Toll-like receptor variants are associated with infant HIV-1 acquisition and peak plasma HIV-1 RNA level.
Toll-like receptor variants are associated with infant HIV-1 acquisition and peak plasma HIV-1 RNA level.
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DOI：
10.1097/qad.0b013e3283629117
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发表时间：
2013-09-24
期刊：
影响因子：
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通讯作者：
John-Stewart GC
中科院分区：
文献类型：
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作者：
Beima-Sofie KM;Bigham AW;Lingappa JR;Wamalwa D;Mackelprang RD;Bamshad MJ;Maleche-Obimbo E;Richardson BA;John-Stewart GC
我们评估了TLR单核苷酸多态性（SNPs）与婴儿HIV-1感染和病毒控制的关系。在肯尼亚围产期HIV-1队列中评估婴儿HIV-1结局。对婴儿进行TLR 2、3、4、7、8和9、MYD 88和TIRAP中6个候选和118个单倍型标记多态性的基因分型。进行考克斯比例风险和线性回归，以评估与HIV-1感染时间、婴儿死亡时间和病毒载量峰值（VL）的相关性。在368名婴儿中，56名（15%）在1个月内感染了HIV-1，17名（4.6%）在1至12个月内感染。携带TLR 9 1635 A的婴儿（rs352140）变异的人更有可能在1个月内感染HIV-1（HR=1.81，95%置信区间[CI] =1.05-3.14，p=0.033）和12个月时（HR=1.62，CI=1.01-2.60，p=0.044）在校正母体血浆HIV-1 RNA水平和遗传血统的显性模型中。在56例≤1月龄感染的婴儿中，TLR 9 1635 A等位基因拷贝数≥1与峰值VL降低0.58 log 10 c/ml相关（p=0.002）。TLR 8 1G（rs3764880）变异体拷贝数≥1的女婴VL峰值高0.78 log 10 c/ml（p=0.0009），单倍型标记TLR 7变异体（rs 1634319）的C等位基因拷贝数≥1的女婴VL峰值高0.80 log 10 c/ml（p=0.0003）。在这个非洲围产期队列中，我们发现了几个TLR多态性与HIV-1的获得和进展相关。确定这些TLR关联的机制可能会为利用先天反应的HIV-1预防策略提供信息。
We evaluated the association of single nucleotide polymorphisms (SNPs) in TLRs with infant HIV-1 acquisition and viral control. Infant HIV-1 outcomes were assessed in a Kenyan perinatal HIV-1 cohort. Infants were genotyped for six candidate and 118 haplotype-tagging polymorphisms in TLRs 2, 3, 4, 7, 8, and 9, MYD88 and TIRAP. Cox proportional hazards and linear regression were performed to assess associations with time to HIV-1 acquisition, time to infant mortality, and peak viral load (VL). Among 368 infants, 56 (15%) acquired HIV-1 by month 1 and 17 (4.6%) between 1 and 12 months. Infants with the TLR9 1635A (rs352140) variant were more likely to acquire HIV-1 by 1 month (HR=1.81, 95% confidence interval [CI] =1.05-3.14, p=0.033) and by 12 months (HR=1.62, CI=1.01-2.60, p=0.044) in dominant models adjusted for maternal plasma HIV-1 RNA level and genetic ancestry. Among 56 infants infected at ≤1 month of age, ≥1 copy of the TLR9 1635A allele was associated with a 0.58 log10 c/ml lower peak VL (p=0.002). Female infants with ≥1 copy of the TLR8 1G (rs3764880) variant had a 0.78 log10 c/ml higher peak VL (p=0.0009) and having ≥1 copy of the C allele for a haplotype tagging TLR7 variant (rs1634319) was associated with a 0.80 log10 c/ml higher peak VL in female infants (p=0.0003). In this African perinatal cohort, we found several TLR polymorphisms associated with HIV-1 acquisition and progression. Defining mechanisms for these TLR associations may inform HIV-1 prevention strategies that leverage innate responses.