Transcriptional down-regulation of ccr5 in a subset of HIV+ controllers and their family members

HIV +Elite and Viremic controllers (EC/VCs) are able to control virus infection, perhaps because of host genetic determinants. We identified 16% (21 of 131) EC/VCs with CD4 +T cells with resistance specific to R5-tropic HIV, reversed after introduction of ccr5. R5 resistance was not observed in macrophages and depended upon the method of T cell activation. CD4 +T cells of these EC/VCs had lower ccr2 and ccr5 RNA levels, reduced CCR2 and CCR5 cell-surface expression, and decreased levels of secreted chemokines. T cells had no changes in chemokine receptor mRNA half-life but instead had lower levels of active transcription of ccr2 and ccr5, despite having more accessible chromatin by ATAC-seq. Other nearby genes were also down-regulated, over a region of ~500 kb on chromosome 3p21. This same R5 resistance phenotype was observed in family members of an index VC, also associated with ccr2/ccr5 down-regulation, suggesting that the phenotype is heritable.

HIV +精英控制者和病毒血症控制者（EC/VCs）能够控制病毒感染，这可能是由于宿主的遗传决定因素。我们发现16%（131例中有21例）的EC/VCs的CD4 +T细胞对R5嗜性HIV具有特异性抗性，在引入ccr5后这种抗性逆转。在巨噬细胞中未观察到R5抗性，且该抗性取决于T细胞的激活方法。这些EC/VCs的CD4 +T细胞具有较低的ccr2和ccr5 RNA水平，CCR2和CCR5细胞表面表达降低，分泌的趋化因子水平下降。T细胞的趋化因子受体mRNA半衰期没有变化，但ccr2和ccr5的活性转录水平较低，尽管通过ATAC - seq检测到染色质可及性更高。其他附近的基因在3p21号染色体上约500 kb的区域内也被下调。在一名索引VC的家庭成员中也观察到了相同的R5抗性表型，且也与ccr2/ccr5下调有关，这表明该表型是可遗传的。