Marked epitope- and allele- specific differences in rates of mutation in human immunodeficiency type 1 (HIV-1) Gag, Pol, and Nef cytotoxic T-lymphocyte epitopes in acute/early HIV-1 infection
Marked epitope- and allele- specific differences in rates of mutation in human immunodeficiency type 1 (HIV-1) Gag, Pol, and Nef cytotoxic T-lymphocyte epitopes in acute/early HIV-1 infection
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DOI：
10.1128/jvi.01041-08
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发表时间：
2008-09-01
影响因子：
5.4
通讯作者：
Walker, Bruce D.
中科院分区：
文献类型：
--
作者：
Brumme, Zabrina L.;Brumme, Chanson J.;Walker, Bruce D.
在急性人类免疫缺陷病毒1型（HIV-1）感染期间，早期宿主细胞免疫应答驱动病毒进化。然而，这些突变的速率和程度仍然不完全表征。在一个队列中的98个人新感染HIV-1亚型B，我们纵向的速度和程度的HLA介导的逃逸和逆转Gag，Pol，Nef使用一个合理的定义归因于突变的基础上分析的一个大的独立亚型B的数据集。我们证明了快速和戏剧性的艾滋病毒进化的免疫压力，一般反映了建立细胞毒性T淋巴细胞（CTL）反应的层次结构在早期感染。在群体水平上，在类似于80%的已发表的CTL表位中观察到HLA驱动的进化。10个进化最快的表位中有5个受到保护性HLA等位基因的限制（HLA-B * 13/B* 51/B* 57/B* 5801; P = 0.01），这支持了HIV控制中强早期CTL应答的重要性。与已知的逃逸适应性成本一致，Gag中的B* 57相关突变是在传递到非B * 57表达个体后最快速回复的位置之一，而许多其他HLA相关多态性显示缓慢或可忽略的回复。总体而言，估计至少30%的Gag/Pol和60%的Nef中观察到的置换可归因于HLA相关的逃逸和回复事件。结果强调了免疫压力在驱动早期宿主内HIV进化中的主导作用。观察到不同密码子、基因和HLA限制的逃逸和回复率的巨大差异，突出了病毒适应宿主免疫应答的复杂性。
During acute human immunodeficiency virus type 1 (HIV-1) infection, early host cellular immune responses drive viral evolution. The rates and extent of these mutations, however, remain incompletely characterized. In a cohort of 98 individuals newly infected with HIV-1 subtype B, we longitudinally characterized the rates and extent of HLA-mediated escape and reversion in Gag, Pol, and Nef using a rational definition of HLA-attributable mutation based on the analysis of a large independent subtype B data set. We demonstrate rapid and dramatic HIV evolution in response to immune pressures that in general reflect established cytotoxic T-lymphocyte (CTL) response hierarchies in early infection. On a population level, HLA-driven evolution was observed in similar to 80% of published CTL epitopes. Five of the 10 most rapidly evolving epitopes were restricted by protective HLA alleles (HLA-B* 13/B* 51/B* 57/B* 5801; P = 0.01), supporting the importance of a strong early CTL response in HIV control. Consistent with known fitness costs of escape, B* 57-associated mutations in Gag were among the most rapidly reverting positions upon transmission to non-B* 57-expressing individuals, whereas many other HLA-associated polymorphisms displayed slow or negligible reversion. Overall, an estimated minimum of 30% of observed substitutions in Gag/Pol and 60% in Nef were attributable to HLA-associated escape and reversion events. Results underscore the dominant role of immune pressures in driving early within-host HIV evolution. Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response.