Abstract
The Herpevac Trial for Women revealed that three dose HSV-2 gD vaccine was 58% protective against culture-positive HSV-1 genital disease, but it was not protective against HSV-2 infection or disease. To determine whether vaccine-induced immune responses had selected for a particular gD sequence in strains infecting vaccine recipients compared with viruses infecting control subjects, genetic sequencing studies were carried out on viruses isolated from subjects infected with HSV-1 or HSV-2. We identified naturally occurring variants among the gD sequences obtained from 83 infected subjects. Unique or low frequency amino acid substitutions in the ectodomain of gD were found in 6 of 39 HSV-1-infected subjects and in 7 of 44 HSV-2-infected subjects. However, no consistent amino acid change was identified in isolates from gD-2 vaccine recipients compared with infected placebo recipients. gC and gE surround and partially shield gD from neutralizing antibody, and gB also participates closely in the viral entry process. Therefore, these genes were sequenced from a number of isolates to assess whether sequence variation may alter protein conformation and influence the virus strain’s capacity to be neutralized by vaccine-induced antibody. gC and gE genes sequenced from HSV-1-infected subjects showed more variability than their HSV-2 counterparts. The gB sequences of HSV-1 oral isolates resembled each other more than they did gB sequences rom genital isolates. Overall, however, comparison of glycoprotein sequences of viral isolates obtained from infected subjects did not reveal any singular selective pressure on the viral cell attachment protein or surrounding glycoproteins due to administration of gD-2 vaccine.
Highlights
Herpes simplex virus 1 (HSV-1) and HSV-2 are highly related human herpesviruses
Results from the Herpevac Trial for Women indicated protection was associated with antibody titer but not CD4 or CD8 T cells against HSV-1, and neutralizing antibodies evoked by vaccination have been considered critical to successfully preventing HSV infection [32]
We determined whether glycoprotein sequences differed between virus isolates from Glycoprotein D (gD)-2 vaccine recipients in the Herpevac Trial who became infected and isolates from infected, control-vaccinated subjects
Summary
Herpes simplex virus 1 (HSV-1) and HSV-2 are highly related human herpesviruses. Their 152 to 155 kb colinear genomes share 87% amino acid sequence identity and encode 84 proteins [1]. Both viruses share structural features including an icosahedral capsid, a dense layer of tegument proteins, and a host cell-derived lipid envelope studded with viral glycoproteins important in cell attachment and penetration. In addition to the direct impacts of HSV on the physical and psychosocial health of infected individuals, women can pass the virus to their babies during birth, resulting in severe and often lethal disease [9]. The ability to control HSV infections would have a wideranging positive impact on public health
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