TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women
TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women
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DOI：
10.1172/jci.insight.136047
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发表时间：
2020-06-18
期刊：
影响因子：
8
通讯作者：
Guery, Jean-Charles
中科院分区：
文献类型：
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作者：
Azar, Pascal;Mejia, Jose Enrique;Guery, Jean-Charles
在急性HIV-1感染期间，浆细胞样DC（pDC）响应于TLR 7刺激而产生I型IFN（IFN-I），但pDC衍生的IFN-I在控制或促进HIV-1感染中的作用尚不明确。我们在这里报告了一个性别偏见的干扰表型的一个常见的单核苷酸多态性的人类TLR 7，rs 179008，显示急性HIV-1感染的关键参数的影响。我们显示了等位基因rs 179008 T，以确定女性细胞中较低的TLR 7蛋白丰度，特别是可能通过密码子使用降低TLR 7 mRNA翻译效率。亚型TLR 7表型通过雌性pDC的TLR 7驱动的IFN-I产生减少来反映。在来自法国ANRS PRIMO急性HIV-1患者队列的女性中，等位基因rs 179008 T的携带与较低的病毒血症、细胞相关HIV-1 DNA和CXCL 10（IP-10）血浆浓度相关。在T/T纯合子中，RNA病毒载量降低了0.85 log（10）（95% CI，-1.51至-0.18），这些纯合子也表现出较低的急性症状频率。TLR 7作为急性HIV-1病毒血症的重要控制位点出现，并且由30%-50%的欧洲妇女携带的等位基因rs 179008 T的临床表型支持在急性HIV-1感染期间通过pDC减弱TLR 7驱动的IFN-I产生的有益效果。
Type I IFN (IFN-I) production by plasmacytoid DCs (pDCs) occurs during acute HIV-1 infection in response to TLR7 stimulation, but the role of pDC-derived IFN-I in controlling or promoting HIV-1 infection is ambiguous. We report here a sex-biased interferogenic phenotype for a frequent single-nucleotide polymorphism of human TLR7, rs179008, displaying an impact on key parameters of acute HIV-1 infection. We show allele rs179008 T to determine lower TLR7 protein abundance in cells from women, specifically - likely by diminishing TLR7 mRNA translation efficiency through codon usage. The hypomorphic TLR7 phenotype is mirrored by decreased TLR7-driven IFN-I production by female pDCs. Among women from the French ANRS PRIMO cohort of acute HIV-1 patients, carriage of allele rs179008 T associated with lower viremia, cell-associated HIV-1 DNA, and CXCL10 (IP-10) plasma concentrations. RNA viral load was decreased by 0.85 log(10) (95% CI, -1.51 to -0.18) among T/T homozygotes, who also exhibited a lower frequency of acute symptoms. TLR7 emerges as an important control locus for acute HIV-1 viremia, and the clinical phenotype for allele rs179008 T, carried by 30%-50% of European women, supports a beneficial effect of toning down TLR7-driven IFN-I production by pDCs during acute HIV-1 infection.