Varicella-zoster virus infection of human mononuclear cells

Gilden, Don; Hayward, Anthony R.; Krupp, Jan R.; Hunter-Laszlo, Mary; Huff, J. Clark; Vafai, Abbas

doi:10.1016/0168-1702(87)90074-8

Cited by 42 publications

(20 citation statements)

References 26 publications

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“…VZV tropism for human lymphocytes was suspected based on isolation of infectious virus from the nonadherent fraction of peripheral blood mononuclear cells (PBMCs), as well as the morphology of PBMCs that harbored viral DNA determined by in situ hybridization, but a more precise identification of the subpopulation of PBMCs involved in VZV viremia has been hampered for technical reasons (2,11,18,27). Our previous experiments in which thymus/liver implants in SCID-hu mice were infected with VZV showed that the virus replicates very efficiently in both CD4 ϩ and CD8 ϩ T cells, as well as immature CD4 ϩ CD8 ϩ T cells in vivo (24).…”

Section: Discussionmentioning

confidence: 99%

Tropism of Varicella-Zoster Virus for Human Tonsillar CD4⁺T Lymphocytes That Express Activation, Memory, and Skin Homing Markers

Ku¹,

Padilla²,

Grose³

et al. 2002

J Virol

134

129

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Varicella-zoster virus (VZV) is an alphaherpesvirus with the characteristic neurotropism of this group, but VZV also infects T cells productively and downregulates major histocompatibility complex (MHC) class I expression on infected T cells, as shown in the SCID-hu mouse model. T-cell tropism is likely to be critical for the cell-associated viremia associated with primary VZV infection. In these experiments, we found that VZV infects human tonsillar CD4؉ T cells in culture, with 15 to 25% being positive for VZV proteins as detected by polyclonal anti-VZV immunoglobulin G (IgG) staining and monitored by flow cytometry analysis. RNA transcripts for VZV gE, a late gene product, were detected in T-cell populations that expressed VZV surface proteins, but not in the VZV-negative cell fraction. Exposure to phorbol myristate acetate resulted in an increase in VZV-positive T cells, indicating that viral DNA was present within these cells and that VZV gene expression could be induced by T-cell activation. By immune scanning electron microscopy, VZV virions were detected in abundance on the surfaces of infected tonsillar T cells. The predominant CD4؉ T-lymphocyte subpopulations that became infected were activated CD69 ؉ T cells with the CD45RA ؊ memory phenotype. Subsets of CD4؉ T cells that expressed skin homing markers, cutaneous leukocyte antigen, and chemokine receptor 4 were also infected with VZV. By chemotaxis assay, VZV-infected T cells migrated to SDF-1, demonstrating that skin migratory function was intact despite VZV infection. The susceptibility of tonsil T cells to VZV suggests that these cells may be important targets during the initial VZV infection of upper respiratory tract sites. Viral transfer to migrating T cells in the tonsils may facilitate cell-associated viremia, and preferential infection of CD4 T cells that express skin homing markers may enhance VZV transport to cutaneous sites of replication.Varicella-zoster virus (VZV) is a human alphaherpesvirus that has a linear double-stranded DNA genome consisting of approximately 125,000 bp and encoding at least 69 unique proteins (34). VZV is a highly contagious pathogen. Primary infection leads to varicella (chickenpox) in susceptible individuals and establishment of latency in sensory ganglia; VZV may reactivate as herpes zoster (shingles) (3). Healthy individuals acquire VZV through contact with skin lesions of an infected person, followed by inoculation of respiratory mucosa, or by direct inoculation of virus in respiratory secretions. By analogy with mousepox, VZV has been presumed to be transferred to regional lymph nodes, where it is thought to initiate a primary viremic phase within a few days after inoculation (12). The mechanism of VZV transport from respiratory mucosa to regional lymph nodes is not known. A secondary viremia has been demonstrated to occur at the end of a 10-to 21-day incubation period, accompanied by the appearance of skin lesions. VZV has been recovered from cultured mononuclear cells obtained from 5 days before until 2 days...

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Section: Discussionmentioning

confidence: 99%

Tropism of Varicella-Zoster Virus for Human Tonsillar CD4⁺T Lymphocytes That Express Activation, Memory, and Skin Homing Markers

Ku¹,

Padilla²,

Grose³

et al. 2002

J Virol

134

129

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“…Since the ratio of nonneuronal cells to neurons is approximately 100:1 [10], the HSV-1-and VZV DNA copy numbers per latently infected neuron are 14-225 and 7-757, respectively. However, neither in situ hybridization nor immunohistochemistry techniques used to detect latent HSV-1 and VZV in human ganglia were designed to determine whether virus DNA is concentrated in discrete hot spots or more evenly distributed throughout the ganglion [11][12][13][14][15][16]. The present study addresses the distribution of virus DNA in ganglia.…”

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confidence: 96%

Distribution of Latent Herpes Simplex Virus Type-1 and Varicella Zoster Virus DNA in Human Trigeminal Ganglia

2005

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Trigeminal ganglia removed at autopsy from immunocompetent individuals without cutaneous signs of herpesvirus infection were fixed, cut into 5-microm sections, and screened at 100-microm intervals (20 adjacent sections) by PCR for latent herpes simplex type 1(HSV-1) and varicella zoster virus (VZV) DNA. Sections that contained >5 neurons with nuclei stained by hematoxylin/eosin revealed HSV-1 DNA in most samples and VZV DNA in approximately 50% of samples. HSV-1 and VZV DNA were distributed throughout each latently infected ganglion.

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“…This does not appear to stimulate a ganglionic infiltration of T cells (28,62). VZV may also productively or abortively infect antigen-presenting cells, including immature and mature dendritic cells (2,27,50), monocytes, macrophages, and B lymphocytes (4,20,30,35).…”

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confidence: 99%

Downregulation of Class I Major Histocompatibility Complex Surface Expression by Varicella-Zoster Virus Involves Open Reading Frame 66 Protein Kinase-Dependent and -Independent Mechanisms

Eisfeld

Yee²,

Erazo

et al. 2007

J Virol

100

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We show here that the varicella-zoster virus (VZV) open reading frame 66 (ORF66) protein kinase is one mechanism employed to reduce class I major histocompatibility complex (MHC-I) surface expression in VZV-infected cells. Cells expressing enhanced green fluorescent protein-tagged functional and inactivated ORF66 (GFP-66 and GFP-66kd) from replication-defective adenovirus vectors revealed that ORF66 reduced MHC-I surface levels in a manner dependent on kinase activity. Cells infected with recombinant VZV expressing GFP-66 exhibited a significantly greater reduction in MHC-I surface expression than that observed in cells infected with VZV disrupted in GFP-66 expression. MHC-I maturation was delayed in its transport from the endoplasmic reticulum through the Golgi in both adenovirus-transduced cells expressing only GFP-66 and in VZV-infected cells expressing high levels of GFP-66, and this was predominantly kinase dependent. MHC-I levels were reduced in VZV-infected cells, and analyses of intracellular MHC-I revealed accumulation of folded MHC-I in the Golgi region, irrespective of ORF66 expression. Thus, the ORF66 kinase is important for VZV-mediated MHC-I downregulation, but additional mechanisms also may be involved. Analyses of the VZV ORF9a protein, the ortholog of the bovine herpesvirus 1 transporter associated with antigen processing inhibitor UL49.5 revealed no effects on MHC-I. These results establish a new role for viral protein kinases in immune evasion and suggest that VZV utilizes unique mechanisms to inhibit antigen presentation.Varicella-zoster virus (VZV) is the human-restricted member of the herpesvirus subfamily Alphaherpesvirinae and causes chicken pox upon primary infection and herpes zoster (shingles) following reactivation from a prolonged period of neuronal latency in the sensory ganglia. Based on the current model of pathogenesis (38), efficient dissemination, disease, and establishment of latency within the infected host requires VZV growth in multiple cell types. Following inhalation, VZV is spread to epidermal sites of replication by a T-lymphocyteassociated viremia. Infection likely occurs in the tonsils, with VZV preferentially infecting memory CD4 ϩ T lymphocytes (39). These T cells can home to and mediate infection of human skin allografts in the severe combined immunodeficient (SCID)-hu model of VZV infection (40). In humans, skin lesions occur 10 to 21 days after the initial inoculation, and VZV DNA is detected in peripheral blood mononuclear cells during primary infection (13,45). VZV accesses axons of innervating sensory neurons in the skin and establishes a lifelong latent infection in neurons of the dorsal root ganglia. In contrast with latency of the closely related herpes simplex virus type 1 (HSV-1), VZV latency is characterized by persistent transcription, and possibly expression, of several viral lytic genes, including open reading frames (ORFs) 4, 21, 29, 62, 63, and 66 (10,

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Varicella-zoster virus infection of human mononuclear cells

Cited by 42 publications

References 26 publications

Tropism of Varicella-Zoster Virus for Human Tonsillar CD4⁺T Lymphocytes That Express Activation, Memory, and Skin Homing Markers

Tropism of Varicella-Zoster Virus for Human Tonsillar CD4⁺T Lymphocytes That Express Activation, Memory, and Skin Homing Markers

Distribution of Latent Herpes Simplex Virus Type-1 and Varicella Zoster Virus DNA in Human Trigeminal Ganglia

Downregulation of Class I Major Histocompatibility Complex Surface Expression by Varicella-Zoster Virus Involves Open Reading Frame 66 Protein Kinase-Dependent and -Independent Mechanisms

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Varicella-zoster virus infection of human mononuclear cells

Cited by 42 publications

References 26 publications

Tropism of Varicella-Zoster Virus for Human Tonsillar CD4+T Lymphocytes That Express Activation, Memory, and Skin Homing Markers

Tropism of Varicella-Zoster Virus for Human Tonsillar CD4+T Lymphocytes That Express Activation, Memory, and Skin Homing Markers

Distribution of Latent Herpes Simplex Virus Type-1 and Varicella Zoster Virus DNA in Human Trigeminal Ganglia

Downregulation of Class I Major Histocompatibility Complex Surface Expression by Varicella-Zoster Virus Involves Open Reading Frame 66 Protein Kinase-Dependent and -Independent Mechanisms

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Tropism of Varicella-Zoster Virus for Human Tonsillar CD4⁺T Lymphocytes That Express Activation, Memory, and Skin Homing Markers

Tropism of Varicella-Zoster Virus for Human Tonsillar CD4⁺T Lymphocytes That Express Activation, Memory, and Skin Homing Markers