Progress and problems in understanding and managing primary Epstein-Barr virus infections

Abstract

Epstein-Barr virus (EBV) is a gammaherpesvirus that infects a large fraction of the human population. Primary infection is often asymptomatic but results in lifelong infection, which is kept in check by the host immune system. In some cases, primary infection can result in infectious mononucleosis. Furthermore, when host-virus balance is not achieved, the virus can drive potentially lethal lymphoproliferation and lymphomagenesis. In this review, we describe the biology of EBV and the host immune response. We review the diagnosis of EBV infection and discuss the characteristics and pathogenesis of infectious mononucleosis. These topics are approached in the context of developing therapeutic and preventative strategies.

FIG. 1.

EBV infection in healthy carriers. Primary EBV infection begins in the oral cavity. EBV uses different glycoproteins to infect epithelial cells and naïve B cells. Viral entry results in transport of the EBV genome into the B-cell nucleus, where replication by cellular and viral DNA polymerases begins. EBV gene products activate the B-cell growth program, resulting in the proliferation of blasting B cells. Priming of naïve T cells by antigen-presenting cells occurs in parallel. Normally, these blasting B cells are destroyed by cytotoxic T lymphocytes. Once in the circulation, previously activated memory B cells may continue to undergo lytic replication or, if EBV shuts down most of its protein-encoding genes, latency occurs. At a later time, as cells recirculate between the oral and peripheral compartments, resting B cells may be activated, resulting in viral reactivation and shedding.

FIG. 2.

Kinetics of EBV-specific antibodies and viral load in infectious mononucleosis. The graph shows the evolution of EBV replication and EBV-specific antibodies measured by EIA during primary infection. At presentation, EBV may not be detected in the blood but is usually found in large quantities in the oral cavity. Virus is cleared from the blood much more rapidly than from the oral compartment. Oral viral shedding can persist for months and recurs intermittently for years in most healthy adults. At the onset of illness, most patients have IgM antibodies to EBV VCA; these decline between 2 and 6 months after infection. VCA IgG antibodies may be detected as early as during the first 2 weeks of illness. Essentially 100% of patients have detectable VCA IgG antibodies during convalescence, and these persist for life. EBNA1 IgG antibodies do not develop until 3 to 6 months after infection but then persist for life.