Herpesvirus Interference with Major Histocompatibility Complex Class II-Restricted T-Cell Activation

Immune evasion strategies are thought to contribute to successful persistence of viruses in the infected immunocompetent host, delaying elimination of the infected cell long enough to enable the virus to replicate. Exemplary in this context are herpesviruses, which are carried as persistent infections by the vast majority of adults (65). Immune evasion strategies have been identified for members of all three subfamilies, for example, herpes simplex virus (HSV; an alphaherpesvirus), human cytomegalovirus (HCMV; a betaherpesvirus), and Epstein-Barr virus (EBV; a gammaherpesvirus). In the infected cell, herpesviruses use general evasive approaches, such as blocking the induction of programmed cell death and shutting down host protein synthesis (65). In addition, herpesviruses specifically perturb recognition by virus-specific T cells, among others. To this end, herpesviruses appear to exploit a combination of characteristics. First, they are able to establish a latent state of infection, in which exposure of viral antigens to the immune system is limited due to an expression profile that is greatly restricted both in the amount and in the copy number of the viral genes expressed. This strategy forces antiviral CD4+ and CD8+ T cells directed against, for instance, EBV latent antigens (17) to always operate at their detection limit. Second, herpesviruses dedicate part of their genomes to functions that modulate immune recognition, suppressing antiviral detection and elimination mechanisms. Most specific immune evasion strategies described to date allow viruses to escape from major histocompatibility complex (MHC) class I-restricted cytotoxic T cells. As reviewed previously, every step of the class I processing and presentation pathway appears to be thwarted by one or more herpesviruses (4, 47, 80, 87, 89). In contrast, much less is known about viral interference with MHC class II-restricted immune responses; in the following sections, we will therefore discuss recent developments in this field, with an emphasis on the human herpesviruses.