Abstract
After HSV infection, some trigeminal ganglion neurons support productive cycle gene expression, while in other neurons the virus establishes a latent infection. We previously demonstrated that HSV-1 and HSV-2 preferentially establish latent infection in A5+ and KH10+ sensory neurons, respectively, and that exchanging the latency-associated transcript (LAT) between HSV-1 and HSV-2 also exchanges the neuronal preference. Since many viral genes besides the LAT are functionally interchangeable between HSV-1 and HSV-2, we co-infected HSV-1 and HSV-2, both in vivo and in vitro, to determine if trans-acting viral factors regulate whether HSV infection follows a productive or latent pattern of gene expression in sensory neurons. The pattern of HSV-1 and HSV-2 latent infection in trigeminal neurons was no different following co-infection than with either virus alone, consistent with the hypothesis that a trans-acting viral factor is not responsible for the different patterns of latent infection of HSV-1 and HSV-2 in A5+ and KH10+ neurons. Since exchanging the LAT regions between the viruses also exchanges neuronal preferences, we infected transgenic mice that constitutively express 2.8 kb of the LAT region with the heterologous viral serotype. Endogenous expression of LAT did not alter the pattern of latent infection after inoculation with the heterologous serotype virus, demonstrating that the LAT region does not act in trans to direct preferential establishment of latency of HSV-1 and HSV-2. Using HSV1-RFP and HSV2-GFP in adult trigeminal ganglion neurons in vitro, we determined that HSV-1 and HSV-2 do not exert trans-acting effects during acute infection to regulate neuron specificity. Although some neurons were productively infected with both HSV-1 and HSV-2, no A5+ or KH10+ neurons were productively infected with both viruses. Thus, trans-acting viral factors do not regulate preferential permissiveness of A5+ and KH10+ neurons for productive HSV infection and preferential establishment of latent infection.
Highlights
Following peripheral inoculation with either herpes simplex virus 1 (HSV-1) or HSV-2, the virus gains access to the axons of sensory neurons and is transported in a retrograde fashion to neuronal cell bodies in primary sensory ganglia, where infection follows either a productive or latent pathway of viral gene expression
Given that several viral factors are functionally interchangeable between HSV-1 and HSV-2, we hypothesized that any trans-acting viral factors involved in regulating neuronal preferences that are produced by one viral species, may be capable of directing a phenotypic change in the preferential establishment of latency of the other viral species, permitting identification of trans-acting factors involved in neuron specificity
In the trigeminal ganglia (TG) of mice that had been co-infected with a mixture of KOS and 333 at 106 pfu/ml, 27.6% of the HSV-1 latency-associated transcript (LAT)+ neurons co-labeled with monoclonal antibodies (mAbs) A5 and 2.3% of HSV-1 LAT+ neurons colabeled with mAb KH10+ (Table 1)
Summary
Following peripheral inoculation with either herpes simplex virus 1 (HSV-1) or HSV-2, the virus gains access to the axons of sensory neurons and is transported in a retrograde fashion to neuronal cell bodies in primary sensory ganglia, where infection follows either a productive or latent pathway of viral gene expression. The factors that determine whether HSV progresses through the productive cycle or establishes a latent infection in specific neurons are not clear, there is evidence that the latency-associated transcript plays a role in this process [2,3]. Some neuronal populations of the trigeminal ganglion (TG) are much less permissive for productive viral infection than others, and permissiveness differs between HSV-1 and HSV-2. The neuronal population identified by mAb A5 is relatively non-permissive for HSV-1 productive infection in vitro, compared to other types of sensory neurons, and serves as the principal reservoir of latent HSV-1 in vivo [1,4]. The neuronal population identified by mAb KH10 is relatively nonpermissive for HSV-2 productive infection in vitro and serves as the principal reservoir of latent HSV-2 in vivo [2,4]. Latent infection with HSV may be the default pattern of viral gene expression in a neuron that is nonpermissive for productive infection
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