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.

Alphaaphine疱疹病毒1（AlHV-1）是属于Macavirus属的γ-疱疹病毒（γ-HV），它持续感染其天然宿主牛羚，而不会引起任何临床症状。然而，向其他反刍动物的交叉传播会导致致命的淋巴增生性疾病，称为恶性卡他热（MCF）。AlHV-1 ORF73编码潜伏期相关的核抗原（LANA）同源蛋白（aLANA）。最近，已显示aLANA对于病毒在体内的持久性和MCF的诱导至关重要，这表明aLANA具有其他γ-HV基因组维持蛋白的关键特性。在这里，我们研究了通过aLANA逃避免疫反应的过程。我们发现富含甘氨酸/谷氨酸（GE）的重复域足以抑制顺式与aLANA相关的表位的呈现。尽管在没有GE的情况下抗原呈递依赖于蛋白酶体对aLANA的降解，但是缺乏GE并不影响蛋白质更新。然而，蛋白质的自我合成从头被LANA GE下调，这是一种与减少体外抗原呈递直接相关的机制。重要的是，阿拉纳GE的密码子修饰导致增加的抗原呈递体外和增强的抗原-特异性CD8感应⁺ T细胞应答在体内，这表明在GE mRNA的约束，而不是肽序列负责顺-抗原呈递的限制。尽管如此，在MCF期间，GE介导的在aLANA顺式中抗原呈递的限制是可有可无的，因为兔子感染病毒后会发展成该病，而与全长或GE缺失的aLANA的表达无关。总之，我们提供的证据表明，通过GE抑制顺式蛋白质合成可能参与了对牛羚自然宿主中AlHV-1潜在持久性的长期免疫逃避，但在MCF发病机理中却是不可或缺的。