EBV-associated diseases: Current therapeutics and emerging technologies

Abstract

EBV is a prevalent virus, infecting >90% of the world's population. This is an oncogenic virus that causes ~200,000 cancer-related deaths annually. It is, in addition, a significant contributor to the burden of autoimmune diseases. Thus, EBV represents a significant public health burden. Upon infection, EBV remains dormant in host cells for long periods of time. However, the presence or episodic reactivation of the virus increases the risk of transforming healthy cells to malignant cells that routinely escape host immune surveillance or of producing pathogenic autoantibodies. Cancers caused by EBV display distinct molecular behaviors compared to those of the same tissue type that are not caused by EBV, presenting opportunities for targeted treatments. Despite some encouraging results from exploration of vaccines, antiviral agents and immune- and cell-based treatments, the efficacy and safety of most therapeutics remain unclear. Here, we provide an up-to-date review focusing on underlying immune and environmental mechanisms, current therapeutics and vaccines, animal models and emerging technologies to study EBV-associated diseases that may help provide insights for the development of novel effective treatments.

Keywords: EBV animal models; EBV therapeutics; EBV vaccines; EBV-associated diseases and cancers; high-throughput sequencing technologies; molecular mechanisms of EBV-host interactions.

Figure 1

Model of EBV infection cycle. (A) Upon primary infection through saliva, EBV infects B cells. The figure depicts a model of EBV infection, where in EBV drives naïve B cells into latency III program. This activation leads to their differentiation into latency I/O memory B cells. This is often followed by spontaneous or induced reactivation of EBV within circulating memory B cells. This figure is adapted/modified from Guo et al (44). (B) Depending on the type of latency or lytic program, EBV infected cells are associated with different malignancies.*Gastric cancer cells also express genes that are associated with latency II programs. **Post-transplant lymphoproliferative disorders express some of the genes in latency III as well.

Figure 2

A few examples of key host cellular processes perturbed by EBV. Examples of EBV-encoded gene products that are related to the indicated mechanism are shown.

Figure 3

Therapeutic approaches hypothesized or in clinical use, for the treatment of EBV-associated malignancies. Shown are broad categories of treatments (red), subcategories (bold) and specific examples (italicized). HDAC: Histone deacetylase; DNMT: DNA methyltransferase; R-CHOP: Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone.

Figure 4

Ltic induction or cytolytic virus activation therapy (CLVA). CLVA can make latently infected cells susceptible to antivirals ang immune recognition.