Resistance of major histocompatibility complex class B (MHC-B) to Nef-mediated downregulation relative to that of MHC-A is conserved among primate lentiviruses and influences antiviral T cell responses in HIV-1-infected individuals.
Resistance of major histocompatibility complex class B (MHC-B) to Nef-mediated downregulation relative to that of MHC-A is conserved among primate lentiviruses and influences antiviral T cell responses in HIV-1-infected individuals.
复制标题
相对于 MHC-A，主要组织相容性复合体 B 类 (MHC-B) 对 Nef 介导的下调的抵抗力在灵长类慢病毒中是保守的，并影响 HIV-1 感染个体的抗病毒 T 细胞反应。
DOI：
10.1128/jvi.01409-17
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发表时间：
2018
影响因子：
5.4
通讯作者：
T Ueno
中科院分区：
文献类型：
--
作者：
F Mwimanzi;M Toyoda;M Mahiti;J Mann;J Martin;D Bangsberg;M Brockman;P Goulder;F Kirchhoff;Z Brumme;T Ndung’u;T Ueno
患者来源的HIV-1亚型B Nef克隆下调HLA-A比HLA-B更有效。然而，目前尚不清楚这种特性是否是灵长类慢病毒中Nef蛋白的共同特性，以及抗病毒免疫反应如何受到影响。我们检查了来自不同灵长类慢病毒的263个Nef克隆，包括不同的流行性HIV-1 M组亚型，以确定其下调细胞表面主要组织相容性复合物A类（MHC-A）和MHC-B的能力。尽管慢病毒Nef蛋白在它们的绝对MHC-A和MHC-B下调能力上显著不同，但所有慢病毒Nef谱系下调MHC-A的效率平均比MHC-B高11%至32%。Nef基因型/表型分析在一个队列的HIV-1亚型C感染的患者（n= 168），连同定点诱变，揭示Nef的位置9作为一个亚型特异性决定因素的差异HLA-A与HLA-B下调活性。Nef克隆在第9位密码子处携带非共有变异体，其下调HLA-B（尽管不是HLA-A）的效果显著优于在该位点携带共有序列的克隆，导致HIV-1特异性CD 8+效应细胞对感染靶细胞的体外识别减少。在表达保护性HLA I类等位基因的人群中，携带Nef密码子9变异体也与体内HIV特异性T细胞应答减少相关。我们的研究结果表明，Nef的下调MHC-B相比，MHC-A的能力是保守的灵长类慢病毒，并表明，这种属性影响抗病毒细胞免疫responses.IMPORTANCEPrimate慢病毒编码的Nef蛋白，在建立持续感染在各自的宿主物种中起着至关重要的作用。Nef与MHC-A和MHC-B分子的胞质区域相互作用，并从感染的细胞表面下调它们以逃避宿主细胞免疫的识别。使用一组从包括大流行HIV-1 M组亚型在内的多种灵长类慢病毒中分离的Nef等位基因，我们证明了所有慢病毒谱系中的Nef蛋白比MHC-B更有效地下调MHC-A约20%。我们进一步确定了一个天然的多态性位点在Nef的位置9，有助于MHC-B下调功能的HIV-1亚型C和显示，携带Nef变异增强MHC-B下调能力与减少的宽度和幅度的MHC-B限制性细胞免疫反应在HIV感染者的个人。我们的研究强调了慢病毒和灵长类动物免疫系统之间进化上保守的相互作用，这可能有助于发病机制。
Patient-derived HIV-1 subtype B Nef clones downregulate HLA-A more efficiently than HLA-B. However, it remains unknown whether this property is common to Nef proteins across primate lentiviruses and how antiviral immune responses may be affected. We examined 263 Nef clones from diverse primate lentiviruses including different pandemic HIV-1 group M subtypes for their ability to downregulate major histocompatibility complex class A (MHC-A) and MHC-B from the cell surface. Though lentiviral Nef proteins differed markedly in their absolute MHC-A and MHC-B downregulation abilities, all lentiviral Nef lineages downregulated MHC-A, on average, 11 to 32% more efficiently than MHC-B. Nef genotype/phenotype analyses in a cohort of HIV-1 subtype C-infected patients (n= 168), together with site-directed mutagenesis, revealed Nef position 9 as a subtype-specific determinant of differential HLA-A versus HLA-B downregulation activity. Nef clones harboring nonconsensus variants at codon 9 downregulated HLA-B (though not HLA-A) significantly better than those harboring the consensus sequence at this site, resulting in reduced recognition of infected target cells by HIV-1-specific CD8+effector cellsin vitro. Among persons expressing protective HLA class I alleles, carriage of Nef codon 9 variants was also associated with reducedex vivoHIV-specific T cell responses. Our results demonstrate that Nef's inferior ability to downregulate MHC-B compared to that of MHC-A is conserved across primate lentiviruses and suggest that this property influences antiviral cellular immune responses.IMPORTANCEPrimate lentiviruses encode the Nef protein that plays an essential role in establishing persistent infection in their respective host species. Nef interacts with the cytoplasmic region of MHC-A and MHC-B molecules and downregulates them from the infected cell surface to escape recognition by host cellular immunity. Using a panel of Nef alleles isolated from diverse primate lentiviruses including pandemic HIV-1 group M subtypes, we demonstrate that Nef proteins across all lentiviral lineages downregulate MHC-A approximately 20% more effectively than MHC-B. We further identify a naturally polymorphic site at Nef position 9 that contributes to the MHC-B downregulation function in HIV-1 subtype C and show that carriage of Nef variants with enhanced MHC-B downregulation ability is associated with reduced breadth and magnitude of MHC-B-restricted cellular immune responses in HIV-infected individuals. Our study underscores an evolutionarily conserved interaction between lentiviruses and primate immune systems that may contribute to pathogenesis.