Purchase this article with an account.
P. R. Kinchington, S. Ramachandran, K. Davoli, R. L. Hendricks; CD8+T Cells Directed to a "True Late" Viral Antigen, Made After Onset of Viral DNA Replication, Can Still Block HSV-1 Reactivation From Latency. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6336.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Means to prevent the continual reactivation of HSV-1 from the latent state could reduce the high level of blinding herpetic stromal keratitis seen in US populations. Our groups have shown that the CD8+T cell infiltrate associated with latent HSV-1 infections of the trigeminal ganglia (TG) is partly responsible for maintaining HSV-1 latency, and can block viral reactivation in ex vivo ganglionic cultures.
In C57Bl6 mice, HSV gB498-505 specific CD8+T cells predominate the latently infected TG infiltrate and can block reactivation. gB is expressed as a "gamma1" regulated gene, made at low levels (as soon as 2h) prior to viral DNA replication. Detection of early viral antigens is presumed to allow CD8+T cells to block reactivation in a timely manner. Here, we asked if CD8+T cells specific to a late viral antigen (made only after onset of viral DNA replication) could still block reactivation.
Latent infections were established in B6 mice following corneal infection with an HSV-1 recombinant, gCpgB, which expresses gB from the strict gamma2, DNA replication dependent gC promoter; or its repaired virus. Viral pathogenesis and the phenotype of the TG CD8+T cell infiltrate were assessed. Reactivation rates of virus from latently-infected TG cultures depleted of endogenous CD8+T cells were determined in the absence or presence of exogenous gB487-505 specific CD8+T cells.
HSV-1 expressing gB as a true late gene was marginally impaired in culture and on the corneal surface, but more severely impaired in ganglionic replication and establishment of latency. In contrast to the high level (>52%) of gB498-505 specific CD8+ T cells maintained in the TG latently infected with rescue HSV-1 between day 14 and day 56, that in gCpgB infected TG was significantly lower at day 14 (23%) and further reduced as latency progressed. However, reactivation of HSV-1 from TG cultures were still blocked by co-culture with gB498-505 specific CD8+T cells.
These observations establish that early antigen expression is necessary for the maintenance of an antigen-specific CD8+ T cell infiltrate in the TG, but that CD8+T cells directed to true late antigens can still block reactivation from latency. This implies that CD8+ T cells can act very quickly to block reactivation at late stage viral processes following cellular commitment to viral DNA replication. This also has implications for HSV-1 antigen components in vaccines designed to augment the ganglionic HSV-1 specific CD8+T cell infiltrate and its reactivation blocking abilities.
This PDF is available to Subscribers Only