AMINO-TERMINAL ALTERATION OF THE HLA-A-ASTERISK-0201-RESTRICTED HUMAN-IMMUNODEFICIENCY-VIRUS POL PEPTIDE INCREASES COMPLEX STABILITY AND IN-VITRO IMMUNOGENICITY
AMINO-TERMINAL ALTERATION OF THE HLA-A-ASTERISK-0201-RESTRICTED HUMAN-IMMUNODEFICIENCY-VIRUS POL PEPTIDE INCREASES COMPLEX STABILITY AND IN-VITRO IMMUNOGENICITY
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DOI：
10.1073/pnas.92.18.8166
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发表时间：
1995-08-29
影响因子：
11.1
通讯作者：
MATSUI, M
中科院分区：
文献类型：
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作者：
POGUE, RR;ERON, J;MATSUI, M
最初的研究表明，主要组织相容性复合体I类限制性病毒表位可以通过存在称为锚定的特定残基来预测，然而，最近的研究表明，表位的非锚定位置对于细胞毒性T淋巴细胞(CTL)与I类的结合和识别也是重要的。我们研究了改变非锚定氨基酸是否可以增加天然病毒表位的I类亲和力、复合体稳定性和T细胞识别能力，这一概念通过使用逆转录酶(Poll)的人类免疫缺陷病毒1型限制表位进行了验证。强调了位置1(P1)的氨基酸替换，因为P1的改变可能不会改变T细胞受体的相互作用。在细胞裂解产物组装实验中，用P1酪氨酸取代异亮氨酸的多肽(I1Y)与HLA-A*0201的结合亲和力与野生型POL的亲和力相似，令人惊讶的是，I1Y显著增加了细胞表面的HL-A*0201-肽复合体的稳定性，I1Y敏化了表达HL-A*0201的靶细胞，用于野生型POL特异性CTL裂解。用I1Y和野生型POL体外刺激3例人类白细胞抗原A2 HIV阳性个体的外周血淋巴细胞。在所有三个供者中，I1Y刺激的野生型POL特异性CTL反应均高于野生型POL。因此，I1Y可能是一种用于基于CTL的人类免疫缺陷病毒疫苗成分的“改进”表位，改进表位的设计对预防和治疗性疫苗的开发具有重要的指导意义。
Initial studies suggested that major histocompatibility complex class I-restricted viral epitopes could be predicted by the presence of particular residues termed anchors, However, recent studies showed that nonanchor positions of the epitopes are also significant for class I binding and recognition by cytotoxic T lymphocytes (CTLs). We investigated if changing nonanchor amino acids could increase class I affinity, complex stability, and T-cell recognition of a natural viral epitope, This concept was tested by using the HLA-A*0201-restricted human immunodeficiency virus type 1 epitope from reverse transcriptase (pol). Position 1 (P1) amino acid substitutions were emphasized because P1 alterations may not alter the T-cell receptor interaction. The peptide with the P1 substitution of tyrosine for isoleucine (I1Y) showed a binding affinity for HLA-A*0201 similar to that of the wild-type pol peptide in a cell lysate assembly assay, Surprisingly, I1Y significantly increased the HLA-A*0201-peptide complex stability at the cell surface, I1Y sensitized HLA-A*0201-expressing target cells for wild-type pol-specific CTL lysis as well as wild-type pol. Peripheral blood lymphocytes from three HLA-A2 HIV-seropositive individuals were stimulated in vitro with I1Y and wild-type pol. I1Y stimulated a higher wild-type pol-specific CTL response than wild-type pol in all three donors. Thus, I1Y may be an ''improved'' epitope for use as a CTL-based human immunodeficiency virus vaccine component, The design of improved epitopes has important ramifications for prophylaxis and therapeutic vaccine development.