Rhesus cytomegalovirus contains functional homologues of US2, US3, US6, and US11.
Human cytomegalovirus (HCMV) is a paradigm for mechanisms subverting antigen presentation by major histocompatibility complex (MHC) molecules. Due to its limited host range, HCMV cannot be studied in animals. Thus, the in vivo importance of inhibiting antigen presentation for the establishment and maintenance of infection with HCMV is unknown. Rhesus cytomegalovirus (RhCMV) is an emerging animal model that shares many of the features of HCMV infection. The recent completion of the genomic sequence of RhCMV revealed a significant degree of homology to HCMV. Strikingly, RhCMV contains several genes with low homology to the HCMV US6 gene family of inhibitors of the MHC I antigen presentation pathway. Here, we examine whether the RhCMV US6 homologues (open reading frames Rh182, -184, -185, -186, -187, and -189) interfere with the MHC I antigen-processing pathway. We demonstrate that Rh182 and Rh189 function similarly to HCMV US2 and US11, respectively, mediating the proteasomal degradation of newly synthesized MHC I. The US3 homologue, Rh184, delayed MHC I maturation. Unlike US3, MHC I molecules eventually escaped retention by Rh184, so that steady-state surface levels of MHC I remained unchanged. Rh185 acted similarly to US6 and inhibited peptide transport by TAP and, consequently, peptide loading of MHC I molecules. Thus, despite relatively low sequence conservation, US6 family-related genes in RhCMV are functionally closely related to the conserved structural features of HCMV immunomodulators. The conservation of these mechanisms implies their importance for immune evasion in vivo, a question that can now be addressed experimentally.
Pande
Nupur T
NT
Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA.
Powers
Colin
C
Ahn
Kwangseog
K
Früh
Klaus
K
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001692:Biological Transport; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D006023:Glycoproteins; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000235:genetics / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D006023:Glycoproteins; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; C095111:US3 protein, cytomegalovirus; C432877:US6 protein, Human cytomegalovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D046988:Proteasome Endopeptidase Complex