Differential Establishment of Latency in Neurons Between Herpes Simplex Virus Type 1 and Type 2

Abstract

Abstract: : Purpose: Neuronal sub–populations of the mouse trigeminal ganglion (TG) have different permissiveness for productive and latent infection with herpes simplex virus type 1 (HSV–1). Neurons identified by monoclonal antibody (MAb) KH10 are very permissive for productive infection and rarely serve as latent sites of infection. In contrast, neurons identified by MAb A5 are not very permissive for productive infection and serve as the principle reservoir of latent infection. The rest of the TG neurons (∼75%) have an intermediate permissiveness of infection with HSV–1, somewhere between these two extremes. In the current study we investigated whether KH10+ and A5+ neurons are differentially permissive for productive and latent infection with HSV–2. Methods: Six week old female Swiss Webster mice were infected by corneal or footpad inoculation with either HSV–1 (KOS) or HSV–2 (333). Mice infected with HSV–2 were treated with oral acyclovir starting 40 hours after infection. This permitted ganglionic infection but prevented death of infected mice. At 21 days post–infection mice were euthanized by cardiac perfusion with PBS followed by perfusion with paraformaldehyde. Ganglia were then removed, sectioned and assayed by fluorescent in situ hybridization and immunofluorescent staining to determine which neuronal populations harbor latent infection. Results: Following ocular inoculation with HSV–1 50% of the latently infected TG neurons were A5+, while only 7% expressed the KH10 marker. In contrast, following ocular inoculation with HSV–2, 42% of latently infected TG neurons were KH10+, and only 4% were A5– positive. Similar results were observed in dorsal root ganglion (DRG) neurons following footpad inoculation. Control experiments demonstrated that these results could not be explained by the neuronal composition of infected ganglia, differential access of virus to A5+ and KH10+ neurons, treatment of mice with acyclovir, or differential expression of LAT in A5+ and KH10+ neurons. Conclusions: In both the TG and DRG HSV–1 preferentially establishes latent infection in A5+ neurons, whereas HSV–2 preferentially establishes latent infection in KH10+ neurons. This appears to be due to different permissiveness of these neuronal populations for productive infection with HSV–1 and HSV–2 and may help to explain differences in the patterns of disease caused by these two viruses.

Keywords: herpes simplex virus • ganglion cells • in situ hybridization