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Abstract：
The major barrier to an HIV cure is the HIV reservoir: latently-infected cells that persist despite effective antiretroviral therapy (ART). There have been few cohort-based studies evaluating host genomic or transcriptomic predictors of the HIV reservoir. We performed host RNA sequencing and HIV reservoir quantification (total DNA [tDNA], unspliced RNA [usRNA], intact DNA) from peripheral CD4+ T cells from 191 ART-suppressed people with HIV (PWH). After adjusting for nadir CD4+ count, timing of ART initiation, and genetic ancestry, we identified two host genes for which higher expression was significantly associated with smaller total DNA viral reservoir size, P3H3 and NBL1, both known tumor suppressor genes. We then identified 17 host genes for which lower expression was associated with higher residual transcription (HIV usRNA). These included novel associations with membrane channel (KCNJ2, GJB2), inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10), and innate immunity (TLR7) genes (FDR-adjusted q<0.05). Gene set enrichment analyses further identified significant associations of HIV usRNA with TLR4/microbial translocation (q = 0.006), IL-1/NRLP3 inflammasome (q = 0.008), and IL-10 (q = 0.037) signaling. Protein validation assays using ELISA and multiplex cytokine assays supported these observed inverse host gene correlations, with P3H3, IL-10, and TNF-α protein associations achieving statistical significance (p<0.05). Plasma IL-10 was also significantly inversely associated with HIV DNA (p = 0.016). HIV intact DNA was not associated with differential host gene expression, although this may have been due to a large number of undetectable values in our study. To our knowledge, this is the largest host transcriptomic study of the HIV reservoir. Our findings suggest that host gene expression may vary in response to the transcriptionally active reservoir and that changes in cellular proliferation genes may influence the size of the HIV reservoir. These findings add important data to the limited host genetic HIV reservoir studies to date.
摘要：
HIV治愈的主要障碍是HIV的储库：尽管有效的抗逆转录病毒疗法（ART），潜伏感染的细胞仍然存在。很少有基于队列的研究评估HIV库的宿主基因组或转录组预测因子。我们进行了宿主RNA测序和HIV储层定量(总DNA[tDNA]，未剪接的RNA[usRNA]，完整的DNA）来自191名ART抑制的HIV感染者（PWH）的外周CD4T细胞。在调整了最低CD4+计数后,ART启动的时机，和遗传祖先，我们确定了两个宿主基因，其中较高的表达与较小的总DNA病毒库大小显着相关，P3H3和NBL1，都是已知的抑癌基因。然后我们鉴定了17个宿主基因，这些基因的较低表达与较高的残余转录（HIVusRNA）相关。这些包括与膜通道（KCNJ2，GJB2）的新关联，炎性体（IL1A，CSF3,TNFAIP5,TNFAIP6,TNFAIP9,CXCL3,CXCL10),和先天免疫（TLR7）基因（FDR调整的q<0.05）。基因集富集分析进一步确定了HIVusRNA与TLR4/微生物易位的显著关联（q=0.006），IL-1/NRLP3炎性体（q=0.008），和IL-10(q=0.037)信号传导。使用ELISA和多重细胞因子测定的蛋白质验证测定支持这些观察到的反向宿主基因相关性，与P3H3、IL-10和TNF-α蛋白相关性达到统计学意义(p<0.05)。血浆IL-10也与HIVDNA显著负相关(p=0.016)。HIV完整DNA与差异宿主基因表达无关，尽管这可能是由于我们的研究中存在大量无法检测到的值.据我们所知,这是最大的HIV宿主转录组研究.我们的发现表明，宿主基因表达可能会随着转录活性储库的变化而变化，并且细胞增殖基因的变化可能会影响HIV储库的大小。这些发现为迄今为止有限的宿主遗传HIV库研究增加了重要数据。
