Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes.
Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes.
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作者：
Du Y;Zhang TH;Dai L;Zheng X;Gorin AM;Oishi J;Wu TT;Yoshizawa JM;Li X;Yang OO;Martinez-Maza O;Detels R;Sun R
某些“保护性”主要组织相容性复合体I类（MHC-I）等位基因，如B*57和B*27，与通过CD 8+细胞毒性T淋巴细胞（CTL）应答介导的体内HIV-1的长期控制相关。然而，这种上级保护的机制尚未完全理解。在这里，我们结合了高通量的适应性分析的突变HIV-1 Gag，在计算机上预测的MHC-肽结合亲和力，和分析人内病毒的进化，系统地比较CTL逃逸突变之间的差异表位的保护性MHC-I等位基因和非保护性MHC-I等位基因的目标。我们观察到突变对病毒复制和MHC-I结合亲和力的影响是CTL逃逸的决定因素。由保护性MHC-I等位基因呈递的Gag表位中的突变与相对于MHC-I的显著更高的适应性成本和更低的结合亲和力降低相关。解释突变对病毒复制能力和MHC-I结合的影响的线性回归模型可以解释MHC-I等位基因的保护功效。最后，我们发现了一个一致的模式，在长期非进展者与进展者的Gag表位的演变。总体而言，我们的研究结果表明，某些保护性MHC-I等位基因允许通过靶向表位对HIV-1进行上级控制，其中突变通常会导致高适应性成本和MHC-I结合亲和力的小幅降低。了解在具有保护性HLA等位基因的长期不进展者中实现的病毒控制机制为开发HIV感染的功能性治愈提供了见解。通过对感染者中CTL逃逸突变的表征，先前的研究者假设保护性等位基因靶向逃逸突变显著降低病毒复制能力的表位。然而，这些研究通常仅限于在体内观察到的少数突变。在这里，我们利用我们最近开发的高通量适应性分析方法来定量测量整个HIV-1 Gag中突变的适应性。这些数据使我们能够将结果与MHC-肽结合亲和力的计算机预测和人内病毒进化的分析相结合，以系统地确定保护性HLA等位基因靶向的表位与非保护性HLA等位基因靶向的表位之间CTL逃逸突变的差异。我们观察到Gag表位突变对HIV复制适应性和MHC-I结合亲和力的影响是CTL逃逸的主要决定因素之一。
Certain “protective” major histocompatibility complex class I (MHC-I) alleles, such as B*57 and B*27, are associated with long-term control of HIV-1 in vivo mediated by the CD8+ cytotoxic-T-lymphocyte (CTL) response. However, the mechanism of such superior protection is not fully understood. Here we combined high-throughput fitness profiling of mutations in HIV-1 Gag, in silico prediction of MHC-peptide binding affinity, and analysis of intraperson virus evolution to systematically compare differences with respect to CTL escape mutations between epitopes targeted by protective MHC-I alleles and those targeted by nonprotective MHC-I alleles. We observed that the effects of mutations on both viral replication and MHC-I binding affinity are among the determinants of CTL escape. Mutations in Gag epitopes presented by protective MHC-I alleles are associated with significantly higher fitness cost and lower reductions in binding affinity with respect to MHC-I. A linear regression model accounting for the effect of mutations on both viral replicative capacity and MHC-I binding can explain the protective efficacy of MHC-I alleles. Finally, we found a consistent pattern in the evolution of Gag epitopes in long-term nonprogressors versus progressors. Overall, our results suggest that certain protective MHC-I alleles allow superior control of HIV-1 by targeting epitopes where mutations typically incur high fitness costs and small reductions in MHC-I binding affinity. Understanding the mechanism of viral control achieved in long-term nonprogressors with protective HLA alleles provides insights for developing functional cure of HIV infection. Through the characterization of CTL escape mutations in infected persons, previous researchers hypothesized that protective alleles target epitopes where escape mutations significantly reduce viral replicative capacity. However, these studies were usually limited to a few mutations observed in vivo. Here we utilized our recently developed high-throughput fitness profiling method to quantitatively measure the fitness of mutations across the entirety of HIV-1 Gag. The data enabled us to integrate the results with in silico prediction of MHC-peptide binding affinity and analysis of intraperson virus evolution to systematically determine the differences in CTL escape mutations between epitopes targeted by protective HLA alleles and those targeted by nonprotective HLA alleles. We observed that the effects of Gag epitope mutations on HIV replicative fitness and MHC-I binding affinity are among the major determinants of CTL escape.