Lymphoid cells involved in EBV+ LPD In the "germinal center model" for the normal maturation of B cells, naive B cells enter the germinal centers of lymph nodes and other lymphoid tissues and in the process of becoming competent for producing functional antibodies, mature into lymphoblasts, centroblasts, centrocytes, memory B cells, and ultimately plasma cells. During this maturation, the B cells rearrange their immunoglobulin genes at multiple sites. The first lymphoid cell type invaded by EBV is the naïve B cell. Following this invasion, the virus express genes that control this cell's advance through these maturation stages; it can force the naïve B cell that it infects to: arrest maturation at any of these stages; become undetectable as an infected cell by the host's immune system; proliferate excessively; and develop into a B cell-based LPD. The virus may also exit the B cell it initially infects; invade T- or NK cells; and cause these cells to avoid detection by the immune system, proliferate, and progress to a T- or NK cell-based LPD. The T cells that may become infected by EBV are natural killer T cells (NK cells), Gamma delta T cells (γδ T cells), cytotoxic T cells (CTL), helper T cells (Th cells), and follicular B helper T cells (TFH cells). The means by which EBV establishes an dendritic-histiocytic cell (i.e. follicular dendritic cell) infection are unclear. Follicular dendritic cells are connective tissue rather than lymphoid cells. They do, however, have a surface membrane receptor, CD21 (also known as complement receptor type 2), which EBV uses to enter B cells. EBV may escape their infected B cell to invade follicular dendritic cells through this CD21 entry pathway. However, it is also thought possible that the EBV may direct its infected lymphoid cell to mature into an apparent follicular dendritic cell.<unk><unk> Barr virus infection The<unk><unk> Barr virus (also termed human herpesvirus 4) belongs to the Herpes family of Group I double-stranded DNA viruses. It is spread by transfer from the oral/nasal secretions of an infected individual to the oral cavity of an uninfected individual. Once in the oral cavity, the virus invades, reproduces in, establishes its lytic phase in, and lyses (i.e. bursts open) epithelial cells that line the oral mucosa of the newly infected individual. The freed virus then invades naïve B cells located in submucosal lymphoid tissue e.g. tonsils or adenoids. Here, it establishes either a lytic phase that allows it to infect other lymphoid cells or expresses genes that suppress the lytic cycle and impose one of four latency phases. Initially, the virus establishes latency III by expressing nuclear proteins encoded by its EBNA-1, -2, -3A, -3B, -3C, LP, LMP-1, -2A, and -2B and BART genes; cell surface membrane proteins encoded by its LMP-1, -2A, and 3A genes; and microRNAs encoded by its EBER-1 and EBER-2 genes. The products of these genes immortalize, promote the growth and survival, and regulate the maturation of the infected B cell. However, products of some latency III genes (particularly the viral cell surface proteins) make the infected cell susceptible to attack by the host's immune system. The virus avoids this by limiting expression of its latency genes to EBNA-1, LMP-1, -2A, -2B, some BARTs, and the two EBERs. This Latency II pattern of gene expression continues the infected cells' immortalization and proliferation, helps the cells escape the immune surveillance, and forces them to differentiate (i.e. mature) into memory B cells. EBV may establish and maintain a Latency I state in its infected memory B cells by expressing only EBNA1 and the two EBER genes. The products of the latter genes keep the virus in a mostly dormant state. Finally, EBV may establish and maintain a Latency 0 phase by expressing only EBER genes. In latency 0, EBV is in memory B cells as fully dormant, non-reproductive viruses but in this, as in all of the other latency phases, it can revert to its lytic phase. The following table gives more information on the actions of the EBV latency genes. EBV product Latency Function EBNA-1 III, II, I Promote replication of the viral genome; controls the infected cell's expression of nuclear and surface membrane proteins that regulate the virus's latency phases. EBNA-2 III Induces expression of the virus's LMP gene and ~300 genes of the infected cell (e.g. the MYC proto-oncogene) which promote this cell's proliferation, survival, and malignancy; required for the malignant transformation of this cell. EBNA-3A III Represses expression of the infected cell's p16INK4a protein thereby promoting its proliferation; represses expression the infected cell's BCL2L11 protein thereby inhibiting apoptosis to promote this cell's survival. EBNA-3B III Inhibits the infected cell's proliferation; attracts lymphoid cells to its infected cell; inactivates promoters of its infected cell's genes possibly thereby causing this cell more able to evade the host's immune system and to become malignant. EBNA-3C III Required for the malignant transformation of infected cells; along with EBNA-3A, represses the infected cell's p16INK4a and BCL2L11 proteins thereby promoting, respectively, this cell's proliferation and repressing its apoptosis; disturbs cell cycle checkpoints in the infected cell to promote its proliferation or locking it in the non-reproductive cell cycle state of G1. EBNA-LP III Overcomes the innate immune responses of infected cells to promote the virus's survival; acts with EBNA-2 to promote the malignant transformation of its infected cells. LMP-1 III, II Induces the expression of the infected cell's NF-κB and BCL2 proteins thereby blocking this cells apoptosis and stimulating its proliferation; regulates the infected cell's maturation. LMP-2A III, II Prevents the establishment of EBV's lytic cycle; stimulates the infected cell's AKT and B cell receptor proteins thereby blocking this cell's apoptosis and promoting its survival and proliferation. LMP-2B III, II Inhibits the ability of the virus's LMP-2A protein to establish EBV's lytic cycle; stimulates the infected host cell's AKT and B cell receptor proteins thereby blocking this cell's apoptosis and promoting its survival and proliferation. BART microRNAs III, II, I While abundantly expressed, the functions of BART microRNAs are unclear; may help evade the infected cell avoid attack by uninfected T- and NK-cells or modify the infected cell's notch signaling pathway to promote its proliferation; not required for EBV-induced B cell immortalization or malignant transformation. EBER1/2 nucelar RNAs III, II, I, 0 Abundantly expressed by EBV-infected cells in all latency stages; causes infected cell to produce interleukin 10 which may promote this cell to proliferate and avoid attack by host cytotoxic T cells; may block apoptosis in the infected cell.
Epstein–Barr virus–associated lymphoproliferative diseases
Tuberculosis in relation to HIV
AIDS-related lymphoma
HIV/AIDS
Epstein–Barr virus infection
AIDS-related complex
HIV superinfection
Autoimmune lymphoproliferative syndrome