Of all the pathogens, DNA viruses that can establish chronic infections have evolved the greatest diversity of mechanisms for subverting or escaping immune defenses. Unlike RNA viruses, DNA viruses have relatively low mutation rates and are thus less able to employ antigenic variation to evade immune defenses. However, because their lower rate of mutation allows them to support much larger genomes, these viruses have been able to accommodate a remarkable number of viral genes encoding proteins that can subvert nearly every aspect of antiviral defense. In the case of poxvirus, adenovirus, and especially herpesviruses, all of them large DNA viruses that will be our focus here, over 50% of the genome can be dedicated to immune evasionrelated genes. Further, some of these viruses, particularly the herpesviruses, have evolved mechanisms that allow them to enter a state known as latency, in which the virus is not actively replicated. In the latent state, the virus does not cause disease; however, because no viral peptides are produced to load MHC class I molecules that signal the virus’s presence to cytolytic T cells, it cannot be eliminated, and can establish lifelong infections. As we will discuss in Section 1324, latent infections can be reactivated, resulting in recurrent illness. Of the eight types of herpesvirus that infect humans, at least one of the five most common types—herpes simplex virus (HSV)1 and 2 (both of which can cause labial and genital herpes), Epstein–Barr virus (EBV, which causes infectious mononucleosis), varicellazoster (which causes chickenpox and shingles), and cytomegalovirus (CMV)—infects nine out of ten people, and typically establishes lifelong latency. Here we highlight major mechanisms by which these viruses succeed (Fig. 13.23).
Central to the longterm survival of the DNA viruses is evasion of CTLs and NK cells. The presentation of viral peptides by MHC class I molecules at a cell surface signals CD8 T cells to kill the infected cell. Many of the large DNA viruses evade immune recognition by producing proteins called immunoevasins, which prevent the appearance of viral peptide:MHC class I complexes on the infected cell (Fig. 13.24). Indeed, at least one viral inhibitor of every key step in the processing and presentation of peptide:MHC class I complexes has been described. Some immunoevasins block peptide entry into the endoplasmic reticulum by targeting the TAP transporter (Fig. 13.25, left panel). Viral proteins can also prevent peptide:MHC complexes from reaching the cell surface by retaining MHC class I molecules in the endoplasmic reticulum (see Fig. 13.25, middle panel). Several viral proteins catalyze the degradation of newly synthesized MHC class I molecules by a process known as dislocation, which initiates the pathway normally used to degrade misfolded endoplasmic reticulum proteins by directing them back into the cytosol (Fig. 13.25, right panel). By preventing the formation of stably assembled/folded peptide:MHC class I complexes, these viral proteins divert the peptide:MHC class I complexes into the ERassociated degradation (ERAD) pathway for disposal. Through these multiple mechanisms, viral factors impair or completely block the presentation of viral peptides to CTLs. The actions of viral inhibitors are not limited to the MHC class I pathway, as viral inhibitors of the class II processing pathway have also been described; these inhibitors ultimately target CD4 T cells. Finally, as many viruses target cells other than dendritic cells, their antigens come to the attention of CD8 T cells via crosspresentation. Viral mechanisms that interfere with this pathway are not well described, although it is known that because the viruses are not required to persist in dendritic cells, the viruses can block recognition and destruction of their cellular hosts even after primed CTL effectors have been generated.