Immune escape of γ-herpesviruses from adaptive immunity

Abstract

Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are two γ-herpesviruses identified in humans and are strongly associated with the development of malignancies. Murine γ-herpesvirus (MHV-68) is a naturally occurring rodent pathogen, representing a unique experimental model for dissecting γ-herpesvirus infection and the immune response. These γ-herpesviruses actively antagonize the innate and adaptive antiviral responses, thereby efficiently establishing latent or persistent infections and even promoting development of malignancies. In this review, we summarize immune evasion strategies of γ-herpesviruses. These include suppression of MHC-I-restricted and MHC-II-restricted antigen presentation, impairment of dendritic cell functions, downregulation of costimulatory molecules, activation of virus-specific regulatory T cells, and induction of inhibitory cytokines. There is a focus on how both γ-herpesvirus-derived and host-derived immunomodulators interfere with adaptive antiviral immunity. Understanding immune-evasive mechanisms is essential for developing future immunotherapies against EBV-driven and KSHV-driven tumors.

Figure 1

Gammaherpesviruses inhibit MHC-I-restricted antigen presentation. vIRF1 interacts with the transcriptional coactivator p300 and thereby interferes with the MHC-I transcription. BGLF5, SOX and muSOX promote the degradation of host mRNAs and shutoff of MHC-I gene expression. EBNA1, LANA1 and mLANA escape being processed by the proteasome and inhibit their own translation. BNLF2a shuts down TAP-mediated import of antigenic peptides. mK3 directs immature MHC-I molecules to the cytosol and also degrades TAP and tapasin. BILF1, kK3 and kK5 trigger endocytosis of cell surface MHC-I molecules and promote their lysosomal degradation. vIL-10 downregulates TAP1 and bli/LMP2 (a subunit of proteasome) at the mRNA level.

Figure 2

Gammaherpesviruses inhibit MHC-II-restricted antigen presentation. SOCS3 expression is upregulated by KSHV infection, which inhibits IFN-γ-induced phosphorylation of STAT1, thereby downregulating the transactivation of CIITA gene. BZLF1 and vIRF3 bind to the promoters of CIITA genes and thus interfere with its transactivation. BZLF1 reduces IFN-γR α expression at both the mRNA and protein level, and in that way shuts down the entire IFN-γ-induced CIITA signaling cascade. gp42 blocks TCR and MHC-II engagement. vIL-10 reduces IFN-γ synthesis and inhibits both basal and IFN-γ-induced expressions of MHC-II.