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Poxviruses are large, complex, DNA viruses whose various members infect animals and insects. The term pox derives from the English pocks, referring to blister-like skin lesions that are the hallmark of smallpox and other poxvirus infections. Poxviruses have base-paired DNA genomes that range in size from 130 to 300 kbp. They encode all enzymes needed for RNA and DNA synthesis and replicate in the cell cytoplasm. Poxviruses are also masters of evading innate and adaptive immune responses, using a variety of proteins encoded by their large genomes. Virions are enveloped, their surfaces covered with proteinaceous ridges or tubules. Viewed in thin section, a central tubular region (often dumbbell-shaped) contains DNA. Electron dense lateral bodies are positioned in the curves of the core and are surrounded by the lipid envelope.

Differential diagnosis of urticaria and angioedema has been based on the phenotype as either acute or chronic depending on the duration of more than 6 to 8 weeks, respectively. Additional subdivisions include poorly defined terms such as idiopathic, spontaneous, or autoimmune. In this article, the author suggests that an increased understanding of the acquired and innate immune system and data from novel proteomic technology have blurred the lines between these categories of diagnosis. Specific molecular pathways and response to specific medications should be incorporated in classification and diagnosis schemes.

EBV (Epstein Barr Virus) has been associated with numerous autoimmune syndromes in epidemiologic studies. In this work immunoglobulin G response to EBV antigens similar to antigens from host proteins was analyzed using a laser printed microarray ( PEPperprint.com ). IgG response to overlapping peptides derived from immunologically important EBV proteins including ZEBRA (BZLF-1 encoded protein), BALF-2 recombinase expressed primarily during the viral lytic replication cycle, and EBNA-1 (Epstein Barr Virus Nuclear Antigen) expressed during the viral latency cycle respectively were characterized. These viral proteins have domains shared with host DNA–binding proteins in the human immune response that may cross-react through “molecular mimicry” triggering antinuclear and other autoantibodies. IgG response to conserved “A/T hooks” in EBV-encoded proteins such as EBNA-1 and the BALF-2 recombinase related to host DNA–binding proteins including RAG-1 recombinase and histones, and EBV-encoded virokines such as the IL-10 homologue BCRF-1 suggest further directions for clinical research. Proteomic “molecular fingerprints” of the immune response to viral proteins is relatively inexpensive and potentially useful in monitoring autoantibody production and response to therapy.

The genomes of certain types of human and primate herpesviruses contain functional homologs of important host cytokines (IL-6, IL-17, and IL-10), or so-called virokines. Virokines can interact with immune cell receptors, transmit a signal to them, and thus switch the type of immune response that facilitates viral infection development. In this work, we have summarized possible ways of virokine origin and proposed an evolutionary scenario of virokine acquisition with involvement of retroviral coinfection of the host. This scenario is probably valid for vIL-6 of HHV-8 and MRV-5 viruses, vIL-17 of HVS virus, and vIL-10 of HHV-4, Bonobo-HV, RhLCV, and BaLCV viruses. The ability to acquire cytokine genes allows herpesviruses to implement unique strategies of avoiding the immune response and provides them an evolutionary advantage: more than 90% of the host population can be chronically infected with different herpesviruses. It is possible that the biological success of herpesviruses can be partially due to their cooperation with another group of viruses. This hypothesis emphasizes the importance of studies on the reciprocal influence of pathogens on their coinfection, as well as their impact on the host organism.

Epstein-Barr virus (also termed HHV-4, EBV), a component of the human virome or metagenome, is associated as a co-factor in many common human autoimmune diseases through epidemiologic evidence. Numerous EBV genes are functional as well as structural homologues of important immune response genes. For example, EBV-encoded BCRF1 is a functional homologue of IL-10, a critical cytokine regulator of immune tolerance. BZLF-1, an EBV-encoded transcription factor, contains regions with functional homology to both AP-1 and NF-κB DNA binding immune response regulatory factors. The author proposes a paradigm of "gene sharing" between viral- and host-encoded proteins as extension of molecular mimicry that has been largely overlooked in animal models that consider only host genomic factors rather than viral pathogens and the metagenome. Gene sharing may trigger chaotic behavior in human autoimmune disease through unstable feedback loops and perturbations of immune tolerance.

Purpose During rejection, leukocytes are recruited from the peripheral circulation into the graft leading to the damage of endothelial cells, capillary perfusion failure and graft loss. Chemokines play a pivotal role in the recruitment of leukocytes to the endothelium. Viral macrophage inflammatory protein-II (vMIP-II), a human herpes virus-8 DNA-encoded protein, is a broad-spectrum chemokine antagonist. The aim of the study was to prove the beneficial activity of vMIP-II treatment on acute rat kidney allograft damage. Methods Heterotopic rat kidney transplantation was performed in the Fischer 344 to Lewis transplantation model and animals were treated with vMIP-II (2 × 15 µg or 100 µg/day) for 7 days. Rejection-induced damage was analyzed by histology, and microcirculatory changes within the graft were analyzed by in vivo microscopy. Results Viral macrophage inflammatory protein-II significantly improved acute glomerular damage and tubulointerstitial inflammation and lowered the extent of vascular and tubulointerstitial damage of the treated allografts. Functional microcirculation of peritubular capillaries was significantly improved in vivo, and the firm adherence of leukocytes was significantly reduced by vMIP-II treatment. Conclusions The administration of the broad-spectrum antagonist vMIP-II improved acute renal allograft damage, mainly by a reduction in leukocyte recruitment with a subsequently improved renal cortical microcirculation in vivo.

Since the discovery of virokines in the 1980s, much time and research has been dedicated to exploring their potential use as therapeutic agents. Simply put, virokines are virally encoded proteins that are secreted from the infected host cell. Most of these proteins possess the ability to modulate different aspects of the host immune system, to better maintain a suitable habitat for viral replication. These proteins are often highly homologous to host immune proteins but are often smaller and more powerful. Examples of virokines include viral secreted proteins that: block components of the complement system, act as serine protease inhibitors, function as chemokine and cytokine agonists or antagonists and contribute to cell proliferation. Many of these proteins are currently being investigated for use as novel therapeutic immunomodulators to manage immune disorders, inflammation after trauma, graft rejection and autoimmune diseases.

Cowpox virus (CPV) is a member of the Orthopoxvirus genus and has the genetic capacity to encode a multitude of genes that interfere with the host inflammatory and immune response or modulate the physiological state of infected and non-infected cells. Among these CPV factors are receptors homologous to interferon and tumor necrosis factor receptors and also a viral cellular serine-proteinase analog. Here we describe the detection of a CPV gene that encodes a protein homologous to epidermal growth factor, transforming growth factor alpha and poxvirus growth factors, such as the vaccinia growth factor (VGF). The VGF and other poxvirus growth factors are produced early in the infection and are secreted into the medium where they bind to the EGF receptors, generating mytotic responses. The cowpox growth factor (CGF) gene was detected in three copies on the virus genome by PCR, and by northern and southern blot hybridization using VGF nucleotide sequences as primers and probes. The CPV gene has a strong nucleotide and predicted amino acid similarity with VGF, and is also produced early in the infection.

In order to replicate efficiently within the host, viruses have evolved multiple strategies to evade the host's immune system. In many cases viruses have actually hijacked various components of the host's immune system to ensure their own survival. One such strategy is the expression of virus encoded cytokines and cytokine receptors. Members of the poxvirus and herpesvirus families have been particularly successful with this strategy. The study of virus survival strategies provides important information regarding both virus biology as well as information about the immune system itself.

Ligands for ErbB1-4 receptor tyrosine kinases, such as epidermal growth factor (EGF) and neuregulins, regulate brain development and function. Thus, abnormalities in their signaling are implicated in the etiology or pathology of schizophrenia and Parkinson's disease. Among the ErbB receptors, ErbB1, and ErbB4 are expressed in dopamine and GABA neurons, while ErbB1, 2, and/or 3 are mainly present in oligodendrocytes, astrocytes, and their precursors. Thus, deficits in ErbB signaling might contribute to the neurological and psychiatric diseases stemming from these cell types. By incorporating the latest cancer molecular biology as well as our recent progress, we discuss signal cross talk between the ErbB1-4 subunits and their neurobiological functions in each cell type. The potential contribution of virus-derived cytokines (virokines) that mimic EGF and neuregulin-1 in brain diseases are also discussed.

During evolution, DNA viruses have captured a broad array of cellular genes involved in immune recognition and growth control that are nonessential for viral replication. The encoded virokines and viroceptors may act as mimetics or antagonists of their cellular homologues, altering signal transduction and cell communication towards survival of virus-infected cells. Human herpesvirus type 8 (HHV8) is the most recently identified human oncogenic herpesvirus. It is associated with Kaposi's sarcoma and lymphoproliferative diseases, such as pleural effusion lymphomas and multicentric Castleman's disease. HHV8 has captured a unique number of cellular regulatory genes, which redirect gene expression and cell growth, prevent apoptosis and immune recognition, and interfere with tumor suppressor gene function. HHV8 encodes a unique virokine, viral interleukin-6, which is particularly relevant for the pathogenesis of HHV8-associated tumors, since it participates in transformation and mediates autocrine and paracrine mitogenic and proinflammatory effects. Viral IL-6 differs fundamentally from human IL-6 in receptor engagement for signal transduction and thus constitutes a singular model to understand the facets of human and viral cytokine biology. We provide an overview of the role of virokines in cancer, with a particular focus on the differences of human and viral IL-6 in the pathophysiology of HHV8-associated tumors.

Large DNA viruses defend against hostile assault executed by the host immune system by producing an array of gene products that systematically sabotage key components of the inflammatory response. Poxviruses target many of the primary mediators of innate immunity including interferons, tumor necrosis factors, interleukins, complement, and chemokines. Poxviruses also manipulate a variety of intracellular signal transduction pathways such as the apoptotic response. Many of the poxvirus genes that disrupt these pathways have been hijacked directly from the host immune system, while others have demonstrated no clear resemblance to any known host genes. Nonetheless, the immunological targets and the diversity of strategies used by poxviruses to disrupt these host pathways have provided important insights into diverse aspects of immunology, virology, and inflammation. Furthermore, because of their anti-inflammatory nature, many of these poxvirus proteins hold promise as potential therapeutic agents for acute or chronic inflammatory conditions.

Many poxviruses encode a plethora of immunomodulatory proteins, including homologs of cellular cytokine receptors. These receptor mimics, also referred to as viroceptors, are believed to function by binding and sequestering host cytokines thus preventing their signaling cascade prior to receptor engagement. The M-T2 protein of myxoma virus is a TNF receptor homolog that has two distinct activities: the secreted dimeric M-T2 protein binds and inhibits TNF α while the intracellular version permits myxoma virus replication in infected T-lymphocytes by blocking the cellular apoptosis response to the virus infection. Studies with M-T2 mutants reveal that distinct protein domains mediate these two anti-immune properties of this protein.