背景:人类遗传对HIV进展的贡献仍未得到充分解释。1型干扰素(IFN)途径对于HIV的宿主控制很重要,1型IFN基因的变异可能会导致疾病进展。这项研究评估了1型IFN基因和途径水平变化对HIV-1病毒载量(VL)的影响。
方法:分别分析了两个早期(START)或晚期(FIRST)感染HIV(PLWH)的抗逆转录病毒(ART)初治参与者。1型IFN基因(n=17)和受体亚基(IFNAR1,IFNAR2)进行了累积的1型IFN途径分析和个体基因分析。SKAT-O用于检测基因型和HIV-1研究进入病毒载量(log10转化)之间的关联,作为设定点VL的代理;使用Bonferroni校正P值(P<0.0025)。
结果:对早期感染者的分析包括来自五大洲的2429名个体。研究条目HIVVL的中位数为14,623(IQR3460-45100)拷贝/mL。在19个1型IFN基因内的673个SNP中,未检测到与研究进入VL显著相关.相反,在START中检查单个基因显示,IFNW1和研究条目VL之间存在边界显着关联(P=0.0025)。在对年龄进行单独调整后,这一意义仍然存在,CD4+T细胞计数,CD4+/CD8+T细胞比例和近期感染。当使用线性混合效应模型(LME)控制人口结构时,除了主模型中使用的主成分之外,这不再显著(p=0.0244).在按地理区域分层的亚组分析中,IFNW1和研究进入VL之间的关联仅在非洲参与者中观察到,虽然,当使用LME控制人口结构时,这种关联并不显著。在IFNW1区域内的17个SNP中,在单一SNP关联分析中,只有rs79876898(A>G)与研究条目VL相关(p=0.0020,β=0.32;G与高于A的研究条目VL相关).研究结果未在FIRST参与者中再现。
结论:在19个1型IFN基因中,只有IFNW1与HIV-1研究进入VL相关,在感染早期接受ART治疗的个体队列中,然而,这在使用LME控制人群结构的敏感性分析中不再显著.
Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL).
Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025).
The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4+ T-cell count, CD4+/CD8+ T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants.
Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.