Beijing You An Hospital, Capital Medical University, Beijing 100069, People's Republic of China.
J Immunol. 2011 Jul 15;187(2):684-91. doi: 10.4049/jimmunol.1100316. Epub 2011 Jun 13.
Polymorphism in the HLA region of a chromosome is the major source of host genetic variability in HIV-1 outcome, but there is limited understanding of the mechanisms underlying the beneficial effect of protective class I alleles such as HLA-B57, -B27, and -B51. Taking advantage of a unique cohort infected with clade B' HIV-1 through contaminated blood, in which many variables such as the length of infection, the infecting viral strain, and host genetic background are controlled, we performed a comprehensive study to understand HLA-B51-associated HIV-1 control. We focused on the T cell responses against three dominant HLA-B51-restricted epitopes: Gag327-345(NI9) NANPDCKTI, Pol743-751(LI9) LPPVVAKEI, and Pol283-289(TI8) TAFTIPSI. Mutations in all three dominant epitopes were significantly associated with HLA-B51 in the cohort. A clear hierarchy in selection of epitope mutations was observed through epitope sequencing. L743I in position 1 of epitope LI9 was seen in most B51(+) individuals, followed by V289X in position 8 of the TI8, and then, A328S, in position 2 of the NI9 epitope, was also seen in some B51(+) individuals. Good control of viral load and higher CD4(+) counts were significantly associated with at least one detectable T cell response to unmutated epitopes, whereas lower CD4(+) counts and higher viral loads were observed in patients who had developed escape mutations in all three epitopes or who lacked T cell responses specific to these epitope(s). We propose that patients with HLA-B51 benefit from having multiple layers of effective defense against the development of immune escape mutations.
染色体 HLA 区域的多态性是 HIV-1 结局中宿主遗传变异的主要来源，但对于保护性 I 类等位基因（如 HLA-B57、-B27 和 -B51）的有益效应的机制了解有限。利用通过污染血液感染 B' 组 HIV-1 的独特队列，其中许多变量（如感染时间、感染病毒株和宿主遗传背景）得到控制，我们进行了一项全面的研究，以了解 HLA-B51 相关的 HIV-1 控制。我们专注于针对三个主要的 HLA-B51 限制性表位的 T 细胞反应：Gag327-345（NI9）NANPDCKTI、Pol743-751（LI9）LPPVVAKEI 和 Pol283-289（TI8）TAFTIPSI。在队列中，所有三个主要表位的突变都与 HLA-B51 显著相关。通过表位测序观察到表位突变选择的明显层次结构。LI9 表位第 1 位的 L743I 出现在大多数 B51(+)个体中，其次是 TI8 第 8 位的 V289X，然后是 NI9 表位第 2 位的 A328S，也出现在一些 B51(+)个体中。未突变表位的至少一种可检测 T 细胞反应与病毒载量的良好控制和更高的 CD4(+)计数显著相关，而在所有三个表位均发生逃逸突变或缺乏针对这些表位的特异性 T 细胞反应的患者中，观察到较低的 CD4(+)计数和更高的病毒载量。我们提出，具有 HLA-B51 的患者受益于针对免疫逃逸突变发展的多层有效防御。
