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

Abstract

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 ...

CD8 + T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

“…Furthermore, reactivation of HSV-1 appears to be restricted in human dorsal root ganglion (DRG) xenografts in SCID mice, despite the absence of adaptive immunity in that strain (41), suggesting that a factor(s) other than CD8 ؉ T cells works to maintain latency. However, it was previously demonstrated that only a minority of LAT ϩ neurons are surrounded by T cells and that a subset of LAT Ϫ neurons are also contacted by T cells (42).…”

Function and regulation of the fusogen EFF-1 during axonal repair

“…It has been noted that EFF-1 and AFF-1 are sometimes expressed simultaneously in adjacent cells, and that this alternate expression could help to specify fusion partners 40,41 . In the pharynx, two neighboring cells undergo developmental self-fusion to form unicellular tubes.…”

“…Accumulation of EFF-1 might also promote engagement of the membranes and therefore improve chances of fusion. Importantly, while close apposition of membranes can be mediated by various molecular complexes, such as integrins and cadherins, the complete reduction of this gap to achieve fusion can only be achieved by bone fide fusogens 41 .…”

“…EFF-1 must be inserted into both membranes to mediate fusion; current models suggest that its mechanism of action involves the formation of trimers in trans across apposing membranes 28,31 . Its activity is known to be precisely regulated in development, ensuring it mediates fusion at the correct place and time 23, .AFF-1 functions similarly to EFF-1 by mediating specific membrane fusion events during C.elegans development [39][40][41][42] . The mechanism through which it mediates fusion has not yet been determined, but similarly to EFF-1, it requires insertion into both membranes 26 .…”

“…elegans development [39][40][41][42] . The mechanism through which it mediates fusion has not yet been determined, but similarly to EFF-1, it requires insertion into both membranes 26 .…”