Herpes simplex virus 1 (HSV-1) and HSV-2 establish latency in different neuronal subtypes (A5؉ and KH10؉) in murine trigeminal ganglia, results which correlate with restricted productive infection in these neurons in vitro. HSV-2 latency-associated transcript (LAT) contains a cis-acting regulatory element near the transcription start site that promotes productive infection in A5؉ neurons and a second element in exon 1 that inhibits productive infection in KH10؉ neurons. HSV-1 contains no such regulatory sequences, demonstrating different mechanisms for regulating productive HSV infection in neurons. Herpes simplex virus 1 (HSV-1) and HSV-2 express productive cycle genes in some neurons and establish latent infection in others. We previously demonstrated that HSV-1 and HSV-2 preferentially establish latency in different neuronal subtypes in murine sensory ganglia: HSV-1 in A5ϩ neurons and HSV-2 in KH10ϩ neurons (1, 2). In dissociated adult murine trigeminal cultures (AMTC), we previously found that HSV-1 productively infected KH10ϩ but not A5ϩ neurons while HSV-2 productively infected A5ϩ but not KH10ϩ neurons (Fig. 1A) (3). Thus, the neuronal subtypes that restrict productive HSV infection in vitro are the same neurons that harbor latent infection in vivo. Both host and viral factors may play roles in regulating neuronal specificity (1, 2, 4-7). To determine if the latency-associated transcript (LAT) region regulates productive infection in A5ϩ and KH10ϩ neurons, we assayed HSV infection of AMTC using a series of LAT deletion and chimeric viruses (5).The HSV-2 LAT region contains two regulatory sequences for productive infection of neurons. HSV-2 (333) productively infects 36% of A5ϩ neurons in AMTC but only 3% of KH10ϩ neurons (Fig. 1B). In contrast, dLAT (NotI-NotI deletion of the HSV-2 LAT promoter) (Fig. 1D) (8) productively infects only 5% of A5ϩ neurons (Fig. 1B). The LAP2 virus (LAT promoter 2 deletion in HSV-2 exon 1) (Fig. 1D) (9) productively infects A5ϩ and KH10ϩ neurons equivalently (39% and 36%, respectively) (Fig. 1B). Thus, two distinct functional elements within HSV-2 LAT regulate productive infection: the NotI-NotI region promotes productive infection in A5ϩ neurons, and the LAP2 region inhibits productive infection in KH10ϩ neurons.HSV-2/LAT1 is a chimera in which 2.8 kb of the HSV-2 LAT region (promoter, exon 1, and ϳ1.5 kb of the intron, excluding ICP0 coding sequences) was replaced by the same region from HSV-1 (10). HSV-2/LAT1 preferentially establishes latency in A5ϩ neurons in vivo, suggesting that HSV-1 LAT in the context of HSV-2 changes the viral phenotype to that of HSV-1 (1). In AMTC, HSV-2/LAT1 productively infects 22% of KH10ϩ neurons but only 4% of A5ϩ neurons, in contrast to HSV-2 or the rescuant, HSV-2/LAT1-R (Fig. 1C). Thus, the pattern of productive infection with HSV-2/LAT1 resembles that of HSV-1, with productive infection in KH10ϩ neurons but restricted infection in A5ϩ neurons. Since the HSV-1 LAT region in HSV-2/LAT1 replaces sequences that were deleted in dLAT and LAP2, ...
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.
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