There are two reasons why the sensory neuron remains infected: first, the virus is quiescent and generates few virusderived peptides to present on MHC class I molecules; second, neurons carry very low levels of MHC class I molecules, which makes it harder for CD8 cytotoxic T cells to recognize infected neurons and attack them. The low level of MHC class I expression is beneficial because it reduces the risk that neurons, which have a limited capacity for regeneration, will be targeted inappropriately by cytotoxic T cells. It does, however, make neurons attractive as cellular reservoirs for persistent infections. Herpesviruses often enter latency. Herpes zoster (varicellazoster), which causes chickenpox, remains latent in one or a few dorsal root ganglia after the acute illness is over, and can be reactivated by stress or immunosuppression. It then spreads down the nerve and reinfects the skin to cause the disease herpes zoster, or shingles, which is marked by the reappearance of the classic varicella rash in the area of skin served by the infected dorsal root. Unlike herpes simplex, which reactivates frequently, herpes zoster usually reactivates only once in a lifetime in an immunocompetent host.
Yet another herpesvirus, the Epstein–Barr virus (EBV), establishes a persistent infection in most individuals. EBV enters latency in B cells after a primary infection that often passes without being diagnosed. In a minority of infected individuals, the initial acute infection of B cells is more severe, causing the disease known as infectious mononucleosis or glandular fever. EBV infects B cells by binding to CR2 (CD21), a component of the Bcell coreceptor complex, and to MHC class II molecules. In the primary infection, most of the infected cells proliferate and produce virus, leading in turn to the proliferation of antigenspecific T cells and the excess of mononuclear white cells in the blood that gives the disease its name. Virus is released from the B cells, destroying them in the process, and virus can be recovered from saliva. The infection is eventually controlled by virusspecific CD8 cytotoxic T cells, which kill the infected proliferating B cells. A fraction of memory B lymphocytes become latently infected, however, and EBV remains quiescent in these cells.
These two forms of infection are accompanied by quite different patterns of expression of viral genes. EBV has a large DNA genome encoding more than 70 proteins. Many of these are required for viral replication and are expressed by the replicating virus, providing a source of viral peptides by which infected cells can be recognized. In a latent infection, in contrast, the virus survives within the host B cells without replicating, and a very limited set of viral proteins is expressed. One of these is the Epstein–Barr nuclear antigen 1 (EBNA1), which is needed to maintain the viral genome. EBNA1 interacts with the proteasome (see Section 62) to prevent its own degradation into peptides that would otherwise elicit a Tcell response.
Latently infected B cells can be isolated by culturing B cells from individuals who have apparently cleared their EBV infection: in the absence of T cells, latently infected cells retaining the EBV genome become transformed into socalled immortal cell lines, the equivalent of tumorigenesis in vitro. Infected B cells occasionally undergo malignant transformation in vivo, giving rise to a Bcell lymphoma called Burkitt’s lymphoma. In this lymphoma, expression of the peptide transporters TAP1 and TAP2 is downregulated (see Section 63), and so cells are unable to process endogenous antigens for presentation on HLA class I molecules (the human MHC class I). This deficiency provides one explanation for how these tumors escape attack by CD8 cytotoxic T cells. Patients with acquired and inherited immunodeficiencies of Tcell function have an increased risk of developing EBVassociated lymphomas, presumably as a result of a failure of immune surveillance.