Эпштейн-Барр вирусы: зерттеулер мен аурулар спектрі

Virus of the herpes family

The Epstein–Barr virus (EBV), formally called Human gammaherpesvirus 4, is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double stranded DNA virus. Epstein–Barr virus (EBV) is the first identified oncogenic virus, which establishes permanent infection in humans. EBV causes infectious mononucleosis and is also tightly linked to many malignant diseases. Various vaccine formulations underwent testing in different animals or in humans. However, none of them were able to prevent EBV infection and no vaccine has been approved to date. The virus causes infectious mononucleosis ("mono" or "glandular fever"). It is also associated with various non malignant, premalignant, and malignant Epstein–Barr virus associated lymphoproliferative diseases such as Burkitt lymphoma, hemophagocytic lymphohistiocytosis, and Hodgkin's lymphoma; non lymphoid malignancies such as gastric cancer and nasopharyngeal carcinoma; and conditions associated with human immunodeficiency virus such as hairy leukoplakia and central nervous system lymphomas. The virus is also associated with the childhood disorders of Alice in Wonderland syndrome and acute cerebellar ataxia and, by some evidence, higher risks of developing certain autoimmune diseases, especially dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome. About 200,000 cancer cases globally per year are thought to be attributable to EBV. In 2022, a large study (population of 10 million over 20 years) suggested EBV as the leading cause of multiple sclerosis, with a recent EBV infection causing a 32 fold increase in the risk of developing multiple sclerosis. Infection with EBV occurs by the oral transfer of saliva and genital secretions. Most people become infected with EBV and gain adaptive immunity. In the United States, about half of all five year old children and about 90% of adults have evidence of previous infection. Infants become susceptible to EBV as soon as maternal antibody protection disappears. Many children who become infected with EBV display no symptoms or the symptoms are indistinguishable from the other mild, brief illnesses of childhood. When infection occurs during adolescence or young adulthood, it causes infectious mononucleosis 35 to 50% of the time. EBV infects B cells of the immune system and epithelial cells. Once EBV's initial lytic infection is brought under control, EBV latency persists in the individual's memory B cells for the rest of their life. In July 2020, a team of researchers reported the first complete atomic model of the nucleocapsid of the virus. This "first complete atomic model [includes] the icosahedral capsid, the capsid associated tegument complex (CATC) and the dodecameric portal—the viral genome translocation apparatus."

The term viral tropism refers to which cell types that EBV infects. EBV can infect different cell types, including B cells and epithelial cells. The viral three part glycoprotein complexes of gHgL gp42 mediate B cell membrane fusion; although the two part complexes of gHgL mediate epithelial cell membrane fusion. EBV that are made in the B cells have low numbers of gHgLgp42 complexes, because these three part complexes interact with Human leukocyte antigen class II molecules present in B cells in the endoplasmic reticulum and are degraded. In contrast, EBV from epithelial cells are rich in the three part complexes because these cells do not normally contain HLA class II molecules. As a consequence, EBV made from B cells are more infectious to epithelial cells, and EBV made from epithelial cells are more infectious to B cells. Viruses lacking the gp42 portion are able to bind to human B cells, but unable to infect.

Latent EBV in B cells can be reactivated to switch to lytic replication. This is known to happen in vivo, but what triggers it is not known precisely. In vitro, latent EBV in B cells can be reactivated by stimulating the B cell receptor, so it is likely reactivation in vivo takes place after latently infected B cells respond to unrelated infections. EBNA 2, EBNA 3C, and LMP 1, are essential for transformation, whereas EBNA LP and the EBERs are not. Following natural infection with EBV, the virus is thought to execute some or all of its repertoire of gene expression programs to establish a persistent infection. Given the initial absence of host immunity, the lytic cycle produces large numbers of virions to infect other (presumably) B lymphocytes within the host. The latent programs reprogram and subvert infected B lymphocytes to proliferate and bring infected cells to the sites at which the virus presumably persists. Eventually, when host immunity develops, the virus persists by turning off most (or possibly all) of its genes and only occasionally reactivates and produces progeny virions. A balance is eventually struck between occasional viral reactivation and host immune surveillance removing cells that activate viral gene expression. The manipulation of the human body's epigenetics by EBV can alter the genome of the cell to leave oncogenic phenotypes. The site of persistence of EBV may be bone marrow. EBV positive patients who have had their own bone marrow replaced with bone marrow from an EBV negative donor are found to be EBV negative after transplantation.

All EBV nuclear proteins are produced by alternative splicing of a transcript starting at either the Cp or Wp promoters at the left end of the genome (in the conventional nomenclature). The genes are ordered EBNA LP/EBNA 2/EBNA 3A/EBNA 3B/EBNA 3C/EBNA 1 within the genome. The initiation codon of the EBNA LP coding region is created by an alternate splice of the nuclear protein transcript. In the absence of this initiation codon, EBNA 2/EBNA 3A/EBNA 3B/EBNA 3C/EBNA 1 will be expressed depending on which of these genes is alternatively spliced into the transcript.

Protein/gene/antigen Stage Description EBNA 1 latent+lytic EBNA 1 protein binds to a replication origin (oriP) within the viral genome and mediates replication and partitioning of the episome during division of the host cell. It is the only viral protein expressed during group I latency. EBNA 2 latent+lytic EBNA 2 is the main viral transactivator. EBNA 3 latent+lytic These genes also bind the host RBP Jκ protein. LMP 1 latent LMP 1 is a six span transmembrane protein that is also essential for EBV mediated growth transformation. LMP 2 latent LMP 2A/LMP 2B are transmembrane proteins that act to block tyrosine kinase signaling. EBER latent EBER 1/EBER 2 are small nuclear RNAs, which bind to certain nucleoprotein particles, enabling binding to PKR (dsRNA dependent serin/threonin protein kinase), thus inhibiting its function. EBERs are by far the most abundant EBV products transcribed in EBV infected cells. They are commonly used as targets for the detection of EBV in histological tissues. ER particles also induce the production of IL 10, which enhances growth and inhibits cytotoxic T cells. v snoRNA1 latent Epstein–Barr virus snoRNA1 is a box CD snoRNA generated by the virus during latency. V snoRNA1 may act as a miRNA like precursor that is processed into 24 nucleotide sized RNA fragments that target the 3'UTR of viral DNA polymerase mRNA. miRNAs latent EBV microRNAs are encoded by two transcripts, one set in the BART gene and one set near the BHRF1 cluster. The three BHRF1 pri miRNAS (generating four miRNAs) are expressed during type III latency, whereas the large cluster of BART miRNAs (up to 20 miRNAs) are expressed highly during type II latency and only modestly during type I and II latency. The previous reference also gives an account of the known functions of these miRNAs. EBV EA lytic early antigen EBV MA lytic membrane antigen EBV VCA lytic viral capsid antigen EBV AN lytic alkaline nuclease

The Epstein–Barr virus was named after M. A. Epstein, and Yvonne Barr, who discovered the virus together with Bert Achong. In 1961, Epstein, a pathologist and expert electron microscopist, attended a lecture on "The commonest children's cancer in tropical Africa—a hitherto unrecognised syndrome" by D. P. Burkitt, a surgeon practicing in Uganda, in which Burkitt described the "endemic variant" (pediatric form) of the disease that now bears his name. In 1963, a specimen was sent from Uganda to Middlesex Hospital to be cultured. Virus particles were identified in the cultured cells, and the results were published in The Lancet in 1964 by Epstein, Achong, and Barr. In 1968, they discovered that EBV can directly immortalize B cells after infection, mimicking some forms of EBV related infections, and confirmed the link between the virus and infectious mononucleosis.

As a relatively complex virus, EBV is not yet fully understood. Laboratories around the world continue to study the virus and develop new ways to treat the diseases it causes. One popular way of studying EBV in vitro is to use bacterial artificial chromosomes. Epstein–Barr virus can be maintained and manipulated in the laboratory in continual latency (a property shared with Kaposi's sarcoma associated herpesvirus, another of the eight human herpesviruses). Although many viruses are assumed to have this property during infection of their natural hosts, there is not an easily managed system for studying this part of the viral lifecycle. Genomic studies of EBV have been able to explore lytic reactivation and regulation of the latent viral episome. Although under active research, an Epstein–Barr virus vaccine is not yet available. The development of an effective vaccine could prevent up to 200,000 cancers globally per year. Like other human herpesviruses Epstein Barr might allow its own eradication via a course of the drug valaciclovir, but further research is needed to determine if eradication is actually achievable. Antiviral agents act by inhibiting viral DNA replication, but there is little evidence that they are effective against Epstein–Barr virus. Moreover, they are expensive, risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant side effects.