The Specificity and Polymorphism of the MHC Class I Prevents the Global Adaptation of HIV-1 to the Monomorphic Proteasome and TAP

The large diversity in MHC class I molecules in a population lowers the chance that a virus infects a host to which it is pre-adapted to escape the MHC binding of CTL epitopes. However, viruses can also lose CTL epitopes by escaping the monomorphic antigen processing components of the pathway (proteasome and TAP) that create the epitope precursors. If viruses were to accumulate escape mutations affecting these monomorphic components, they would become pre-adapted to all hosts regardless of the MHC polymorphism. To assess whether viruses exploit this apparent vulnerability, we study the evolution of HIV-1 with bioinformatic tools that allow us to predict CTL epitopes, and quantify the frequency and accumulation of antigen processing escapes. We found that within hosts, proteasome and TAP escape mutations occur frequently. However, on the population level these escapes do not accumulate: the total number of predicted epitopes and epitope precursors in HIV-1 clade B has remained relatively constant over the last 30 years. We argue that this lack of adaptation can be explained by the combined effect of the MHC polymorphism and the high specificity of individual MHC molecules. Because of these two properties, only a subset of the epitope precursors in a host are potential epitopes, and that subset differs between hosts. We estimate that upon transmission of a virus to a new host 39%–66% of the mutations that caused epitope precursor escapes are released from immune selection pressure.

种群内主要组织相容性复合体I类（Major Histocompatibility Complex class I, MHC I）分子的高度多样性，会降低病毒感染其预先适配的宿主的概率：此类病毒可逃逸该宿主的细胞毒性T淋巴细胞（Cytotoxic T Lymphocyte, CTL）表位的MHC结合过程。然而，病毒也可通过逃逸该通路中的单态型抗原加工组分（蛋白酶体（proteasome）与抗原加工转运体（Transporter associated with Antigen Processing, TAP））来丢失CTL表位，这类组分负责合成表位前体。若病毒积累影响这些单态型组分的逃逸突变，那么无论宿主的MHC多态性如何，病毒都将对所有宿主实现预先适配。为评估病毒是否会利用这一明显的易感性，我们借助可预测CTL表位的生物信息学工具，研究人类免疫缺陷病毒1型（Human Immunodeficiency Virus 1, HIV-1）的演化过程，并量化抗原加工逃逸事件的发生频率与积累情况。我们发现，在宿主个体内部，蛋白酶体与TAP逃逸突变的出现频率较高。但在种群层面，此类逃逸突变并未发生积累：在过去30年间，人类免疫缺陷病毒1型B亚型中预测得到的表位与表位前体总数始终保持相对稳定。我们认为，这种缺乏适应性的现象可通过MHC多态性与单个MHC分子的高特异性的共同作用来解释。基于这两项特性，宿主体内仅存在一部分表位前体可成为潜在表位，且不同宿主的该潜在表位子集存在差异。我们估算，当病毒传播至新宿主时，39%~66%曾引发表位前体逃逸的突变会脱离免疫选择压力的约束。