Patterns of immunodominance in HIV-1-specific cytotoxic T lymphocyte responses in two human histocompatibility leukocyte antigens (HLA)-identical siblings with HLA-A*0201 are influenced by epitope mutation.
Patterns of immunodominance in HIV-1-specific cytotoxic T lymphocyte responses in two human histocompatibility leukocyte antigens (HLA)-identical siblings with HLA-A*0201 are influenced by epitope mutation.
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DOI：
10.1084/jem.185.8.1423
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发表时间：
1997-04-21
期刊：
影响因子：
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通讯作者：
McMichael AJ
中科院分区：
文献类型：
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作者：
Goulder PJ;Sewell AK;Lalloo DG;Price DA;Whelan JA;Evans J;Taylor GP;Luzzi G;Giangrande P;Phillips RE;McMichael AJ
原发性人类免疫缺陷病毒（HIV）感染主要由HIV特异性细胞毒性T淋巴细胞（CTL）控制至病毒载量的稳态水平，这强烈影响疾病进展的最终速率。CTL对抗原表位的选择可能是免疫控制病毒程度的重要决定因素。本报告描述了两个HLA相同的血友病兄弟谁暴露于相同批次的因子VIII和成为血清反应阳性的10周内的另一个的CTL反应。HLA-A*0201。两个同胞的CTL应答非常不同，一个供体对p17 Gag内的两个表位（HLA-A*0201限制性SLYNTVATL和HLA-A3限制性RLRPGGKKK）产生强烈应答。该同胞对两个表位都没有反应，但对HLA-B7呈递的两个表位有强烈反应。这不是表位呈递差异的结果。然而，在无反应者的前病毒序列中发现了p17 Gag反应者的两个免疫显性表位的突变。然后，我们记录了对两个HLA-A*0201限制性表位的CTL应答，在Gag（SLYNTVATL）和Pol（ILKEPVHGV）中，在22个其他感染HLA-A*0201的HIV供体中。大多数（71%）对Gag表位产生应答。在29%的供体在标准测定中未能对Gag表位应答，存在使用PBMC的肽刺激的低频记忆CTL应答的证据，并且这些供体中的大多数还显示Gag表位中或周围的突变。我们的结论是，HLA I类基因型决定表位的选择最初，但在免疫显性表位的突变可以深刻地改变CTL反应的模式。
Primary human immunodeficiency virus (HIV) infection is controlled principally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-state level of virus load, which strongly influences the ultimate rate of progression to disease. Epitope selection by CTL may be an important determinant of the degree of immune control over the virus. This report describes the CTL responses of two HLA-identical hemophiliac brothers who were exposed to identical batches of Factor VIII and became seropositive within 10 wk of one another. Both have HLA-A*0201. The CTL responses of the two siblings were very dissimilar, one donor making strong responses to two epitopes within p17 Gag (HLA-A*0201–restricted SLYNTVATL and HLA-A3–restricted RLRPGGKKK). The sibling responded to neither epitope, but made strong responses to two epitopes presented by HLA-B7. This was not the result of differences in presentation of the epitopes. However, mutations in both immunodominant epitopes of the p17 Gag responder were seen in proviral sequences of the nonresponder. We then documented the CTL responses to two HLA-A*0201–restricted epitopes, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected donors with HLA-A*0201. The majority (71%) generated responses to the Gag epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL responses using peptide stimulation of PBMC, and most of these donors also showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that mutation in immunodominant epitopes can profoundly alter the pattern of CTL response.