Robust pro-inflammatory and lesser anti-inflammatory immune responses during primary simian varicella virus infection and reactivation in rhesus macaques

Traina‐Dorge, Vicki; Sanford, Robert A.; James, Stephanie; Doyle-Meyers, Lara A.; Haro, Eileen de; Wellish, Mary; Gilden, Don; Mahalingam, Ravi

doi:10.1007/s13365-014-0274-2

Cited by 11 publications

(14 citation statements)

References 17 publications

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“…Primate models of varicella pathogenesis have revealed that the virus enters ganglia hematogenously before the appearance of skin rash 47 , memory T cells disseminate SVV to lung and ganglia during primary infection 48 , and T-cell infiltration correlates with expression of CXCL10, a chemokine that recruits activated T cells and natural killer (NK) cells, in ganglia at the time of zoster 49 . Pro-inflammatory cytokines and chemokines and anti-inflammatory mediators are elevated at the time of zoster in immunosuppressed monkeys 50 . All T-cell subsets decreased during immunosuppression and peaked (except for CD8 T cells) 2 weeks before zoster 51 .…”

Section: Efforts To Produce Vzv Latency and Reactivation In Animalsmentioning

confidence: 99%

Varicella Zoster Virus in the Nervous System

et al. 2015

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Varicella zoster virus (VZV) is a ubiquitous, exclusively human alphaherpesvirus. Primary infection usually results in varicella (chickenpox), after which VZV becomes latent in ganglionic neurons along the entire neuraxis. As VZV-specific cell-mediated immunity declines in elderly and immunocompromised individuals, VZV reactivates and causes herpes zoster (shingles), frequently complicated by postherpetic neuralgia. VZV reactivation also produces multiple serious neurological and ocular diseases, such as cranial nerve palsies, meningoencephalitis, myelopathy, and VZV vasculopathy, including giant cell arteritis, with or without associated rash. Herein, we review the clinical, laboratory, imaging, and pathological features of neurological complications of VZV reactivation as well as diagnostic tests to verify VZV infection of the nervous system. Updates on the physical state of VZV DNA and viral gene expression in latently infected ganglia, neuronal, and primate models to study varicella pathogenesis and immunity are presented along with innovations in the immunization of elderly individuals to prevent VZV reactivation.

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Section: Efforts To Produce Vzv Latency and Reactivation In Animalsmentioning

confidence: 99%

Varicella Zoster Virus in the Nervous System

et al. 2015

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“…Depletion of CD4 T cells during primary SVV infection in rhesus macaques led to higher viremia and disseminated varicella (27). Monkeys latently infected with SVV and immunosuppressed using a combination of radiation, tacrolimus, and prednisone developed zoster, with robust proinflammatory and decreased antiinflammatory responses in serum just before zoster rash (28,29). At the time of zoster in immunosuppressed monkeys, SVV antigens were detected in the skin, lungs, and ganglia, although only a limited amount of DNA was seen in blood.…”

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confidence: 99%

Reactivation of Simian Varicella Virus in Rhesus Macaques after CD4 T Cell Depletion

Traina‐Dorge

Palmer

Coleman

et al. 2019

J Virol

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Rhesus macaques intrabronchially inoculated with simian varicella virus (SVV), the counterpart of human varicella-zoster virus (VZV), developed primary infection with viremia and rash, which resolved upon clearance of viremia, followed by the establishment of latency. To assess the role of CD4 T cell immunity in reactivation, monkeys were treated with a single 50-mg/kg dose of a humanized monoclonal anti-CD4 antibody; within 1 week, circulating CD4 T cells were reduced from 40 to 60% to 5 to 30% of the total T cell population and remained low for 2 months. Very low viremia was seen only in some of the treated monkeys. Zoster rash developed after 7 days in the monkey with the most extensive CD4 T cell depletion (5%) and in all other monkeys at 10 to 49 days posttreatment, with recurrent zoster in one treated monkey. SVV DNA was detected in the lung from two of five monkeys, in bronchial lymph nodes from one of the five monkeys, and in ganglia from at least two dermatomes in three of five monkeys. Immunofluorescence analysis of skin rash, lungs, lymph nodes, and ganglia revealed SVV ORF63 protein at the following sites: sweat glands in skin; type II cells in lung alveoli, macrophages, and dendritic cells in lymph nodes; and the neuronal cytoplasm of ganglia. Detection of SVV antigen in multiple tissues upon CD4 T cell depletion and virus reactivation suggests a critical role for CD4 T cell immunity in controlling varicella virus latency. IMPORTANCE Reactivation of latent VZV in humans can result in serious neurological complications. VZV-specific cell-mediated immunity is critical for the maintenance of latency. Similar to VZV in humans, SVV causes varicella in monkeys, establishes latency in ganglia, and reactivates to produce shingles. Here, we show that depletion of CD4 T cells in rhesus macaques results in SVV reactivation, with virus antigens found in zoster rash and SVV DNA and antigens found in lungs, lymph nodes, and ganglia. These results suggest the critical role of CD4 T cell immunity in controlling varicella virus latency. KEYWORDS CD4 T cell depletion, animal model, simian varicella virus reactivation V aricella-zoster virus (VZV) causes chickenpox (varicella) in children, becomes latent in ganglia, and reactivates decades later to produce shingles (zoster) in the elderly due to the decline of VZV-specific T cells important in maintaining virus latency (1). Reactivation of latent VZV is associated with serious neurological complications, including postherpetic neuralgia (the most common cause of suicide in the elderly), characterized by the persistence of pain for more than 3 months after zoster (2). VZV reactivation can result in vasculopathy (3) and giant cell arteritis, which causes primary systemic vasculitis, leading to blindness and stroke, and other multisystem diseases that can occur without rash (4-6). Persistent inflammation, with the predominance of T cells and macrophages, is seen for RESULTSPrimary SVV infection in rhesus macaques and establishment of latency. Five Indian rhesus macaques, ...

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“…Studies have shown that the following cytokines are signi icantly elevated during ARN: IL-6, IL-8, IL-10, IL-18, IL-15, MIF, MCP-1, Eotoxin, IP10, sICAM-1, and sVCAM-1 and their levels correlate with disease activity, while low levels of the following cytokines have been encountered: IL-2, IL-4, IL-13, and IFN-α [411,412]. IFN-γ release assay may be useful as a surrogate test for measuring VZV-speci ic immunity [413]. Also, characterization of cytokine, chemokine and growth factor responses during different stages of VZV infection may facilitate the development of effective immunotherapeutic as well as vaccine strategies [414].…”

Section: Role Of Cytokines In Vzv Infectionsmentioning

confidence: 99%

The beneficial effects of varicella zoster virus

Al-Anazi¹,

Wk²,

Al-Jasser³

2019

J Hematol Clin Res

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Varicella zoster virus behaves differently from other herpes viruses as it differs from them in many aspects. Recently, there has been growing evidence on the benefi cial effects of the virus in immune compromised hosts and these effects are translated into prolongation of survival. The reported benefi cial effects of the virus include: (1) stimulation of bone marrow activity in patients with hematologic malignancies and bone marrow failure syndromes, (2) antitumor effects in various hematologic malignancies and solid tumors, and (3) association with graft versus host disease which has anticancer effects. Additionally, there are several reports on the safety of the live-attenuated even in severely immune suppressed individuals and on the emerging role of the virus in cancer immunotherapy. In this review, the following aspects of the virus will be thoroughly discussed: (1) new data on the genetic background, pathogenesis, vaccination, and new therapeutic modalities; (2) bone marrow microenvironment and hematopoiesis; (3) cells involved in the pathogenesis of the virus such as: mesenchymal stem cells, dendritic cells, natural killer cells, T-cells and mononuclear cells; (4) cellular proteins such as open reading frames, glycoproteins, promyelocytic leukemia protein, chaperons, and SUMOs; (5) extracellular vesicles, exosomes, and micro-RNAs; and (6) signaling pathways, cytokines, and interferons.

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Robust pro-inflammatory and lesser anti-inflammatory immune responses during primary simian varicella virus infection and reactivation in rhesus macaques

Cited by 11 publications

References 17 publications

Varicella Zoster Virus in the Nervous System

Varicella Zoster Virus in the Nervous System

Reactivation of Simian Varicella Virus in Rhesus Macaques after CD4 T Cell Depletion

The beneficial effects of varicella zoster virus

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