Investigation of the mechanism by which herpes simplex virus type 1 LAT sequences modulate preferential establishment of latent infection in mouse trigeminal ganglia - PubMed (original) (raw)

Investigation of the mechanism by which herpes simplex virus type 1 LAT sequences modulate preferential establishment of latent infection in mouse trigeminal ganglia

Yumi Imai et al. J Virol. 2009 Aug.

Abstract

We previously demonstrated that herpes simplex virus type 1 (HSV-1) preferentially establishes latent infection in monoclonal antibody (MAb) A5-positive ganglionic neurons and that a 2.8-kb portion of the HSV-1 genome, corresponding to the 5' end of the LAT (latency-associated transcript) coding region, is responsible for this phenotype (38, 65). In the current study we carried out further genetic mapping of this latency phenotype and investigated some of the mechanisms that might be responsible. Studies with the chimeric virus HSV-1 17syn+/LAT2, an HSV-1 virus engineered to express HSV-2 LAT, demonstrated that this virus exhibited an HSV-2 latency phenotype, preferentially establishing latency in MAb KH10-positive neurons. This result is complementary to that previously described for the chimeric virus HSV-2 333/LAT1 and indicate that the HSV-1 latency phenotype can be changed to that of HSV-2 by substitution of a 2.8-kb piece of complementary viral DNA. Sequential studies in which we evaluated the pattern of HSV-1 latent infection of the mouse trigeminal ganglion following ocular inoculation with viruses with deletions of functional thymidine kinase, glycoprotein E, ICP0, and US9 protein demonstrate that preferential establishment of HSV-1 latent infection in A5-positive neurons is not a consequence of (i) differential access of HSV-1 to A5-positive neurons,(ii) differential cell-to-cell spread of HSV-1 to A5-positive neurons, (iii) differential "round-trip" spread of HSV-1 to A5-positive neurons, or (iv) expression of ICP0. Additional mapping studies with the HSV-1 LAT deletion viruses dLAT371, 17DeltaSty, and 17Delta348 indicate that most of the LAT 5' exon is not required for HSV-1 to preferentially establish latent infection in A5-positive neurons.

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Figures

FIG. 1.

FIG. 1.

Identification of TG neurons latently infected with 17syn+/LAT2 or 17syn+/LAT2R. Sections of murine TG were assayed by both in situ hybridization for LAT (red-labeled nuclei) and IF staining with MAbs A5 and KH10 (green-labeled cell bodies) in order to identify the neuronal subpopulations latently infected with either a chimeric virus or its rescuant. HSV-2-specific probes were used to detect LAT expression in 17syn+/LAT2-infected tissue, and HSV-1-specific probes were used to detect LAT expression in 17syn+/LAT2R-infected tissue. In these representative images, LAT expression of 17syn+/LAT2 is colocalized with a KH10-positive neuron but not with A5-positive neurons. In contrast, LAT expression of 17syn+/LAT2R is colocalized with an A5-positive neuron but not with KH10-positive neurons. Bar, 20 μm.

FIG. 2.

FIG. 2.

Identification of TG neurons latently infected with _tk_LTRZ1. Sections of murine TG were assayed by both in situ hybridization for LAT (red-labeled nuclei) and IF staining with MAbs A5 (left) and KH10 (right) to identify the neuronal subpopulations (green-labeled cell bodies) latently infected with _tk_LTRZ1. In these representative images, LAT expression does not colocalize with either A5- or KH10-positive neurons. Bar, 20 μm.

FIG. 3.

FIG. 3.

Viral titers of TG acutely infected with KOS and _n_212. For each time point after ocular inoculation, TG from five mice were assayed for infectious virus by standard plaque assay. Data are presented as mean and standard error of the mean per mouse.

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