelsey L Rowe,Lynda A Morrison,Miguel A Minaya,Robert B Belshe,Neal A Deluca

doi:10.1371/journal.pone.0212877

Kelsey L Rowe, Lynda A Morrison + Show 3 more

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https://doi.org/10.1371/journal.pone.0212877

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Journal: PloS one	Publication Date: Mar 8, 2019
Citations: 2	License type: CC BY 4.0

Affiliation: Saint Louis University

Abstract

Herpes simplex virus 2 (HSV-2) is a large double-stranded DNA virus that causes genital sores when spread by sexual contact and is a principal cause of viral encephalitis in newborns and infants. Viral glycoproteins enable virion entry into and spread between cells, making glycoproteins a prime target for vaccine development. A truncated glycoprotein D2 (gD2) vaccine candidate, recently tested in the phase 3 Herpevac Trial for Women, did not prevent HSV-2 infection in initially seronegative women. Some women who became infected experienced multiple recurrences during the trial. The HSV US7, US8, and US9 genes encode glycoprotein I (gI), glycoprotein E (gE), and the US9 type II membrane protein, respectively. These proteins participate in viral spread across cell junctions and facilitate anterograde transport of virion components in neurons, prompting us to investigate whether sequence variants in these genes could be associated with frequent recurrence. The nucleotide sequences and dN/dS ratios of the US7-US9 region from viral isolates of individuals who experienced multiple recurrences were compared with those who had had a single episode of disease. No consistent polymorphism(s) distinguished the recurrent isolates. In frequently recurring isolates, the dN/dS ratio of US7 was low while greater variation (higher dN/dS ratio) occurred in US8, suggesting conserved function of the former during reactivation. Phylogenetic reconstruction of the US7-US9 region revealed eight strongly supported clusters within the 55 U.S. HSV-2 strains sampled, which were preserved in a second global phylogeny. Thus, although we have demonstrated evolutionary diversity in the US7-US9 complex, we found no molecular evidence of sequence variation in US7-US9 that distinguishes isolates from subjects with frequently recurrent episodes of disease.

Highlights

ObjectivesBecause the main objective of this research is to evaluate whether sequence differences in the glycoprotein E (gE)/glycoprotein I (gI) and US9 proteins obtained from Herpes simplex virus 2 (HSV-2) U.S isolates are associated with more frequent recurrence, a U.S.restricted phylogeny was first calculated
Some women who became infected during the trial experienced multiple episodes of recurrent disease, while others did not. To explore this phenotypic variation, we investigated whether amino acid sequence differences in the glycoprotein E (gE)/glycoprotein I (gI) and US9 proteins are associated with more frequent recurrence
We sequenced isolates from the last disease episode of these subjects who had 3 or more recurrences during the trial and define these as “recurrent.” Among the subjects with multiple recurrent disease episodes, the 4 subjects who received the control hepatitis A vaccine (HAV) had an average of 4.75 recurrent episodes of disease, while the 4 who received the investigational HSV vaccine had an average of 3.75 recurrent episodes of disease (p > 0.05)

Summary

Objectives

Because the main objective of this research is to evaluate whether sequence differences in the gE/gI and US9 proteins obtained from HSV-2 U.S isolates are associated with more frequent recurrence, a U.S.restricted phylogeny was first calculated

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Results

Conclusion