The Life Cycle of Epstein-Barr Virus

Epstein-Barr Virus (EBV) is a large enveloped virus of double-stranded DNA among the eight known herpesviruses. After EBV infection of cells, it accumulates in the nucleus, and there are two life cycles, with alternating phases of latency and lysis. EBV infection is associated with a variety of human malignancies and malignant tissue proliferative diseases, including malignant lymphoma, gastric cancer, nasopharyngeal carcinoma, and hemophagocytic syndrome.

In vivo replication of EBV

A distinguishing feature of EBV and other herpesviruses is the existence of 2 life cycles: latency and lysis. during the incubation period. EBV DNA is present in the nucleus of infected cells, expressing only small amounts of latent proteins. Induction from latency to lysis is called reactivation. EBV can be induced by chemical or biological agents such as histone deacetylase (HDAC), 12-O-tetradecanoyl phorbol-13-acetate (TPA) and calcium ionophores (calcium ionophores) Reactivate.

The lytic phase can be divided into the following stages: early gene expression, DNA replication, late gene expression, assembly and secretion.

Early Gene Expression

The early gene expression is mainly the exogenous expression of immediateearlygene (IE) BZLF or BRLF gene to induce virus reactivation. The IE gene induces the expression of early genes such as BMR F 1, B A L F 2 and B H R F 1 genes. In vitro experiments inferred that BRRF1 may activate transcription in a promoter- and cell-type-dependent manner. The promoter driving the expression of BRRF1 is located within the coding sequence and activated by BZLF1. The ZEBRA protein is a regulator of the lytic cycle, and its expression in latently infected cells is sufficient to initiate the lytic cycle and drive it to completion. In some EBV-positive cell lines, Rta protein also induces the lytic cycle by activating the expression of ZEBRA. During latency, the expression of ZEBRA and Rta was suppressed.

DNA Replication

Lytic viral DNA replication occurs independently of cellular DNA replication. EBV encodes a protein necessary for the replication of lytic DNA, termed the origin of lytic replication (oriLyt), which mediates the replication of viral DNA during lytic infection resulting in hundreds of-fold amplification of associated genes. Due to the circular shape of the EBV genome, the process of cleaved DNA replication follows the “spheronization model”. However, other forms of bidirectional DNA replication may increase the number of circulating viral templates prior to amplification. Lytic replication results in the end-to-end fusion of long tandem linear EBV genomes, which are then cleaved and packaged into the viral capsid. These E gene products act as concatemers to induce replication of the EBV genome.

Late Gene Expression

After replication, late genes encode viral structural proteins, such as major capsid protein (MCP), gp350 and gB.

Assembly and Secretion

EBV-DNA was incorporated into the assembled icosahedral capsid structure. The nucleocapsid buds into the nuclear membrane and is then coated with involucrin and glycoproteins to form progeny viral particles. Epstein-Barr virus can enter epithelial cells through direct fusion of the viral envelope with the cytoplasmic membrane. When entering B cells, five viral glycoproteins are required to cooperate. Among then, gp350/220 binds CD21 on the surface of B cells for attachment; gp42 binds major histocompatibility complex (MHC) class II to initiate fusion; gB and heterodimeric gH/gL constitute the core of the fusion mechanism of Epstein-Barr virus.

Clinical Symptoms after EBV Infection

Epstein-Barr virus infection usually occurs before the age of 5 years, mostly subclinical infection, the infection rate is as high as 98%. Epstein-Barr virus can be latent in epithelial B lymphocytes for a long time, and can be reactivated and proliferated massively under certain circumstances. In some individuals, EBV may cause infectious mononucleosis, or infect various lymphocytes and epithelial cells, which are involved in the development of various diseases, especially malignancies.