EBV
Human tumors have been attributed to both human herpesvirus 8 (Kaposi’s sarcoma, primary effusion lymphoma, and Castleman’s disease) and to EBV (Burkitt’s lymphoma, nasopharyngeal Carcinoma, and Hodgkin’s and non-Hodgkin’s lymphomas Although herpesviruses are ubiquitous in nature, humans serve as the only natural host for EBV. It is now known that EBV infects _90% of the world’s adult population. Upon infection, the individual remains a lifelong carrier of the virus (2). EBV is transmitted by salivary contact. During acute infection, EBV primarily infects and replicates in the stratified squamous epithelium of the oropharynx (3, 4). This is followed by a latent infection of the B Lymphocytes. Virus can continue to be shed from the oropharynx into the saliva for years. Of interest, once the virus has colonized the B-lymphoid compartment, reactivation from latency can occur at any mucosal site where B cells reside (e.g., the cervix).
Morphology
EBV is a herpesvirus with a 184-kbp long, double-stranded DNA genome that encodes _85 genes (12). The viral genome consists of a series of 0.5-kb terminal direct repeats at either end and internal repeat sequences that serve to divide the genome into short and long unique sequence domains that have most of the coding capacity (13). EBV, as with other herpesviruses, has a toroid-shaped protein core wrapped with double-stranded DNA, a nucleocapsid with 162 capsomeres, a protein tegument between the nucleocapsid and envelope, and an outer envelope with external glycoprotein spikes.
When EBV infects a cell, the DNA becomes a circular episome with a characteristic number of terminal repeats, depending on the number of terminal repeats in the parental genome, with variation introduced during viral replication. If the infection is permissive for latent infection but not replication, future generations will have EBV episomes with the same number of terminal repeats.
Two subtypes of EBV are known to infect humans: EBV-1 and EBV-2. EBV-1 and EBV-2 differ in the organization of the genes that code for the EBV nuclear antigen (EBNA-2, EBNA- 3a, EBNA-3b, and EBNA-3c; Ref. 16). EBV-2 is less efficient in produce a tumor cell.
In normal individuals, the result is clinically apparent or milder forms of infectious mononucleosis.
Viral Products
EBNA-1: is a nucleoantigen protein that binds to DNA at multiple sites and elicits replication via host enzymes.
EBNA-2: is a nucleoentigen protein that work as transcription factor and can promote the transcription of proto-oncogenes (c-myc), cell markers (CD 23) via C promoter link.
EBNA-LP: is a protein that interactuate with EBNA-2 inducing b-cell in G1 phase by inhibiting P-53 and Rb-p.
EBNA 3a, 3b, 3c: Are transcription regulators. 3A and 3C are essential for immortalization. 3C may overcome Rb-p.
LMP-1: is a surface protein that mimics the CD-40 that links the usual ligand and trigger a signaling pathway involve in oncogenesis. Via Nf-KB, ATF1, AP-1, jun-nh2 terminal. Therefore, inhibits apoptosis by elevating levels of bcl-2.
EBER’s 1 y 2: immature DNA that can contribute to immortalization but nonessential.
The minimum requirement for membrane fusion to occur with epithelial cells is the coexpression of EBV envelope glycoproteins gH, gL, and gB. EBV additionally requires the gp42 protein for entry into B cells (11, 27, 28). EBV gp42 binds major histocompatibility complex class II (MHC-II) proteins expressed on B cells to trigger viral-cell membrane fusion.
Homologies:
BCRF1 and Il-10: similar in 86%, so EBV can inhibit inflammatory response and stimulate BC growth.
Latency types
I: EBNA1, EBER 1 y 2 – Linfoma de Burkitt
IIa: EBER1 y 2, EBNA1, LMP-1 Y LPM-2 – CA nasofaríngeo, linfoma hodgkin y no hodgkin.
IIb: EBER 1y 2, LMP-2, EBNA1, 2, 3ª, 3B, LP – Leucemia linfocitica crónica.
III: 8 Ag y 2 RNA’s – Inmunocomprometidos, líneas celulares linfoblastoides, desordenes proliferativos pos-transplante.
Oncogenesis
To maintain viral DNA in the cell, EBV establishes latent infection in B lymphocytes. The EBV genome is maintained in these cells, either as a multicopy circular episome in the host cell or by integrating the viral DNA into the host genome. The virus thus ensures transmission to cell progeny when B lymphocytes replicate. EBV latent genes induce an activated phenotype in the infected B cells. Although these cells are not transformed, if they proceed unchecked or acquire oncogenic mutations, they can become neoplastic. In normal individuals, cytotoxic T-cell responses against latent viral proteins prevent the expansion these activated B cells. Through normal differentiation of these cells, EBV eventually enters the resting B-cell memory compartment.
Burkitt’s Lynphoma: is malignant proliferation because of translocation of chromosome 8 with chromosome 14,2 or 22. The mechanism is the adjunction of c-myc (chromosome 8) with another normal protein like a heavy chain IG. Is endemic when EBV is present.
Is not clear if EBV elicits a chromosome translocation. Indeed, in the endemic pattern involves less the bone marrow stead no-endemic pattern.
Hodgkin’s Disease: Is defined by proliferation of reed-sternberg cells wich has been postuladed to be part of BC lineage.
No hodgkin’s disease: It has been compromised with two types of neoplasias: nasal T/ natural killer non hodgkin’s lymphoma and angioinmunoblastic linphadenopathy.
Nasopharyngeal carcinoma: is related almost in every case for undifferentiated carcinoma, and can be caused by both types. Apparently, his entry into the cells is via endocytosis with Ig-A or by a receptor, most probably CD 21.
Dx: The presence of antibody of the IgM type to the viral capsid antigen is indicative of current infection. Antibody of the IgG type to the viral capsid antigen is a marker of past infection and indicates immunity.
References
- Epstein Barr, Virus and Cancer. Matthew P. Thompson and Razelle Kurzrock. University of Texas. 2004. link
- Jawetz - Microbliology - 24 edition
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