The Epstein-Barr Virus (EBV), formally known as human herpesvirus 4 (HHV-4), is a double-stranded DNA virus in the herpesvirus family that establishes lifelong infection in nearly 90% of the global adult population. EBV is most famously associated with infectious mononucleosis (“mono”), which typically manifests when infection occurs during adolescence or adulthood. While many infections are asymptomatic, EBV is also recognized as the first human tumor virus, linked to several malignancies, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. Its persistence relies on a life cycle that alternates between active replication and a silent, dormant state.
Mechanisms of Viral Entry and Target Cells
The initial infection involves two primary cell types: B lymphocytes and epithelial cells lining the throat and salivary glands. The virus employs distinct molecular mechanisms for entry into each cell type, reflecting its dual tropism.
Entry into B Lymphocytes
For B lymphocytes, the process begins when the viral glycoprotein gp350/220 binds specifically to the cellular receptor CD21 (CR2) on the B cell surface. A second viral protein, gp42, then interacts with the host cell’s major histocompatibility complex Class II (HLA Class II) molecules. This coordinated binding triggers conformational changes in the viral envelope glycoproteins, leading to the fusion of the viral and B cell membranes to deliver the viral core into the cytoplasm.
Entry into Epithelial Cells
Entry into epithelial cells utilizes a different set of cellular receptors because HLA Class II is typically absent. Here, the virus relies on viral proteins BMRF-2 and gH/gL to interact with cellular integrins, such as \(\beta 1\) integrins and \(\alpha v \beta 6/\alpha v \beta 8\) integrins. This interaction initiates the fusion process. The distinct receptor usage allows the virus to shift its tropism between B cells, where it establishes persistence, and epithelial cells, where it undergoes productive replication for transmission.
Latency: The State of Viral Persistence
Following initial infection, EBV establishes latency, the defining characteristic of its long-term survival in the host. In this dormant phase, the viral double-stranded DNA genome exists as a circularized structure called an episome within the host cell nucleus, where it replicates alongside the host chromosomes. Latency is characterized by the expression of only a minimal set of viral genes, a strategy to avoid detection by cytotoxic T lymphocytes. The most consistently expressed protein is the EBV nuclear antigen 1 (EBNA1), which anchors the viral episome to the host cell’s mitotic machinery to ensure the viral DNA is passed to daughter cells during division.
The virus utilizes four main programs of latency, designated Type 0, I, II, and III, each defined by a specific profile of expressed latent genes and associated with different infected cell types.
- Latency Type 0: The most restricted form, where virtually no viral proteins are expressed, allowing the virus to hide silently within resting memory B cells in healthy carriers.
- Latency Type I: Seen in tumors like Burkitt lymphoma, expressing only EBNA1 and small non-coding RNAs (EBERs and microRNAs) for episome maintenance and cell survival.
- Latency Type II: Found in Hodgkin lymphoma and nasopharyngeal carcinoma, adding the expression of latent membrane proteins (LMP1 and LMP2) to promote cell growth and survival signals.
- Latency Type III: The most comprehensive expression profile, including all EBV nuclear antigens and latent membrane proteins, typically observed in the initial infection phase and in post-transplant lymphoproliferative disorder (PTLD).
The ability to switch between these programs allows EBV to adapt to the host’s immune environment, transitioning from the highly immunogenic full-expression state (Type III) to the stealth mode (Type 0/I) to ensure lifelong persistence.
The Lytic Cycle: Active Replication and Transmission
The lytic cycle, or productive infection, is the phase dedicated to the mass production of new virus particles, a process essential for host-to-host transmission. This cycle is typically triggered when latent-infected cells, primarily B cells, receive specific external signals, such as B-cell differentiation cues or environmental stresses. The switch from latency is initiated by the expression of two immediate-early genes, BZLF1 (Zta) and BRLF1 (Rta), which act as master transactivators to unleash the cascade of lytic gene expression.
The lytic cycle proceeds through three temporally regulated stages: immediate-early, early, and late. Immediate-early proteins rapidly activate the expression of early genes, whose products are primarily enzymes required for viral DNA replication and metabolism. The viral DNA polymerase is the most important early gene product, which takes over from the host’s machinery to begin synthesizing large, linear copies of the viral genome.
Late genes are expressed after the viral DNA has been replicated and primarily encode the structural components of the new virions, such as the major capsid protein, envelope glycoproteins (like gp350), and scaffolding proteins. These components self-assemble to form new viral capsids, which are filled with the replicated linear DNA. The fully formed virions bud out through the nuclear and cellular membranes, causing the lysis of the host cell and releasing infectious particles into the saliva for transmission.
Molecular Tactics for Immune Evasion
EBV has evolved molecular tactics to evade the immune system across both its latent and lytic phases, ensuring its permanent residence in the host. A primary strategy is the sabotage of antigen presentation pathways, necessary for T cells to recognize infected cells.
Evasion During Latency
During latency, the EBV nuclear antigen 1 (EBNA1) contains a Glycine-Alanine-rich sequence. This sequence physically blocks the proteasome from efficiently processing and presenting protein fragments on MHC Class I molecules, shielding the cell from cytotoxic T cells. Furthermore, the latent membrane protein LMP2A interferes with the B-cell receptor (BCR) signaling pathway, preventing the B cell from differentiating and initiating the lytic cycle, thus maintaining the latent state.
Evasion During the Lytic Cycle
The virus produces specific proteins that interfere with key immune signaling molecules. The lytic protein BCRF1 is a viral homolog of human Interleukin-10 (vIL-10), an anti-inflammatory cytokine, which dampens the host’s pro-inflammatory response and suppresses the function of T cells and Natural Killer (NK) cells. Additionally, the viral glycoprotein gp42 binds to and blocks the HLA Class II molecules on the B cell surface, preventing the activation of helper CD4+ T cells. The virus also expresses the protein BHRF1, which mimics the cellular Bcl-2 protein, inhibiting the host cell’s programmed cell death (apoptosis). This inhibition ensures the survival of the infected cell for the completion of the lytic cycle and virion production.