Varicella zoster virus (VZV) is the causative agent of varicella (chickenpox) and zoster (shingles). Investigating VZV pathogenesis is challenging as VZV is a human-specific virus and infection does not occur, or is highly restricted, in other species. However, the use of human tissue xenografts in mice with severe combined immunodeficiency (SCID) enables the analysis of VZV infection in differentiated human cells in their typical tissue microenvironment. Xenografts of human skin, dorsal root ganglia or foetal thymus that contains T cells can be infected with mutant viruses or in the presence of inhibitors of viral or cellular functions to assess the molecular mechanisms of VZV–host interactions. In this Review, we discuss how these models have improved our understanding of VZV pathogenesis.
Primary infection with varicella-zoster virus (VZV) causes the characteristic syndrome of varicella, or chickenpox. Experiments in severe combined immunodeficiency mice with human skin grafts (SCIDhu mice) indicate that VZV infection of T cells can mediate transfer of infectious virus to skin. VZV-infected T cells reached epithelial sites of replication within 24 h after entering the circulation. Memory CD4+ T cells were the predominant population recovered from skin in SCIDhu mice given uninfected or infected mononuclear cells, suggesting that immune surveillance by memory T cells may facilitate VZV transfer. The increased susceptibility of memory T cells to VZV infection may further enhance their role in VZV pathogenesis. During VZV skin infection, viral gene products down-regulated interferon-α to permit focal replication, whereas adjacent epidermal cells mounted a potent interferon-α response against cell–cell spread. Interleukin-1α, although activated in VZV-infected cells, did not trigger expression of endothelial adhesion molecules, thereby avoiding early recruitment of inflammatory cells. The prolonged varicella incubation period appears to represent the time required for VZV to overcome antiviral responses of epidermal cells and generate vesicles at the skin surface. Modulation of VZV replication by cutaneous innate immunity may avoid an incapacitating infection of the host that would limit opportunities for VZV transmission.
Varicella-zoster virus (VZV) causes varicella and establishes latency in sensory ganglia. VZV reactivation results in herpes zoster. We developed a model using human dorsal root ganglion (DRG) xenografts in severe combined immunodeficient (SCID) mice to investigate VZV infection of differentiated neurons and satellite cells in vivo. DRG engrafted under the kidney capsule and contained neurons and satellite cells within a typical DRG architecture. VZV clinical isolates infected the neurons within DRG. At 14 days postinfection, VZ virions were detected by electron microscopy in neuronal cell nuclei and cytoplasm but not in satellite cells. The VZV genome copy number was 7.1 ؋ 10 7 to 8.0 ؋ 10 8 copies per 10 5 cells, and infectious virus was recovered. This initial phase of viral replication was followed within 4 -8 weeks by a transition to VZV latency, characterized by the absence of infectious virus release, the cessation of virion assembly, and a reduction in VZV genome copies to 3.7 ؋ 10 5 to 4.7 ؋ 10 6 per 10 5 cells. VZV persistence in DRG was achieved without any requirement for VZV-specific adaptive immunity and was associated with continued transcription of the ORF63 regulatory gene. The live attenuated varicella vaccine virus exhibited the same pattern of short-term replication, persistence of viral DNA, and prominent ORF63 transcription as the clinical isolates. VZV-infected T cells transferred virus from the circulation into DRG, suggesting that VZV lymphotropism facilitates its neurotropism. DRG xenografts may be useful for investigating neuropathogenic mechanisms of other human viruses.herpesvirus ͉ latency ͉ neurotropism ͉ varicella vaccine V aricella-zoster virus (VZV) is an alphaherpesvirus that causes varicella (chickenpox), establishes latency in sensory ganglia, and may reactivate to cause herpes zoster (1-3). The VZV double-stranded DNA genome encodes at least 70 proteins, expressed as putative immediate-early (IE) regulatory genes, early genes, and late genes. Primary VZV infection is characterized by inoculation of respiratory mucosal epithelium, viral transport to the skin by a cell-associated viremia, cutaneous lesions, and infection of sensory ganglia (1, 2, 4). VZV DNA has been detected in dorsal root ganglia (DRG), trigeminal ganglia, and cranial nerves obtained at autopsy many decades after primary VZV infection (2, 5). VZV reactivation from latency usually causes a localized vesicular rash and pain affecting one cutaneous dermatome, suggesting that VZ virions migrate to the skin along axons from a single ganglion (1). Herpes zoster is medically important because it is often associated with debilitating postherpetic neuralgia, and immunocompromised individuals may develop life-threatening VZV infection (1). Nevertheless, knowledge about the interactions between VZV and the neurons, satellite cells, and fibroblasts that comprise human sensory ganglia is limited to studies of autopsy specimens, and even the cell type that harbors the VZV genome has been controversial (2). Therefore, we h...
The varicella-zoster virus (VZV) genes ORF47 and ORF66 are predicted to encode serine͞threonine protein kinases, which are homologs of herpes simplex virus 1 (HSV-1) UL13, and US3. When mutants were constructed by inserting stop codons into ORF47 and ORF66, the recombinants ROka47S and ROka66S, as well as intact ROka replicated in tissue culture. In contrast, inoculation of human thymus͞liver or skin implants in SCID-hu mice showed that ORF47 protein was required for viral growth in human T cells and skin. Eliminating ORF66 expression inhibited VZV infectivity for T cells partially but did not impair replication in skin compared with ROka. Infectivity for T cells and skin was restored when ROka47S virus was complemented by insertion of ORF47 into a distant, noncoding site. The ORF47 gene product is the first VZV protein identified as necessary for T cell tropism. It also is essential for skin infectivity in vivo, as is glycoprotein C. Expression of ORF66 did not compensate for the absence of the ORF47 protein. The requirement for ORF47 expression in T cells and skin indicates that this gene product, which is dispensable in vitro, has a critical role within differentiated cells that are essential targets for VZV pathogenesis in vivo.Varicella-zoster virus (VZV) is a human ␣-herpesvirus that causes chickenpox and herpes zoster (shingles). The ␣-herpesviruses contain two highly conserved genes that are predicted to encode protein kinases by sequence homology to eukaryotic serine͞threonine kinases (1, 2). In VZV, these genes are encoded by ORF47, in the unique, long region of the genome, and by ORF66, in the unique, short region. ORF47 encodes a 54-kDa phosphoprotein found in the cytoplasm and nucleus of infected cells and in the virion capsid͞tegument fraction. ORF66 kinase is a 48-kDa phosphoprotein located only in the cytoplasm (3). Homologs of ORF47 are found in ␣-, -and ␥-herpesviruses, but ORF66 homologs are specific to the ␣-herpesviruses (1, 2, 4-9).The ORF47 putative kinase phosphorylates itself and ORF62, the major immediate early (IE) transactivator, uses both ATP and GTP as phosphate donors (10, 11). The other VZV IE proteins encoded by ORF4, ORF61, and ORF63, and the major glycoprotein E (gE), are not phosphorylated by ORF47 kinase in vitro (3,(10)(11)(12). VZV ORF47, like related kinases, is dispensable for replication in vitro (6,(12)(13)(14). The HSV-1 UL13 kinase is autophosphorylated and necessary for the posttranslational modification of HSV-1 regulatory proteins infected cell protein (ICP)22, homolog of VZV ORF63, and ICP0, homolog of VZV ORF61 but not ICP4, the ORF62 homolog (13,(15)(16)(17). The HSV-1 UL13 gene also is required for the virion host shutoff effect (14). More recently, UL13 kinase has been shown to phosphorylate the HSV-1 glycoprotein E͞I Fc receptor complex and the cellular protein elongation factor 1␦ (18,19).Like the ORF47 protein, the ORF66 putative kinase is not required for phosphorylation of the IE genes and is not essential in tissue culture. Although neither muta...
Varicella-zoster virus (VZV) is a human alphaherpesvirus that infects sensory ganglia and reactivates from latency to cause herpes zoster. VZV replication was examined in human dorsal root ganglion (DRG) xenografts in mice with severe combined immunodeficiency using multiscale correlative immunofluorescence and electron microscopy. These experiments showed the presence of VZV genomic DNA, viral proteins, and virion production in both neurons and satellite cells within DRG. Furthermore, the multiscale analysis of VZV-host cell interactions revealed virus-induced cell-cell fusion and polykaryon formation between neurons and satellite cells during VZV replication in DRG in vivo. Satellite cell infection and polykaryon formation in neuronsatellite cell complexes provide mechanisms to amplify VZV entry into neuronal cell bodies, which is necessary for VZV transfer to skin in the affected dermatome during herpes zoster. These mechanisms of VZV neuropathogenesis help to account for the often severe neurologic consequences of herpes zoster.Varicella-zoster virus (VZV) is a human neurotropic alphaherpesvirus with a linear DNA genome that has at least 70 open reading frames (ORFs) encoding viral proteins (4). VZV causes varicella during primary infection, establishes latency in sensory ganglia, and may reactivate to cause herpes zoster (4,12). VZV persistence in cranial nerve and dorsal root sensory ganglia appears to be a consistent consequence of primary VZV infection (4,5,12,31). VZV is related to herpes simplex virus types 1 and 2 (HSV-1 and -2), which are also neurotropic human alphaherpesviruses that establish latency in sensory ganglia, but in contrast to VZV, HSV reactivations are common and usually asymptomatic (30). When VZV reactivates, the characteristic dermatomal rash of herpes zoster is attributed to the axonal transport of VZ virions that were assembled in neuronal cell bodies to the skin. Clinically, herpes zoster is characterized by severe acute pain and a dermatomal rash and often by prolonged neurologic signs and symptoms (12).Because VZV is a highly host-specific pathogen, we have used human tissue xenografts in mice with severe combined immunodeficiency (SCID) to analyze VZV tropisms for differentiated human cells in vivo (35). Autopsy studies provide some limited information about the acute VZV infection that occurs in sensory ganglia during reactivation. A marked disruption of cellular architecture within the ganglion, viral protein expression, and detection of herpesvirus-like particles have been reported (8,14,20,23). Our dorsal root ganglion (DRG) model of neuropathogenesis makes it possible to examine the interactions between VZV and human neurons and satellite cells located within their typical tissue microenvironment (35, 36). In DRG xenografts, VZV inoculation results in viral DNA synthesis, expression of immediate-early (IE) regulatory/tegument proteins IE62 and IE63 and envelope glycoproteins, and the production of infectious virus.The purpose of these experiments was to investigate VZV re...
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