锌指核糖核酸酶 D1（ZNRD1）是一种宿主细胞因子，可影响 HIV-1 的复制和疾病进展。

ZNRD1 (zinc ribbon domain-containing 1) is a host cellular factor that influences HIV-1 replication and disease progression.

机构信息

Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.

出版信息

Clin Infect Dis. 2010 Apr 1;50(7):1022-32. doi: 10.1086/651114.

DOI:10.1086/651114

PMID:20192730

Abstract

BACKGROUND

Human immunodeficiency virus (HIV) takes advantage of multiple host proteins to support its own replication. The gene ZNRD1 (zinc ribbon domain-containing 1) has been identified as encoding a potential host factor that influenced disease progression in HIV-positive individuals in a genomewide association study and also significantly affected HIV replication in a large-scale in vitro short interfering RNA (siRNA) screen. Genes and polymorphisms identified by large-scale analysis need to be followed up by means of functional assays and resequencing efforts to more precisely map causal genes.

METHODS

Genotyping and ZNRD1 gene resequencing for 208 HIV-positive subjects (119 who experienced long-term nonprogression [LTNP] and 89 who experienced normal disease progression) was done by either TaqMan genotyping assays or direct sequencing. Genetic association analysis was performed with the SNPassoc package and Haploview software. siRNA and short hairpin RNA (shRNA) specifically targeting ZNRD1 were used to transiently or stably down-regulate ZNRD1 expression in both lymphoid and nonlymphoid cells. Cells were infected with X4 and R5 HIV strains, and efficiency of infection was assessed by reporter gene assay or p24 assay.

RESULTS

Genetic association analysis found a strong statistically significant correlation with the LTNP phenotype (single-nucleotide polymorphism rs1048412; P = .0004), independently of HLA-A10 influence. siRNA-based functional analysis showed that ZNRD1 down-regulation by siRNA or shRNA impaired HIV-1 replication at the transcription level in both lymphoid and nonlymphoid cells.

CONCLUSION

Genetic association analysis unequivocally identified ZNRD1 as an independent marker of LTNP to AIDS. Moreover, in vitro experiments pointed to viral transcription as the inhibited step. Thus, our data strongly suggest that ZNRD1 is a host cellular factor that influences HIV-1 replication and disease progression in HIV-positive individuals.

摘要

背景

人类免疫缺陷病毒（HIV）利用多种宿主蛋白来支持自身的复制。锌带域蛋白 1（ZNRD1）基因已被确定为编码一种潜在的宿主因子，在全基因组关联研究中，该因子影响 HIV 阳性个体的疾病进展，并且在大规模体外短发夹 RNA（shRNA）筛选中也显著影响 HIV 复制。通过大规模分析鉴定的基因和多态性需要通过功能测定和重测序来进行跟踪，以更精确地定位因果基因。

方法

通过 TaqMan 基因分型测定或直接测序对 208 名 HIV 阳性受试者（119 名经历长期非进展[LTNP]和 89 名经历正常疾病进展）进行基因分型和 ZNRD1 基因重测序。遗传关联分析采用 SNPassoc 包和 Haploview 软件进行。针对 ZNRD1 的短发夹 RNA（shRNA）和短发夹 RNA（shRNA）特异性地瞬时或稳定下调了淋巴和非淋巴细胞中的 ZNRD1 表达。用 X4 和 R5 HIV 株感染细胞，并通过报告基因测定或 p24 测定评估感染效率。