Spontaneous Reactivation of Herpes Simplex Virus Type 1 in Latently Infected Murine Sensory Ganglia

bThe tropism of herpes simplex virus (HSV-1) for human sensory neurons infected in vivo was examined using dorsal root ganglion (DRG) xenografts maintained in mice with severe combined immunodeficiency (SCID). In contrast to the HSV-1 lytic infectious cycle in vitro, replication of the HSV-1 F strain was restricted in human DRG neurons despite the absence of adaptive immune responses in SCID mice, allowing the establishment of neuronal latency. At 12 days after DRG inoculation, 26.2% of human neurons expressed HSV-1 protein and 13.1% expressed latency-associated transcripts (LAT). Some infected neurons showed cytopathic changes, but HSV-1, unlike varicella-zoster virus (VZV), only rarely infected satellite cells and did not induce fusion of neuronal and satellite cell plasma membranes. Cell-free enveloped HSV-1 virions were observed, indicating productive infection. A recombinant HSV-1-expressing luciferase exhibited less virulence than HSV-1 F in the SCID mouse host, enabling analysis of infection in human DRG xenografts for a 61-day interval. At 12 days after inoculation, 4.2% of neurons expressed HSV-1 proteins; frequencies increased to 32.1% at 33 days but declined to 20.8% by 61 days. Frequencies of LAT-positive neurons were 1.2% at 12 days and increased to 40.2% at 33 days. LAT expression remained at 37% at 61 days, in contrast to the decline in neurons expressing viral proteins. These observations show that the progression of HSV-1 infection is highly restricted in human DRG, and HSV-1 genome silencing occurs in human neurons infected in vivo as a consequence of virus-host cell interactions and does not require adaptive immune control.T he simplex viruses, herpes simplex virus types 1 and 2 (HSV-1 and -2), are ubiquitous human viral pathogens that may cause mild to severe mucocutaneous infections (1). In rare instances, these viruses cause meningoencephalitis. The prevalence of HSV-1 infection among adults ranges from 50 to 90%. Primary HSV infection is acquired by inoculation of mucosal epithelium and abraded skin. Local replication facilitates retrograde axonal transport of HSV virions within innervating cutaneous sensory nerve fibers to the corresponding neuronal cell bodies in the peripheral dorsal root ganglia (DRG) or trigeminal ganglia, where latency is established. Although most primary infections are asymptomatic, HSV-1 and HSV-2 have a dynamic relationship with the human host, and transmission to other susceptible individuals is ensured by frequent episodes of reactivation; these episodes are also usually asymptomatic but release infectious virus into oral and genital tract secretions. Notably, the many hundreds of HSV reactivations from latency that occur in sensory ganglia over the lifetime of the infected individual seldom result in ganglionitis, peripheral neuropathy, or spread to the central nervous system (2-4).Lytic HSV-1 infection, which produces infectious progeny virions, involves transcription of more than 80 viral genes in a highly ordered process governed by sequential derepression ...

Section: Discussionmentioning

confidence: 76%

Herpes Simplex Virus 1 Tropism for Human Sensory Ganglion Neurons in the Severe Combined Immunodeficiency Mouse Model of Neuropathogenesis

Zerboni

Che

Reichelt

et al. 2013

“…Recent studies have shown that T cell exhaustion occurred as a result of chronic infection with several different viruses (3,8,30) and that the presence of low-level viral antigen during chronic/latent infection leads to T cell exhaustion (42). HSV-1 latency was originally thought to be a completely dormant situation with no viral gene expression, but recent studies have shown that this is not the case (11,31,34). Thus, to investigate potential differences in the TG from gK-, gD-, and mock-immunized mice, we performed qRT-PCR analysis on the same TG used above to determine the expression levels of mRNAs characteristic of T cells (CD4, CD8) and exhaustion markers (PD-1, Tim-3).…”

Section: Resultsmentioning

confidence: 99%

Immunization with Different Viral Antigens Alters the Pattern of T Cell Exhaustion and Latency in Herpes Simplex Virus Type 1-Infected Mice

Allen¹,

Mott²,

Zandian³

et al. 2010

We have shown previously that immunization with herpes simplex virus type 1 (HSV-1) glycoprotein K (gK) exacerbated corneal scarring (CS) in ocularly infected mice. In this study, we investigated whether higher levels of CS were correlated with higher levels of latency and T cell exhaustion in gK-immunized mice. BALB/c mice were vaccinated with baculovirus-expressed gK or gD or mock immunized. Twenty-one days after the third immunization, mice were ocularly infected with 2 ؋ 10 4 PFU/eye of virulent HSV-1 strain McKrae. On day 5 postinfection, virus replication in the eye was measured, and on day 30 postinfection, infiltration of the trigeminal ganglia (TG) by CD4, CD8, programmed death 1 (PD-1), and T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) was monitored by immunohistochemistry and quantitative real-time PCR (qRT-PCR). This study demonstrated that higher levels of CS were correlated with higher levels of latency, and this was associated with the presence of significantly higher numbers of CD4 ؉ PD-1 ؉ and CD8 ؉ PD-1 ؉ cells in the TG of the gK-immunized group than in both the gD-and mock-immunized groups. Levels of exhaustion associated with Tim-3 were the same among gK-and mock-vaccinated groups but higher than levels in the gD-vaccinated group. In this study, we have shown for the first time that both PD-1 and Tim-3 contribute to T cell exhaustion and an increase of latency in the TG of latently infected mice.

“…The most commonly used animal model of HSK is mice. However, in contrast to HSV-1-infected humans or rabbits, spontaneous virus reactivation in mice is rare (45). The evidence generated using the mouse model suggests that eye disease may be associated with immune responses triggered by the virus, rather than the virus directly.…”

Section: Discussionmentioning

confidence: 99%

Level of Herpes Simplex Virus Type 1 Latency Correlates with Severity of Corneal Scarring and Exhaustion of CD8⁺T Cells in Trigeminal Ganglia of Latently Infected Mice

Mott¹,

Bresee²,

Allen³

et al. 2009

A hallmark of infection with herpes simplex virus type 1 (HSV-1) is the establishment of latency in ganglia of the infected individual. During the life of the latently infected individual, the virus can occasionally reactivate, travel back to the eye, and cause recurrent disease. Indeed, a major cause of corneal scarring (CS) is the scarring induced by HSV-1 following reactivation from latency. In this study, we evaluated the relationship between the amount of CS and the level of the HSV-1 latency-associated transcript (LAT) in trigeminal ganglia (TG) of latently infected mice. Our results suggested that the amount of CS was not related to the amount of virus replication following primary ocular HSV-1 infection, since replication in the eyes was similar in mice that did not develop CS, mice that developed CS in just one eye, and mice that developed CS in both eyes. In contrast, mice with no CS had significantly less LAT, and thus presumably less latency, in their TG than mice that had CS in both eyes. Higher CS also correlated with higher levels of mRNAs for PD-1, CD4, CD8, F4/80, interleukin-4, gamma interferon, granzyme A, and granzyme B in both cornea and TG. These results suggest that (i) the immunopathology induced by HSV-1 infection does not correlate with primary virus replication in the eye; (ii) increased CS appears to correlate with increased latency in the TG, although the possible cause-and-effect relationship is not known; and (iii) increased latency in mouse TG correlates with higher levels of PD-1 mRNA, suggesting exhaustion of CD8 ؉ T cells.