Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study.
Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study.
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DOI：
10.1093/ofid/ofu018
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发表时间：
2014-03
影响因子：
4.2
通讯作者：
Kuritzkes DR
中科院分区：
文献类型：
--
作者：
Henrich TJ;McLaren PJ;Rao SS;Lin NH;Hanhauser E;Giguel F;Gulick RM;Ribaudo H;de Bakker PI;Kuritzkes DR
对来自ACTG A5095中未接受治疗的参与者的593份治疗前血浆HIV-1样本进行了HIV-1辅受体使用的表型测定。没有人类基因变异与能够使用CXCR4进入全基因组水平的病毒显著相关。 我们进行了一项全基因组关联研究，以探索常见宿主遗传变异(>；5%频率)是否与能够使用CXCR4进入的病毒的存在有关。艾滋病临床试验组A5095是一项初步抗逆转录病毒疗法的研究， 表型测定人类免疫缺陷病毒-1辅受体使用率的前血浆样本来自艾滋病临床试验组A5095的初治者。探讨全基因组单核苷酸多态(SNPs)、CCR5HLA32基因、人类白细胞抗原(Δ)I类等位基因与病毒辅受体使用之间的关系。从593名患者中获得了 病毒的表型，这些患者拥有全基因组的单核苷酸多态性数据。通过表型鉴定，44%的受试者携带了能够使用CXCR4进入的病毒。总体而言，没有任何关联，包括编码病毒辅助受体及其启动子区域的基因的多态之间的关联，或者先前与艾滋病毒-1疾病进展相关的人类白细胞抗原基因之间的关联，在任何比较中都没有超过全基因组意义的统计阈值(P<5.0×10−8)。然而，在非基因组范围的分析中，能够使用CXCR4进入的病毒的存在与CCR5CXCR4Δ32基因的存在略有关联。 没有人类基因变异与能够使用CXCR4进入全基因组水平的病毒显著相关。尽管样本量有限，无法明确排除遗传关联，但这些结果表明，宿主遗传因素，包括那些影响辅助受体表达或导致病毒包膜多样性的免疫压力的因素，在决定HIV-1辅助受体使用方面要么很少，要么影响不大。
Phenotypic determination of HIV-1 coreceptor usage was performed on 593 pre-treatment plasma HIV-1 samples from treatment-naive participants in ACTG A5095. No human genetic variants were significantly associated with virus able to use CXCR4 for entry at the genome-wide level. We conducted a genome-wide association study to explore whether common host genetic variants (>5% frequency) were associated with presence of virus able to use CXCR4 for entry. Phenotypic determination of human immunodeficiency virus (HIV)-1 coreceptor usage was performed on pretreatment plasma HIV-1 samples from treatment-naive participants in AIDS Clinical Trials Group A5095, a study of initial antiretroviral regimens. Associations between genome-wide single-nucleotide polymorphisms (SNPs), CCR5 Δ32 genotype, and human leukocyte antigen (HLA) class I alleles and viral coreceptor usage were explored. Viral phenotypes were obtained from 593 patients with available genome-wide SNP data. Forty-four percent of subjects had virus capable of using CXCR4 for entry as determined by phenotyping. Overall, no associations, including those between polymorphisms in genes encoding viral coreceptors and their promoter regions or in HLA genes previously associated with HIV-1 disease progression, passed the statistical threshold for genome-wide significance (P < 5.0 × 10−8) in any comparison. However, the presence of viruses able to use CXCR4 for entry was marginally associated with the CCR5 Δ32 genotype in the nongenome-wide analysis. No human genetic variants were significantly associated with virus able to use CXCR4 for entry at the genome-wide level. Although the sample size had limited power to definitively exclude genetic associations, these results suggest that host genetic factors, including those that influence coreceptor expression or the immune pressures leading to viral envelope diversity, are either rare or have only modest effects in determining HIV-1 coreceptor usage.