da Silva J, Hughes A L
Department of Biology, Pennsylvania State University, University Park 16802, USA.
Mol Biol Evol. 1998 Oct;15(10):1259-68. doi: 10.1093/oxfordjournals.molbev.a025854.
Host cytotoxic T lymphocytes (CTLs) that recognize specific viral peptides (epitopes) are thought to provide the most effective control of viral replication and spread. However, viruses may escape this recognition through mutations in CTL epitopes. We tested the hypothesis that, as an adaptation on the part of the host to constrain parasite escape from immune control, class I major histocompatibility complex (MHC) molecules present peptides that are derived from conserved regions of foreign proteins to CTLs. We did this by estimating the relative conservation of CTL epitopes of the functionally important Nef protein of human immunodeficiency virus 1 (HIV-1) and relating this to the structure and function of the protein. In comparisons among sequences from several HIV-1 subtypes and both major groups, CTL epitopes had lower rates of nonsynonymous nucleotide substitution per site than did the remainder of the protein, indicating the relative conservation of these epitopes. In contrast, helper T-cell epitopes were as conserved as, and monoclonal antibody epitopes less conserved than, the remainder of the protein. The conservation of CTL epitopes is apparently due to their derivation from functionally important domains of Nef, since CTL epitopes coincide with these domains and these domains are conserved relative to the remainder of the protein, in contrast to secondary structural elements, which are not. Recent studies provide evidence of CTL selection on HIV-1 epitopes, but the variational range of viral escape mutants appears to be limited by functional constraints on the protein regions from which epitopes are derived. The presentation of conserved foreign peptides to CTLs by class I MHC molecules may be a general adaptation of vertebrate hosts to constrain the adaptation of their intracellular parasites.
人们认为，识别特定病毒肽段（表位）的宿主细胞毒性T淋巴细胞（CTL）能最有效地控制病毒复制和传播。然而，病毒可能通过CTL表位的突变来逃避这种识别。我们检验了这样一种假说：作为宿主的一种适应性机制，用于限制寄生虫逃避免疫控制，I类主要组织相容性复合体（MHC）分子会将源自外来蛋白质保守区域的肽段呈递给CTL。我们通过估算人类免疫缺陷病毒1型（HIV-1）功能重要的Nef蛋白的CTL表位的相对保守性，并将其与该蛋白的结构和功能相关联来进行验证。在对几种HIV-1亚型和两个主要组别的序列进行比较时，CTL表位每个位点的非同义核苷酸替换率低于该蛋白的其余部分，这表明这些表位具有相对保守性。相比之下，辅助性T细胞表位与该蛋白的其余部分一样保守，而单克隆抗体表位的保守性低于该蛋白的其余部分。CTL表位的保守性显然是由于它们源自Nef的功能重要结构域，因为CTL表位与这些结构域重合，并且与二级结构元件不同，这些结构域相对于该蛋白的其余部分是保守的。最近的研究提供了关于HIV-1表位上CTL选择的证据，但病毒逃逸突变体的变异范围似乎受到表位所源自的蛋白区域功能限制的约束。I类MHC分子将保守的外来肽段呈递给CTL可能是脊椎动物宿主限制其细胞内寄生虫适应性的一种普遍适应性机制。
