Nietfield W, Bauer M, Fevrier M, Maier R, Holzwarth B, Frank R, Maier B, Riviere Y, Meyerhans A
Department of Virology, University of Freiburg, Germany.
J Immunol. 1995 Mar 1;154(5):2189-97.
Previous studies on the variation of an immunodominant HLA-B27-restricted HIV-1 gag p24 epitope (KRWIIL GLNK, amino acids 263-272) have demonstrated the persistence of variants recognized by CTL. Sequence comparisons of HIV isolates showed that this region is relatively conserved and as a consequence might restrict antigenic variation. To evaluate the possibility of HIV-1 to yield infectious mutants of this epitope that lack the ability to bind to HLA-B27 or escape HLA-B27-restricted CTL recognition, single-point mutations were constructed in the infectious molecular clone of HIV-1 Lai. Changes of arginine 264, the anchor amino acid for HLA-B27, to lysine or glycine resulted in infectious HIV-1 variants. The respective synthetic peptides showed reduced ability to sensitize target cells for CTL recognition and a corresponding loss of binding affinity to HLA-B27. In contrast, mutation of glycine 269 to lysine or glutamate abrogated HIV-1 infectivity. The corresponding peptides were able to bind to HLA-B27 but were not recognized by CTL. These data show that HIV-1 tolerates some genetic variation of the HLA-B27-restricted CTL epitope in gag p24 and that single-point mutations can alter quantitatively the immunologic properties. Further, it demonstrates that the mere nonrecognition of peptides derived from quasispecies analysis of small regions might simply correspond to nonviable virus variants and cannot be taken as evidence for CTL escape mutants. Together with the previously published data on the persistence of CTL epitopes, these results suggest that CTL do not play a major role in driving HIV-1 evolution in vivo.
先前关于一种免疫显性的HLA - B27限制性HIV - 1 gag p24表位（KRWIIL GLNK，氨基酸263 - 272）变异的研究表明，细胞毒性T淋巴细胞（CTL）识别的变异体持续存在。HIV分离株的序列比较显示，该区域相对保守，因此可能限制抗原变异。为了评估HIV - 1产生这种表位的感染性突变体的可能性，这些突变体缺乏与HLA - B27结合的能力或逃避HLA - B27限制性CTL识别，在HIV - 1 Lai的感染性分子克隆中构建了单点突变。将HLA - B27的锚定氨基酸精氨酸264突变为赖氨酸或甘氨酸，产生了感染性HIV - 1变异体。各自的合成肽显示出使靶细胞对CTL识别敏感的能力降低，以及与HLA - B27结合亲和力相应丧失。相反，将甘氨酸269突变为赖氨酸或谷氨酸消除了HIV - 1的感染性。相应的肽能够与HLA - B27结合，但不被CTL识别。这些数据表明，HIV - 1耐受gag p24中HLA - B27限制性CTL表位的一些基因变异，单点突变可以定量改变免疫特性。此外，它表明仅从小区域的准种分析中得出的肽不被识别可能仅仅对应于无活力的病毒变异体，不能作为CTL逃逸突变体的证据。与先前发表的关于CTL表位持续存在的数据一起，这些结果表明CTL在体内驱动HIV - 1进化中不发挥主要作用。
