Macavirus latency-associated protein evades immune detection through regulation of protein synthesis in cis depending upon its glycin/glutamate-rich domain

• Published in: PLoS pathogens Vol. 13; no. 10; p. e1006691
• Main Authors: Sorel, Océane, Chen, Ting, Myster, Françoise, Javaux, Justine, Vanderplasschen, Alain, Dewals, Benjamin G.
• Format: Journal Article Web Resource
• Language: English
• Published: United States Public Library of Science 23.10.2017; Public Library of Science (PLoS)
• Subjects: Animals; Antigen presentation; Antigen Presentation - immunology; Biology and Life Sciences; Cattle; CD8 antigen; Deoxyribonucleic acid; DNA; Epitopes; Fever; Funding; Gammaherpesvirinae - immunology; Genomes; Glutamate; Glutamic Acid - immunology; Glycine - immunology; Herpesviruses; Homology; Immune Evasion - immunology; Immune response; Immune system; Immunology; Immunotherapy; Infections; Latency; Latency-associated nuclear antigen; Life sciences; Lymphocytes; Lymphocytes T; Lymphoma; Malignant Catarrh - immunology; Malignant catarrhal fever; Medicine and Health Sciences; mRNA; Médecine vétérinaire & santé animale; Parasitic diseases; Pathogenesis; Peptides; Proteasomes; Protein biosynthesis; Protein synthesis; Protein turnover; Proteins; Rabbits; Research and Analysis Methods; Sciences du vivant; Veterinary medicine; Veterinary medicine & animal health; Viral Proteins - chemistry; Viral Proteins - immunology; Virology; Virus Latency - immunology; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006691

Alcelaphine herpesvirus 1 (AlHV-1) is a γ-herpesvirus (γ-HV) belonging to the macavirus genus that persistently infects its natural host, the wildebeest, without inducing any clinical sign. However, cross-transmission to other ruminant species causes a deadly lymphoproliferative disease named malignant catarrhal fever (MCF). AlHV-1 ORF73 encodes the latency-associated nuclear antigen (LANA)-homolog protein (aLANA). Recently, aLANA has been shown to be essential for viral persistence in vivo and induction of MCF, suggesting that aLANA shares key properties of other γ-HV genome maintenance proteins. Here we have investigated the evasion of the immune response by aLANA. We found that a glycin/glutamate (GE)-rich repeat domain was sufficient to inhibit in cis the presentation of an epitope linked to aLANA. Although antigen presentation in absence of GE was dependent upon proteasomal degradation of aLANA, a lack of GE did not affect protein turnover. However, protein self-synthesis de novo was downregulated by aLANA GE, a mechanism directly associated with reduced antigen presentation in vitro. Importantly, codon-modification of aLANA GE resulted in increased antigen presentation in vitro and enhanced induction of antigen-specific CD8+ T cell responses in vivo, indicating that mRNA constraints in GE rather than peptidic sequence are responsible for cis-limitation of antigen presentation. Nonetheless, GE-mediated limitation of antigen presentation in cis of aLANA was dispensable during MCF as rabbits developed the disease after virus infection irrespective of the expression of full-length or GE-deficient aLANA. Altogether, we provide evidence that inhibition in cis of protein synthesis through GE is likely involved in long-term immune evasion of AlHV-1 latent persistence in the wildebeest natural host, but dispensable in MCF pathogenesis.