The Critical Role of Genome Maintenance Proteins in Immune Evasion During Gammaherpesvirus Latency

Abstract

Gammaherpesviruses are important pathogens that establish latent infection in their natural host for lifelong persistence. During latency, the viral genome persists in the nucleus of infected cells as a circular episomal element while the viral gene expression program is restricted to non-coding RNAs and a few latency proteins. Among these, the genome maintenance protein (GMP) is part of the small subset of genes expressed in latently infected cells. Despite sharing little peptidic sequence similarity, gammaherpesvirus GMPs have conserved functions playing essential roles in latent infection. Among these functions, GMPs have acquired an intriguing capacity to evade the cytotoxic T cell response through self-limitation of MHC class I-restricted antigen presentation, further ensuring virus persistence in the infected host. In this review, we provide an updated overview of the main functions of gammaherpesvirus GMPs during latency with an emphasis on their immune evasion properties.

Keywords: antigen presentation; genome maintenance protein; herpesvirus; immune evasion; viral latency; viral proteins.

FIGURE 1

Schematic representation of representative gammaherpesvirus GMPs. N- and C- terminal domains are separated by a central amino acid repeat domain (CR), highlighted in orange. Repeat residues are indicated. The RG-rich regions of EBNA-1 are depicted in blue. Genus Lymphocryptovirus: EBNA-1 (EBV, strain B95.8), rhEBNA1 (rhLCV, strain LCL8664) and baEBNA-1 (baLCV, strain S594). Genus Rhadinovirus: AtHV3 ORF73 (strain 73), LANA-1 (KSHV, strain JK-18), sLANA (SaHV-2, strain C488), rhLANA (M78114). Genus Percavirus: EHV-2 ORF73 (strain 86/87), EHV-5 (strain 2-141/67). Genus Macavirus: oLANA (OvHV-2, strain BJ1035), and aLANA (AlHV-1, strain C500).

FIGURE 2

Cis-acting immune evasion of MHC Class I antigen presentation of gammaherpesvirus GMPs. The MHC class I antigen presentation pathway is depicted with described GMP-mediated cis-acting immune evasion mechanisms. Cytoplasmic endogenously expressed viral proteins are degraded by the proteasome into antigenic peptides that are then translocated from the cytosol to the endoplasmic reticulum (ER) through the transporter for antigen processing (TAP). Then, antigenic peptides are loaded on MHC class I molecules to form MHC-I-peptides complexes that are subsequently exported to the cell surface through the Golgi apparatus for recognition by CD8⁺ cytotoxic T lymphocytes. GMPs have been demonstrated to inhibit this process through various mechanisms: (1) sLANA and aLANA were shown to decrease their own steady-state RNA levels; (2) EBNA-1 can inhibit pre-mRNA processing of the primary EBNA-1 transcript; (3) structural constraints, such as G-quadruplexes (G4), contained in aLANA and EBNA-1 mRNA rather than protein sequences can regulate self-translation; (4) EBNA-1, aLANA, LANA-1, sLANA, and mLANA are able to induce retardation of self-translation; (5) EBNA-1, mLANA, and LANA-1 were shown to be protected from proteasomal degradation; (6) LANA-1 was reported to hold an inhibitory effect prior to translocation of its own cytoplasmic peptides into the ER.