Different Mechanisms Regulate Productive Herpes Simplex Virus 1 (HSV-1) and HSV-2 Infections in Adult Trigeminal Neurons

Abstract

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, ...

Herpes Simplex Virus 1 Reactivates from Autonomic Ciliary Ganglia Independently from Sensory Trigeminal Ganglia To Cause Recurrent Ocular Disease

“…Sensory neurons recognized by monoclonal antibody Fe-A5 (A5ϩ) limit productive HSV-1 infection (3,4). In contrast, sensory neurons bound by the monoclonal antibody KH10 or isolectin IB4 (IB4ϩ) limit productive infection of HSV-2 (3)(4)(5). Similar percentages of these nonoverlapping populations of sen-sory neurons are found in TG (10 to 12%) and DRG (13 to 15%).…”

“…The latency-associated transcript (LAT) is the most abundant gene expressed during HSV latency. While not required for establishment of latency, LAT exon 1 is necessary for HSV type-specific neuron specificity and characteristic patterns of reactivation (4,13,19). To determine if differences in LAT expression play a role in differences between HSV-1 and HSV-2 recurrence frequency, LAT expression was analyzed in the sensory and autonomic ganglia.…”

“…The sensory neuronal populations that are permissive for productive infection differ between HSV-1 and HSV-2. Sensory neurons recognized by monoclonal antibody Fe-A5 (A5ϩ) limit productive HSV-1 infection (3,4). In contrast, sensory neurons bound by the monoclonal antibody KH10 or isolectin IB4 (IB4ϩ) limit productive infection of HSV-2 (3)(4)(5).…”

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

“…A significant refinement of the Wilcox model is the culturing of adult trigeminal ganglia instead of E21 rat sympathetic ganglia (Bertke et al, 2011). The neuronal subtypes present in the adult mouse trigeminal cultures reflect those seen in adult mice as opposed to neonatal mice, and are currently employed to determine the host and virus components that function to restrict HSV-1 and HSV-2 (human herpesvirus 2) latency to specific neuronal subtypes (Bertke et al, 2013).…”

Prevalence of Herpes Simplex Virus Infection in Patients With Relapsing-Remitting Multiple Sclerosis: A Case-Control Study in the North of Iran

“…Recent surveys determined that 17% of adults in the United States harbor HSV-2 antibodies (7). Reactivation and asymptomatic shedding occur both for HSV-1 and HSV-2 post infection (8,9). Herpesviruses are neurotrophic and have strong ability to remain latent in the nervous system, innervating the site of primary infec-tion for the life span of the host (8).…”