Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
Department of Paediatrics, University of Oxford, Oxford, UK.
AIDS. 2020 Jul 15;34(9):1325-1330. doi: 10.1097/QAD.0000000000002559.
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.
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.
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.
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.
Taken together, our study identifies the Nef genotype, non-Ser9 that subverts host immune control in HIV-1 subtype C infection.
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，但控制水平存在很大差异。目前尚不清楚病毒因素，包括 Nef 介导的免疫逃逸功能是否会降低保护性等位基因对病毒控制的影响。
HIV-1 亚型 C 的 Nef 位置 9 上的天然非丝氨酸变异体最近表现出与 HLA-B 下调功能增强和对 CD8 T 细胞识别的敏感性降低相关联。因此，我们假设这种 Nef 基因型会导致保护性 HLA 等位基因介导的免疫控制减弱。
从携带保护性等位基因的 HIV-1 亚型 C 感染者中分离出 Nef 序列，并研究了包括 HLA-A、HLA-B、CD4 和 SERINC5 下调在内的几种 Nef 功能。在两个独立的南非和博茨瓦纳治疗初治队列中，研究了 Nef 非丝氨酸 9 与血浆病毒载量之间的关联。
与编码 Nef 丝氨酸 9 变异体的保护性等位基因个体相比，从保护性等位基因个体中分离出的 Nef 克隆在下调 HLA-B 方面表现出更强的能力，而其他 Nef 功能，包括 HLA-A、CD4 和 SERINC5 下调活性均未改变。通过分析一组南非慢性感染 HIV-1 亚型 C 的参与者，在携带保护性等位基因的患者中，Nef 非丝氨酸 9 与较高的血浆病毒载量相关。相应地，Nef 非丝氨酸 9 与博茨瓦纳的独立队列中的较高血浆病毒载量相关。
综上所述，我们的研究确定了 Nef 基因型非丝氨酸 9，它会削弱 HIV-1 亚型 C 感染中的宿主免疫控制。
