An HIV-1 Nef genotype that diminishes immune control mediated by protective human leucocyte antigen alleles
An HIV-1 Nef genotype that diminishes immune control mediated by protective human leucocyte antigen alleles
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HIV-1 Nef 基因型可减弱保护性人类白细胞抗原等位基因介导的免疫控制
DOI：
10.1097/qad.0000000000002559
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发表时间：
2020
期刊：
影响因子：
3.8
通讯作者：
Ueno Takamasa
中科院分区：
文献类型：
--
作者：
Mwimanzi Francis;Ngare Isaac;Toyoda Mako;Mori Masahiko;Mann Jaclyn;Ndung’u Thumbi;Goulder Phillip;Ueno Takamasa
目的：某些人类白细胞抗原（HLA）-B等位基因（保护性等位基因）与HIV-1的持久免疫控制相关，但在控制水平上存在实质性异质性。它仍然难以捉摸的病毒因素，包括Nef介导的免疫逃避功能是否减少保护等位基因对viral control.Design的影响：在HIV-1亚型C Nef的位置9的天然存在的非丝氨酸变体最近表现出与增强的HLA-B下调功能和降低的易感性识别的CD 8 + T细胞的关联。因此，我们假设这种Nef基因型导致减少免疫控制介导的保护性HLA alleletics.Methods：Nef序列分离HIV-1亚型C感染的患者窝藏保护性等位基因和几个Nef功能，包括下调HLA-A，HLA-B，CD 4，和SERINC 5进行了检查。Nef非Ser 9和血浆病毒载量之间的关联进行了研究，在两个独立的南非和博茨瓦纳治疗初治cohols.Results：Nef克隆分离的保护性等位基因+个人编码Nef非Ser 9变异表现出更大的能力，下调HLA-B相比，Ser 9变异，而其他Nef功能，包括HLA-A，CD 4和SERINC 5下调活性不变。通过分析一组南非慢性感染C亚型HIV-1的受试者，Nef non-Ser 9与携带保护性等位基因的患者血浆病毒载量较高相关。确证，Nef非Ser 9与更高的血浆病毒载量在一个独立的队列在Botswano.Conclusion：两者合计，我们的研究确定了Nef基因型，非Ser 9颠覆宿主免疫控制HIV-1亚型C感染。
Objectives:Certain human leucocyte antigen (HLA)-B alleles (protective alleles) associate with durable immune control of HIV-1, but with substantial heterogeneity in the level of control. It remains elusive whether viral factors including Nef-mediated immune evasion function diminish protective allele effect on viral control.Design:The naturally occurring non-Ser variant at position 9 of HIV-1 subtype C Nef has recently exhibited an association with enhanced HLA-B downregulation function and decreased susceptibility to recognition by CD8+ T cells. We therefore hypothesized this Nef genotype leads to diminished immune control mediated by protective HLA alleles.Methods:Nef sequences were isolated from HIV-1 subtype C-infected patients harboring protective alleles and several Nef functions including downregulation of HLA-A, HLA-B, CD4, and SERINC5 were examined. Association between Nef non-Ser9 and plasma viral load was examined in two independent South African and Botswanan treatment-naïve cohorts.Results:Nef clones isolated from protective allele+ individuals encoding Nef non-Ser9 variant exhibited greater ability to downregulate HLA-B when compared with the Ser9 variant, while other Nef functions including HLA-A, CD4, and SERINC5 downregulation activity were unaltered. By analyzing a cohort of South African participants chronically infected with subtype C HIV-1, Nef non-Ser9 associated with higher plasma viral load in patients harboring protective alleles. Corroboratively, the Nef non-Ser9 correlated with higher plasma viral load in an independent cohort in Botswana.Conclusion:Taken together, our study identifies the Nef genotype, non-Ser9 that subverts host immune control in HIV-1 subtype C infection.