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

• Published in: PloS one 2019-03, Vol.14 (3), p.e0212877
• Main Authors: Rowe, Kelsey L, Minaya, Miguel A, Belshe, Robert B, Morrison, Lynda A
• Format: Article
• Language: English
• Subjects: Activation; Analysis; Animals; Anterograde transport; Biology and Life Sciences; Cell junctions; Chlorocebus aethiops; Clinical trials; Computer and Information Sciences; Datasets as Topic; Deoxyribonucleic acid; DNA; DNA sequencing; DNA, Viral - genetics; DNA, Viral - isolation & purification; Encephalitis; Evolution, Molecular; Female; Gene sequencing; Genes; Genetic aspects; Genomes; Glycoprotein E; Glycoprotein I; Glycoproteins; Glycoproteins - genetics; Health aspects; Herpes Genitalis - virology; Herpes simplex; Herpes simplex virus; Herpes viruses; Herpesvirus 2, Human - genetics; Herpesvirus 2, Human - isolation & purification; Herpesvirus infections; Humans; Immunology; Infants; Infection; Infections; Infectious diseases; Internal medicine; Medicine; Membrane Glycoproteins - genetics; Membrane proteins; Multigene Family - genetics; Neonates; Neurons; Newborn infants; People and places; Phylogenetics; Phylogeny; Polymorphism; Proteins; Recurrence; Research and Analysis Methods; Vaccine development; Vaccines; Vero Cells; Viral encephalitis; Viral Proteins - genetics; Virions; Virus Activation - genetics; Virus diseases; Viruses; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0212877

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.