Antibody to Varicella-Zoster Virus Immediate-Early Protein 62 Augments Allodynia in Zoster via Brain-Derived Neurotrophic Factor

Hama, Yuka; Shiraki, Kimíyasu; Yoshida, Yasuhiko; Maruyama, Atsushi; Yasuda, Makoto; Tsuda, Masashi; Honda, Minoru; Takahashi, Michiaki; Handa, Hiroshi; Takasaki, Ichiro; Daikoku, Tohru; Tsumoto, Tadaharu

doi:10.1128/jvi.02061-09

Cited by 16 publications

(18 citation statements)

References 39 publications

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“…The extent that other VZV proteins that are expressed in the rat DRG also needs to be addressed. Of interest is the recent suggestion that antibodies to IE62 augment brain-derived neurotrophic factor (BDNF) induced neuronal changes (Hama et al 2010) (see below).…”

Section: The Rodent Model Of Vzv-induced Painmentioning

confidence: 99%

“…An intriguing and quite different mechanism is that the expression of VZV IE62 protein and the intrathecal immune response to it are involved in pain. In a mouse model, antibodies to IE62 may stimulate pain hypersensitivity by cross-reacting with BDNF (Hama et al 2010). The authors showed that antibodies reacting to IE62 region from 414 to 429 cross-reacted with the BDNF dimer and augment the expression of BDNF-related transcripts in neurons.…”

Section: Perspectives and Questionsmentioning

confidence: 99%

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Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models

Kinchington

Goins

2011

J. Neurovirol.

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Pain and post-herpetic neuralgia (PHN) are common and highly distressing complications of herpes zoster that remain a significant public health concern and in need of improved therapies. Zoster results from reactivation of the herpesvirus varicella zoster virus (VZV) from a neuronal latent state established at the primary infection (varicella). PHN occurs in some one fifth to one third of zoster cases with severity, incidence, and duration of pain increasing with rising patient age. While VZV reactivation and the ensuing ganglionic damage trigger the pain response, the mechanisms underlying protracted PHN are not understood, and the lack of an animal model of herpes zoster (reactivation) makes this issue more challenging. A recent preclinical rodent model has developed that opens up the potential to allow the exploration of the underlying mechanisms and treatments for VZV-induced pain. Rats inoculated with live cell-associated human VZV into the hind paw reliably demonstrate thermal hyperalgesia and mechanical allodynia for extended periods and then spontaneously recover. Dorsal root ganglia express a limited VZV gene subset, including the IE62 regulatory protein, and upregulate expression of markers suggesting a neuropathic pain state. The model has been used to investigate treatment modalities and aspects of pain signaling and is under investigation by the authors to delineate VZV genetics involved in the induction of pain. This article compares human zoster-associated pain and PHN to the pain indicators in the rat and poses important questions that, if answered, could be the basis for new treatments.

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Section: The Rodent Model Of Vzv-induced Painmentioning

confidence: 99%

Section: Perspectives and Questionsmentioning

confidence: 99%

Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models

Kinchington

Goins

2011

J. Neurovirol.

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“…Monoclonal antibodies specific to gB and gE were established as previously reported (24). Polyclonal antibodies against IE62 and IE63 were raised in rabbit and guinea pig, respectively, by immunization with glutathione S-transferasefused recombinant proteins (12). To detect them, Alexa Fluor 488-conjugated anti-mouse, rabbit, or guinea pig IgGs (Invitrogen) were used in the IFA.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…The reactivation of VZV caused zoster in every age group, especially in the elderly, at rates of 3 to 8 per 1,000 person-years in a study of 48,388 zoster patients (46). The major complication of zoster is chronic pain (postherpetic neuralgia); the pain is related to peripheral nerve injury and the activation of brain-derived neurotrophic factor by anti-immediate early (IE) 62 antibody (12). However, the mechanism of VZV latency is not clear.…”

mentioning

confidence: 99%

Neutralizing Anti-gH Antibody of Varicella-Zoster Virus Modulates Distribution of gH and Induces Gene Regulation, Mimicking Latency

Shiraki

Daikoku

Takemoto

et al. 2011

J Virol

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The anti-glycoprotein H (gH) monoclonal antibody (anti-gH-MAb) that neutralizes varicella-zoster virus (VZV) inhibited cell-to-cell infection, resulting in a single infected cell without apoptosis or necrosis, and the number of infectious cells in cultures treated with anti-gH-MAb declined to undetectable levels in 7 to 10 days. Anti-gH-MAb modulated the wide cytoplasmic distribution of gH colocalized with glycoprotein E (gE) to the cytoplasmic compartment with endoplasmic reticulum (ER) and Golgi markers near the nucleus, while gE retained its cytoplasmic distribution. Thus, the disintegrated distribution of gH and gE caused the loss of cellular infectivity. Varicella-zoster virus (VZV) infection causes varicella, and then VZV becomes latent in the sensory ganglia. The reactivation of VZV caused zoster in every age group, especially in the elderly, at rates of 3 to 8 per 1,000 person-years in a study of 48,388 zoster patients (46). The major complication of zoster is chronic pain (postherpetic neuralgia); the pain is related to peripheral nerve injury and the activation of brain-derived neurotrophic factor by anti-immediate early (IE) 62 antibody (12). However, the mechanism of VZV latency is not clear. Studies of the latent human ganglia revealed the difference between gene regulation in VZV and herpes simplex virus (HSV). Transcripts from genes 21, 29, 62, 63, and 66 of VZV and the product from gene 63 have been identified in latently infected human ganglia (4-7, 16, 17, 20, 22, 51), in contrast to the presence of noncoding latency-associated transcripts of HSV (29, 40).The thymus leukemia antigen on the cell surface is lost due to anti-thymus leukemia antibody treatment, and this phenomenon is defined as the antigenic modulation of eukaryotic cells (25). Antigenic modulation also is observed in measles virusinfected cells. Antibodies to viral surface antigens modulate measles virus expression in the infected cells, and anti-hemagglutinin antibody reduces the expression of viral fusion protein, matrix protein, and phosphoprotein in measles virus-infected cells (9-11, 14, 26). The biological importance of antigenic modulation has been recognized in various cells by clearing the cell surface expression of the respective antigen with the relevant monoclonal antibody, including monoclonal antibody treatment for immunotherapy in B cells (30,31), red blood cells (52), a human thymic myoid cell line (48), B cells (2,3,45), and differentiating murine embryonic stem cells and embryo fibroblasts (39).VZV expresses the viral glycoproteins glycoprotein E (gE), glycoprotein B (gB), and glycoprotein H (gH) on the surface of infected cells. Anti-gH monoclonal antibody (anti-gH-MAb) neutralizes viral infectivity and inhibits cell-to-cell infection and plaque formation in vitro, while monoclonal antibodies to gE and gB and zoster convalescent-phase sera do not inhibit cell-to-cell infection. When infected cells were treated with anti-gH-MAb after cell-free virus infection, single-cell infection was observed without morphologi...

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“…The MAG artifact may also contribute to the discrepancy between reports of high frequencies of neurons that express VZV proteins and the low frequency of neurons that contain VZV genomes based on LCMD and quantitative PCR (19,29). In addition to the presence of neuronal pigments and immunological cross-reactivity between IE62 and neuron-specific brain-derived neurotrophic factor (BDNF), this report identifies an important new variable that confounds the accurate detection of VZV proteins in sensory neurons (8,32).…”

Section: Demonstration Of Mag Reactivity In Human Neuronal Golgi Zonesmentioning

confidence: 91%

Apparent Expression of Varicella-Zoster Virus Proteins in Latency Resulting from Reactivity of Murine and Rabbit Antibodies with Human Blood Group A Determinants in Sensory Neurons

Zerboni

Sobel

Lai

et al. 2012

J Virol

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Analyses of varicella-zoster virus (VZV) protein expression during latency have been discordant, with rare to many positive neurons detected. We show that ascites-derived murine and rabbit antibodies specific for VZV proteins in vitro contain endogenous antibodies that react with human blood type A antigens in neurons. Apparent VZV neuronal staining and blood type A were strongly associated (by a 2 test, ␣ ‫؍‬ 0.0003). Adsorption of ascites-derived monoclonal antibodies or antiserum with type A erythrocytes or the use of in vitro-derived VZV monoclonal antibodies eliminated apparent VZV staining. Animal-derived antibodies must be screened for anti-blood type A reactivity to avoid misidentification of viral proteins in the neurons of the 30 to 40% of individuals who are blood type A. V aricella-zoster virus (VZV) is a human alphaherpesvirus that establishes latency in ganglionic sensory neurons. In autopsied human ganglia, the frequency of individual VZV-positive neurons was 1.0 to 6.9% by single-cell laser capture microdissection (LCMD) and PCR (29). However, immunostaining analyses of VZV protein expression in latently infected neurons have differed significantly. Mahalingam et al. reported infrequent detection of VZV proteins in cadaver ganglia, and in positive tissues VZV protein expression was restricted to very few neurons, a finding confirmed by Kennedy et al. and our recent study (13,16,32). In contrast, Lungu et al. detected VZV proteins in 9 to 24% of neurons in ganglia from three of three subjects (15). Theil et al. found immediate-early 62 (IE62) proteins in ganglia from 38% of individuals and in 3 to 7% of neurons (25). Discrepancies among reports describing the frequencies of VZV protein-positive neurons in autopsied ganglia require further investigation because of their implications for understanding mechanisms of VZV latency.Using a high-potency rabbit anti-IE63 antibody and preimmune serum control, we detected IE63 proteins in ganglia from only 1 of 18 individuals and in Ͻ2.8% of neurons (32). Subsequently, we observed cytoplasmic immunoreactivity in many neurons in ganglia from several individuals when the neurons were stained with monoclonal antibodies (MAbs) to IE62, glycoprotein E (gE), and the capsid protein ORF40 (MAB8616, MAB8612, and MAB8614, respectively; EMD Millipore, Billerica, MA); different lots had similar reactivities. These commercial reagents against IE62 and gE, known to be specific for viral proteins in cultured cells, have been used in studies that report cytoplasmic localization of VZV proteins in neurons (6,9,10,25,26,28). The failure to confirm IE62 and gE detection with other VZV antibodies, the detection of the ORF40 capsid protein detection in latency, and the Golgi zone-like localization of all three VZV proteins suggested a possible staining artifact.The mouse ascites Golgi (MAG) reaction results from endogenous anti-human blood type A antibodies in MAbs derived from mouse ascites (2, 5, 14, 21-23, 30, 31). Importantly, in blood type A individuals, sensory neurons exp...

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Antibody to Varicella-Zoster Virus Immediate-Early Protein 62 Augments Allodynia in Zoster via Brain-Derived Neurotrophic Factor

Cited by 16 publications

References 39 publications

Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models

Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models

Neutralizing Anti-gH Antibody of Varicella-Zoster Virus Modulates Distribution of gH and Induces Gene Regulation, Mimicking Latency

Apparent Expression of Varicella-Zoster Virus Proteins in Latency Resulting from Reactivity of Murine and Rabbit Antibodies with Human Blood Group A Determinants in Sensory Neurons

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