Varicella-Zoster Virus Proteins in Skin Lesions: Implications for a Novel Role of ORF29p in Chickenpox

Abstract

Skin biopsy samples from varicella-zoster virus (VZV)-infected patients examined by immunohistochemistry demonstrated VZV replication in nonepithelial cell types. ORF29p, a nonstructural nuclear protein, was found in nerves of two of six patients with chickenpox. In tissue culture, ORF29p was secreted by VZV-infected fibroblasts. Extracellular ORF29p can be taken up through endocytosis by human neurons, implying a novel role for this protein in pathogenesis.Varicella-zoster virus (VZV) infects dorsal root ganglia (DRG), enters latency, and may later reactivate to cause zoster. Studies have detected VZV in specific sites at different stages of infection. VZV DNA is present in the oropharynx (27) and in peripheral blood mononuclear cells (PBMCs) of patients with chickenpox (3,16,20). Virus DNA, the glycoproteins gE and gB, and the immediate-early protein 63 (IE63p) are found in skin biopsy samples obtained from patients with chickenpox or zoster (1,(23)(24)(25). VZV is found in keratinocytes, antigen-presenting cells, and endothelial cells during acute zoster (23,25) and in keratinocytes and inflammatory cells during chickenpox (1). VZV is present in neurons and satellite cells of DRG years following primary infection (6-8, 12, 17, 22) and has been observed by electron microscopy in sensory nerves during zoster (10). Other details of VZV pathogenesis remain speculative, including how the virus spreads from respiratory epithelial cells to PBMCs, keratinocytes, and DRG. Because PBMCs, sensory nerves, and epithelial cells are in close proximity in the dermis and epidermis, the skin is likely the site where virus enters the nervous system.By analogy with herpes simplex virus (HSV), it is thought that VZV transcription is temporally regulated. Immediateearly (IE) genes are expressed first, followed by early (E) genes and lastly late (L) genes (5). Some VZV proteins encoded by IE and L genes are incorporated in the virion, including transactivators such as IE63p and structural proteins such as gC (14, 15). ORF29p (for open reading frame 29 protein), the major VZV DNA binding protein, is encoded by a putative E gene and is not detected in purified virions (13). During latency, VZV exhibits limited gene expression (6-9, 22), with the accumulation of specific IE and E gene-encoded proteins in neurons (18,19). During reactivation, all kinetic classes of VZV genes are expressed in neurons (18). Whether VZV is in the lytic or latent state is reflected by the localization of expressed VZV gene products. VZV IE and E proteins that are present in both the nucleus and cytoplasm during productive infection are detected only in the cytoplasm of neurons during latency (18).Early observations suggested that there were inclusion bodies in endothelial cells present in varicella lesions (29); however, there was no known association between histology and viral etiology at that time. To determine if, during primary infection, as in zoster, VZV infects endothelial cells and nerves in the dermis and to characterize the inflammatory cells ...

Mutational Analysis of the Repeated Open Reading Frames, ORFs 63 and 70 and ORFs 64 and 69, of Varicella-Zoster Virus

“…When it is detected in latently infected neurons, ORF63 protein is localized primarily to the cytoplasm, suggesting that its transfer into the nucleus is a characteristic of lytic rather than latent infection (9,23). In skin biopsy specimens analyzed by immunohistochemical or in situ hybridization methods, early lesions showed ORF63 protein in keratinocytes and in dermal nerves and perineural type I dendrocytes (1). The VZV ORF63 protein is also a major target of VZV-specific CD4 and CD8 memory T cells, indicating that it is processed by antigen-presenting cells during primary infection (1).…”

“…In skin biopsy specimens analyzed by immunohistochemical or in situ hybridization methods, early lesions showed ORF63 protein in keratinocytes and in dermal nerves and perineural type I dendrocytes (1). The VZV ORF63 protein is also a major target of VZV-specific CD4 and CD8 memory T cells, indicating that it is processed by antigen-presenting cells during primary infection (1).…”

Open Reading Frame S/L of Varicella-Zoster Virus Encodes a Cytoplasmic Protein Expressed in Infected Cells

“…A skin biopsy specimen that was negative for VZV gC by immunohistochemistry from a patient with Grover's disease, a dermatologic disorder that may be confused with chickenpox clinically but with different histopathologic features, was included as a negative control (1).…”

Ramsay Hunt syndrome revisited–emphasis on Ramsay Hunt syndrome with multiple cranial nerve involvement

“…Children usually exhibit milder symptoms than do adults, mainly manifested as an itching vesicular cutaneous rash; however severe and even fatal complications have been reported. Using the host's immune system, especially its T-cells, the virus is delivered to the skin and sensory nerves [43,44]. The virus is never cleared from the body but establishes a latent infection in the sensory ganglia and the facts that it does not spread is due to host's immune response and VZV antibodies.…”