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Association of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals.
Clinical Microbiology and Infection ( IF 10.9 ) Pub Date : 2019-05-31 , DOI: 10.1016/j.cmi.2019.05.015 F Díez-Fuertes 1 , H E De La Torre-Tarazona 2 , E Calonge 2 , M Pernas 3 , M Bermejo 2 , J García-Pérez 2 , A Álvarez 2 , L Capa 2 , F García-García 4 , M Saumoy 5 , M Riera 6 , A Boland-Auge 7 , C López-Galíndez 3 , M Lathrop 7 , J Dopazo 8 , A Sakuntabhai 9 , J Alcamí 1
Clinical Microbiology and Infection ( IF 10.9 ) Pub Date : 2019-05-31 , DOI: 10.1016/j.cmi.2019.05.015 F Díez-Fuertes 1 , H E De La Torre-Tarazona 2 , E Calonge 2 , M Pernas 3 , M Bermejo 2 , J García-Pérez 2 , A Álvarez 2 , L Capa 2 , F García-García 4 , M Saumoy 5 , M Riera 6 , A Boland-Auge 7 , C López-Galíndez 3 , M Lathrop 7 , J Dopazo 8 , A Sakuntabhai 9 , J Alcamí 1
Affiliation
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OBJECTIVES
The long-term non-progressors (LTNPs) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4+ T-cell counts and partially control viral replication for years in the absence of antiretroviral therapy. The present study aims to identify host single nucleotide polymorphisms (SNPs) associated with non-progression in a cohort of 352 individuals.
METHODS
DNA microarrays and exome sequencing were used for genotyping about 240 000 functional polymorphisms throughout more than 20 000 human genes. The allele frequencies of 85 LTNPs were compared with a control population. SNPs associated with LTNPs were confirmed in a population of typical progressors. Functional analyses in the affected gene were carried out through knockdown experiments in HeLa-P4, macrophages and dendritic cells.
RESULTS
Several SNPs located within the major histocompatibility complex region previously related to LTNPs were confirmed in this new cohort. The SNP rs1127888 (UBXN6) surpassed the statistical significance of these markers after Bonferroni correction (q = 2.11 × 10-6). An uncommon allelic frequency of rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6 knockdown experiments caused an increase in CAV1 expression and its accumulation in the plasma membrane. In vitro infection of different cell types with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replication capacity compared with their corresponding wild-type cells expressing UBXN6.
CONCLUSIONS
A higher prevalence of Ala31Thr in UBXN6 was found among LTNPs within its N-terminal region, which is crucial for UBXN6/VCP protein complex formation. UBXN6 knockdown affected CAV1 turnover and HIV-1 replication capacity.
中文翻译：
HIV阳性个体中ubxn6基因的单核苷酸多态性与长期非进展表型的关联。
目的长期非进展者（LTNP）是一组HIV阳性个体，其特征是在不使用抗逆转录病毒疗法的情况下，能够维持高水平的CD4 + T细胞计数并部分控制病毒复制长达数年。本研究旨在确定与352名个体的非进展相关的宿主单核苷酸多态性（SNP）。方法利用DNA微阵列和外显子组测序对超过2万个人类基因中约24万个功能多态性进行基因分型。将85个LTNP的等位基因频率与对照组进行了比较。与LTNPs相关的SNPs在典型的进展者人群中得到证实。通过在HeLa-P4，巨噬细胞和树突状细胞中进行基因敲除实验，对受影响的基因进行了功能分析。结果在这个新的队列研究中，证实了位于先前与LTNP相关的主要组织相容性复合体区域内的多个SNP。Bonferroni校正后，SNP rs1127888（UBXN6）超过了这些标记的统计学意义（q = 2.11×10-6）。通过与典型的进展者和其他公众可获得的人群进行比较，证实了LTNP中rs1127888的罕见等位基因频率。UBXN6组合式实验导致CAV1表达增加及其在质膜中的积累。与具有HIV-1复制能力的重组病毒在体外感染不同细胞类型相比，与它们相应的表达UBXN6的野生型细胞相比，病毒复制能力降低。结论在UBXN6的N端区域内的LTNP中发现了较高的Ala31Thr发生率，这对于UBXN6 / VCP蛋白复合物的形成至关重要。UBXN6组合件影响CAV1营业额和HIV-1复制能力。
更新日期：2019-12-31
中文翻译：
HIV阳性个体中ubxn6基因的单核苷酸多态性与长期非进展表型的关联。
目的长期非进展者（LTNP）是一组HIV阳性个体，其特征是在不使用抗逆转录病毒疗法的情况下，能够维持高水平的CD4 + T细胞计数并部分控制病毒复制长达数年。本研究旨在确定与352名个体的非进展相关的宿主单核苷酸多态性（SNP）。方法利用DNA微阵列和外显子组测序对超过2万个人类基因中约24万个功能多态性进行基因分型。将85个LTNP的等位基因频率与对照组进行了比较。与LTNPs相关的SNPs在典型的进展者人群中得到证实。通过在HeLa-P4，巨噬细胞和树突状细胞中进行基因敲除实验，对受影响的基因进行了功能分析。结果在这个新的队列研究中，证实了位于先前与LTNP相关的主要组织相容性复合体区域内的多个SNP。Bonferroni校正后，SNP rs1127888（UBXN6）超过了这些标记的统计学意义（q = 2.11×10-6）。通过与典型的进展者和其他公众可获得的人群进行比较，证实了LTNP中rs1127888的罕见等位基因频率。UBXN6组合式实验导致CAV1表达增加及其在质膜中的积累。与具有HIV-1复制能力的重组病毒在体外感染不同细胞类型相比，与它们相应的表达UBXN6的野生型细胞相比，病毒复制能力降低。结论在UBXN6的N端区域内的LTNP中发现了较高的Ala31Thr发生率，这对于UBXN6 / VCP蛋白复合物的形成至关重要。UBXN6组合件影响CAV1营业额和HIV-1复制能力。
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